@article {pmid34570180, year = {2021}, author = {Mintzer, J and Lanctôt, KL and Scherer, RW and Rosenberg, PB and Herrmann, N and van Dyck, CH and Padala, PR and Brawman-Mintzer, O and Porsteinsson, AP and Lerner, AJ and Craft, S and Levey, AI and Burke, W and Perin, J and Shade, D and , }, title = {Effect of Methylphenidate on Apathy in Patients With Alzheimer Disease: The ADMET 2 Randomized Clinical Trial.}, journal = {JAMA neurology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaneurol.2021.3356}, pmid = {34570180}, issn = {2168-6157}, abstract = {Importance: Apathy, characterized by diminished will or initiative and one of the most prevalent neuropsychiatric symptoms in individuals with Alzheimer disease, is associated with significant caregiver burden, excess disability, increased medical costs, and mortality.
Objective: To measure whether methylphenidate compared with placebo decreases the severity of apathy in individuals with Alzheimer disease.
This multicenter randomized placebo-controlled clinical trial was conducted from August 2016 to July 2020 in 9 US clinics and 1 Canadian clinic specializing in dementia care. A total of 307 potential participants were screened. Of those, 52 did not pass screening and 55 were not eligible. Participants with Alzheimer disease, mild to moderate cognitive impairment, and frequent and/or severe apathy as measured by the Neuropsychiatric Inventory (NPI) were included.
Interventions: Ten milligrams of methylphenidate, twice daily, vs matching placebo.
Main Outcomes and Measures: The coprimary outcomes included (1) change from baseline to 6 months in the NPI apathy subscale or (2) improved rating on the Alzheimer's Disease Cooperative Study Clinical Global Impression of Change. Other outcomes include safety, change in cognition, and quality of life.
Results: Of 200 participants, 99 were assigned to methylphenidate and 101 to placebo. The median (interquartile range) age of study participants was 76 (71-81) years; 68 (34%) were female and 131 (66%) were male. A larger decrease was found from baseline to 6 months in the NPI apathy score in those receiving methylphenidate compared with placebo (mean difference, -1.25; 95% CI, -2.03 to -0.47; P = .002). The largest decrease in the NPI apathy score was observed in the first 100 days, with a significant hazard ratio for the proportion of participants with no apathy symptoms receiving methylphenidate compared with placebo (hazard ratio, 2.16; 95% CI, 1.19-3.91; P = .01). At 6 months, the odds ratio of having an improved rating on the Alzheimer's Disease Cooperative Study Clinical Global Impression of Change for methylphenidate compared with placebo was 1.90 (95% CI, 0.95-3.84; P = .07). The difference in mean change from baseline to 6 months estimated using a longitudinal model was 1.43 (95% CI, 1.00-2.04; P = .048). Cognitive measures and quality of life were not significantly different between groups. Of the 17 serious adverse events that occurred during the study, none were related to the study drug. No significant differences in the safety profile were noted between treatment groups.
Conclusions and Relevance: This study found methylphenidate to be a safe and efficacious medication to use in the treatment of apathy in Alzheimer disease.
Trial Registration: ClinicalTrials.gov Identifier: NCT02346201.}, }
@article {pmid34570177, year = {2021}, author = {Vossel, K and Ranasinghe, KG and Beagle, AJ and La, A and Ah Pook, K and Castro, M and Mizuiri, D and Honma, SM and Venkateswaran, N and Koestler, M and Zhang, W and Mucke, L and Howell, MJ and Possin, KL and Kramer, JH and Boxer, AL and Miller, BL and Nagarajan, SS and Kirsch, HE}, title = {Effect of Levetiracetam on Cognition in Patients With Alzheimer Disease With and Without Epileptiform Activity: A Randomized Clinical Trial.}, journal = {JAMA neurology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaneurol.2021.3310}, pmid = {34570177}, issn = {2168-6157}, abstract = {Importance: Network hyperexcitability may contribute to cognitive dysfunction in patients with Alzheimer disease (AD).
Objective: To determine the ability of the antiseizure drug levetiracetam to improve cognition in persons with AD.
The Levetiracetam for Alzheimer's Disease-Associated Network Hyperexcitability (LEV-AD) study was a phase 2a randomized double-blinded placebo-controlled crossover clinical trial of 34 adults with AD that was conducted at the University of California, San Francisco, and the University of Minnesota, Twin Cities, between October 16, 2014, and July 21, 2020. Participants were adults 80 years and younger who had a Mini-Mental State Examination score of 18 points or higher and/or a Clinical Dementia Rating score of less than 2 points. Screening included overnight video electroencephalography and a 1-hour resting magnetoencephalography examination.
Interventions: Group A received placebo twice daily for 4 weeks followed by a 4-week washout period, then oral levetiracetam, 125 mg, twice daily for 4 weeks. Group B received treatment using the reverse sequence.
Main Outcomes and Measures: The primary outcome was the ability of levetiracetam treatment to improve executive function (measured by the National Institutes of Health Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research [NIH-EXAMINER] composite score). Secondary outcomes were cognition (measured by the Stroop Color and Word Test [Stroop] interference naming subscale and the Alzheimer's Disease Assessment Scale-Cognitive Subscale) and disability. Exploratory outcomes included performance on a virtual route learning test and scores on cognitive and functional tests among participants with epileptiform activity.
Results: Of 54 adults assessed for eligibility, 11 did not meet study criteria, and 9 declined to participate. A total of 34 adults (21 women [61.8%]; mean [SD] age, 62.3 [7.7] years) with AD were enrolled and randomized (17 participants to group A and 17 participants to group B). Thirteen participants (38.2%) were categorized as having epileptiform activity. In total, 28 participants (82.4%) completed the study, 10 of whom (35.7%) had epileptiform activity. Overall, treatment with levetiracetam did not change NIH-EXAMINER composite scores (mean difference vs placebo, 0.07 points; 95% CI, -0.18 to 0.32 points; P = .55) or secondary measures. However, among participants with epileptiform activity, levetiracetam treatment improved performance on the Stroop interference naming subscale (net improvement vs placebo, 7.4 points; 95% CI, 0.2-14.7 points; P = .046) and the virtual route learning test (t = 2.36; Cohen f2 = 0.11; P = .02). There were no treatment discontinuations because of adverse events.
Conclusions and Relevance: In this randomized clinical trial, levetiracetam was well tolerated and, although it did not improve the primary outcome, in prespecified analysis, levetiracetam improved performance on spatial memory and executive function tasks in patients with AD and epileptiform activity. These exploratory findings warrant further assessment of antiseizure approaches in AD.
Trial Registration: ClinicalTrials.gov Identifier: NCT02002819.}, }
@article {pmid34569854, year = {2021}, author = {Hairu, R and Close, JCT and Lord, SR and Delbaere, K and Wen, W and Jiang, J and Taylor, ME}, title = {The association between white matter hyperintensity volume and cognitive/physical decline in older people with dementia: A one-year longitudinal study.}, journal = {Aging & mental health}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/13607863.2021.1980859}, pmid = {34569854}, issn = {1364-6915}, abstract = {OBJECTIVES: Understanding the relationship between white matter hyperintensities (WMHs) and cognitive and physical decline in people with dementia will assist in determining potential treatment strategies. Currently there is conflicting evidence describing the association between WMHs and cognitive decline and, WMHs association with declines in objective measures of physical function have not been examined. We examined the relationship between baseline WMH volume and physical/cognitive decline over one-year in older people with dementia.
METHODS: Twenty-six community-dwelling older people with dementia (mean age = 81 ± 8 years; 35% female) were assessed at baseline and follow-up (one-year) using the Addenbrooke's Cognitive Examination-Revised (including verbal fluency), Trail Making Test A, the Physiological Profile Assessment (PPA), timed-up-and-go (TUG) and gait speed. WMH volumes were quantified using a fully automated segmentation toolbox, UBO Detector.
RESULTS: In analyses adjusted for baseline performance, higher baseline WMH volume was associated with decline in executive function (verbal fluency), sensorimotor function (PPA) and mobility (TUG). Executive function (semantic/category fluency) was the only domain association that withstood adjustment for age, and additionally hippocampal volume.
CONCLUSIONS: In unadjusted analyses, WMH volume was associated with one-year declines in cognitive and physical function in older people with dementia. The association with executive function decline withstood adjustment for age. More research is needed to confirm these findings and explore whether vascular risk reduction strategies can reduce WMH volume and associated cognitive and physical impairments in this group.}, }
@article {pmid34558138, year = {2021}, author = {Erekat, NS}, title = {Apoptosis and its therapeutic implications in neurodegenerative diseases.}, journal = {Clinical anatomy (New York, N.Y.)}, volume = {}, number = {}, pages = {}, doi = {10.1002/ca.23792}, pmid = {34558138}, issn = {1098-2353}, abstract = {Neurodegenerative disorders are characterized by progressive loss of particular populations of neurons. Apoptosis has been implicated in the pathogenesis of neurodegenerative diseases, including Parkinson disease, Alzheimer disease, Huntington disease, and amyotrophic lateral sclerosis. In this review, we focus on the existing notions relevant to comprehending the apoptotic death process, including the morphological features, mediators and regulators of cellular apoptosis. We also highlight the evidence of neuronal apoptotic death in Parkinson disease, Alzheimer disease, Huntington disease, and amyotrophic lateral sclerosis. Additionally, we present evidence of potential therapeutic agents that could modify the apoptotic pathway in the aforementioned neurodegenerative diseases and delay disease progression. Finally, we review the clinical trials that were conducted to evaluate the use of anti-apoptotic drugs in the treatment of the aforementioned neurodegenerative diseases, in order to highlight the essential need for early detection and intervention of neurodegenerative diseases in humans.}, }
@article {pmid34556089, year = {2021}, author = {Jiang, Z and Shi, Y and Zhao, W and Zhou, L and Zhang, B and Xie, Y and Zhang, Y and Tan, G and Wang, Z}, title = {Association between chronic periodontitis and the risk of Alzheimer's disease: combination of text mining and GEO dataset.}, journal = {BMC oral health}, volume = {21}, number = {1}, pages = {466}, pmid = {34556089}, issn = {1472-6831}, support = {3502Z20209005//Xiamen Municipal Bureau of Science and Technology/ ; 2020J02063//Natural Science Foundation of Fujian Province/ ; 82072777//National Natural Science Foundation of China/ ; }, abstract = {BACKGROUND: Although chronic periodontitis has previously been reported to be linked with Alzheimer's disease (AD), the pathogenesis between the two is unclear. The purpose of this study is to analyze and screen the relevant and promising molecular markers between chronic periodontitis and Alzheimer's disease (AD).
METHODS: In this paper, we analyzed three AD expression datasets and extracted differentially expressed genes (DEGs), then intersected them with chronic periodontitis genes obtained from text mining, and finally obtained integrated DEGs. We followed that by enriching the matching the matching cell signal cascade through DAVID analysis. Moreover, the MCODE of Cytoscape software was employed to uncover the protein-protein interaction (PPI) network and the matching hub gene. Finally, we verified our data using a different independent AD cohort.
RESULTS: The chronic periodontitis gene set acquired from text abstracting was intersected with the previously obtained three AD groups, and 12 common genes were obtained. Functional enrichment assessment uncovered 12 cross-genes, which were mainly linked to cell morphogenesis involved in neuron differentiation, leading edge membrane, and receptor ligand activity. After PPI network creation, the ten hub genes linked to AD were retrieved, consisting of SPP1, THY1, CD44, ITGB1, HSPB3, CREB1, SST, UCHL1, CCL5 and BMP7. Finally, the function terms in the new independent dataset were used to verify the previous dataset, and we found 22 GO terms and one pathway, "ECM-receptor interaction pathways", in the overlapping functional terms.
CONCLUSIONS: The establishment of the above-mentioned candidate key genes, as well as the enriched signaling cascades, provides promising molecular markers for chronic periodontitis-related AD, which may help the diagnosis and treatment of AD patients in the future.}, }
@article {pmid34551697, year = {2021}, author = {Mengr, A and Hrubá, L and Exnerová, A and Holubová, M and Popelová, A and Železná, B and Kuneš, J and Maletínská, L}, title = {Palmitoylated prolactin-releasing peptide reduced Aβ plaques and microgliosis in the cerebellum: APP/PS1 mice study.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/1567205018666210922110652}, pmid = {34551697}, issn = {1875-5828}, abstract = {BACKGROUND: Prolactin-releasing peptide (PrRP) is a potential drug for the treatment of obesity and associated type 2 diabetes mellitus (T2DM) due to its strong anorexigenic and antidiabetic properties. In our recent study, the lipidized PrRP analog palm11-PrRP31 was proven to exert beneficial effects in APP/PS1 mice, a model of Alzheimer´s disease (AD)-like amyloid-β (Aβ) pathology, reducing the Aβ plaque load, microgliosis and astrocytosis in the hippocampus and cortex.
OBJECTIVE: In this study, we focused on the neuroprotective and anti-inflammatory effects of palm11-PrRP31 and its possible impact on synaptogenesis in the cerebellum of APP/PS1 mice, because others have suggested that cerebellar Aβ plaques contribute to cognitive deficits in AD.
METHODS: APP/PS1 mice were treated subcutaneously with palm11-PrRP31 for 2 months, then immunoblotting and immunohistochemistry were used to quantify pathological markers connected to AD, compared to control mice.
RESULTS: In the cerebella of 8 months old APP/PS1 mice, we found widespread Aβ plaques surrounded by activated microglia detected by ionized calcium-binding adapter molecule (Iba1), but no increase in astrocytic marker glial fibrillary acidic protein (GFAP) compared to controls. Interestingly, no difference in both presynaptic markers syntaxin1A and postsynaptic marker spinophilin was registered between APP/PS1 and control mice. Palm11-PrRP31 treatment significantly reduced the Aβ plaque load and microgliosis in the cerebellum. Furthermore, palm11-PrRP31 increased synaptogenesis and attenuated neuroinflammation and apoptosis in the hippocampus of APP/PS1 mice.
CONCLUSION: These results suggest palm11-PrRP31 is a promising agent for the treatment of neurodegenerative disorders.}, }
@article {pmid34550903, year = {2021}, author = {Jutten, RJ and Sikkes, SAM and Van der Flier, WM and Scheltens, P and Visser, PJ and Tijms, BM and , }, title = {Finding Treatment Effects in Alzheimer Trials in the Face of Disease Progression Heterogeneity.}, journal = {Neurology}, volume = {96}, number = {22}, pages = {e2673-e2684}, doi = {10.1212/WNL.0000000000012022}, pmid = {34550903}, issn = {1526-632X}, abstract = {OBJECTIVE: To investigate the influence of heterogeneity in disease progression for detecting treatment effects in Alzheimer disease (AD) trials, using a simulation study.
METHODS: Individuals with an abnormal amyloid PET scan, diagnosis of mild cognitive impairment or dementia, baseline Mini-Mental State Examination (MMSE) score ≥24, global Clinical Dementia Rating (CDR) score of 0.5, and ≥1 follow-up cognitive assessment were selected from the Alzheimer's Disease Neuroimaging Initiative database (n = 302, age 73 ± 6.7; 44% female; 16.1 ± 2.7 years of education; 69% APOE ε4 carrier). We simulated a clinical trial by randomly assigning individuals to a "placebo" and "treatment" group and subsequently computed group differences on the CDR-sum of boxes (CDR-SB), Alzheimer's Disease Assessment Scale-cognitive subscale-13 and MMSE after 18 months follow-up. We repeated this simulation 10,000 times to determine the 95% range of effect sizes. We further studied the influence of known AD risk factors (age, sex, education, APOE ε4 status, CSF total tau levels) on the variability in effect sizes.
RESULTS: Individual trajectories on all cognitive outcomes were highly variable, and the 95% ranges of possible effect sizes at 18 months were broad (e.g., ranging from 0.35 improvement to 0.35 decline on the CDR-SB). Results of recent anti-amyloid trials mostly fell within these 95% ranges of effect sizes. APOE ε4 carriers and individuals with abnormal baseline tau levels showed faster decline at group level, but also greater within-group variability, as illustrated by broader 95% effect size ranges (e.g., ±0.70 points for the CDR-SB).
CONCLUSIONS: Individuals with early AD show heterogeneity in disease progression, which increases when stratifying on risk factors associated with progression. We provide guidance for a priori effect sizes on cognitive outcomes for detecting true change, which is crucial for future AD trials.}, }
@article {pmid34542571, year = {2021}, author = {Janelidze, S and Teunissen, CE and Zetterberg, H and Allué, JA and Sarasa, L and Eichenlaub, U and Bittner, T and Ovod, V and Verberk, IMW and Toba, K and Nakamura, A and Bateman, RJ and Blennow, K and Hansson, O}, title = {Head-to-Head Comparison of 8 Plasma Amyloid-β 42/40 Assays in Alzheimer Disease.}, journal = {JAMA neurology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaneurol.2021.3180}, pmid = {34542571}, issn = {2168-6157}, abstract = {Importance: Blood-based tests for brain amyloid-β (Aβ) pathology are needed for widespread implementation of Alzheimer disease (AD) biomarkers in clinical care and to facilitate patient screening and monitoring of treatment responses in clinical trials.
Objective: To compare the performance of plasma Aβ42/40 measured using 8 different Aβ assays when detecting abnormal brain Aβ status in patients with early AD.
This study included 182 cognitively unimpaired participants and 104 patients with mild cognitive impairment from the BioFINDER cohort who were enrolled at 3 different hospitals in Sweden and underwent Aβ positron emission tomography (PET) imaging and cerebrospinal fluid (CSF) and plasma collection from 2010 to 2014. Plasma Aβ42/40 was measured using an immunoprecipitation-coupled mass spectrometry developed at Washington University (IP-MS-WashU), antibody-free liquid chromatography MS developed by Araclon (LC-MS-Arc), and immunoassays from Roche Diagnostics (IA-Elc); Euroimmun (IA-EI); and Amsterdam University Medical Center, ADx Neurosciences, and Quanterix (IA-N4PE). Plasma Aβ42/40 was also measured using an IP-MS-based method from Shimadzu in 200 participants (IP-MS-Shim) and an IP-MS-based method from the University of Gothenburg (IP-MS-UGOT) and another immunoassay from Quanterix (IA-Quan) among 227 participants. For validation, 122 participants (51 cognitively normal, 51 with mild cognitive impairment, and 20 with AD dementia) were included from the Alzheimer Disease Neuroimaging Initiative who underwent Aβ-PET and plasma Aβ assessments using IP-MS-WashU, IP-MS-Shim, IP-MS-UGOT, IA-Elc, IA-N4PE, and IA-Quan assays.
Main Outcomes and Measures: Discriminative accuracy of plasma Aβ42/40 quantified using 8 different assays for abnormal CSF Aβ42/40 and Aβ-PET status.
Results: A total of 408 participants were included in this study. In the BioFINDER cohort, the mean (SD) age was 71.6 (5.6) years and 49.3% of the cohort were women. When identifying participants with abnormal CSF Aβ42/40 in the whole cohort, plasma IP-MS-WashU Aβ42/40 showed significantly higher accuracy (area under the receiver operating characteristic curve [AUC], 0.86; 95% CI, 0.81-0.90) than LC-MS-Arc Aβ42/40, IA-Elc Aβ42/40, IA-EI Aβ42/40, and IA-N4PE Aβ42/40 (AUC range, 0.69-0.78; P < .05). Plasma IP-MS-WashU Aβ42/40 performed significantly better than IP-MS-UGOT Aβ42/40 and IA-Quan Aβ42/40 (AUC, 0.84 vs 0.68 and 0.64, respectively; P < .001), while there was no difference in the AUCs between IP-MS-WashU Aβ42/40 and IP-MS-Shim Aβ42/40 (0.87 vs 0.83; P = .16) in the 2 subcohorts where these biomarkers were available. The results were similar when using Aβ-PET as outcome. Plasma IPMS-WashU Aβ42/40 and IPMS-Shim Aβ42/40 showed highest coefficients for correlations with CSF Aβ42/40 (r range, 0.56-0.65). The BioFINDER results were replicated in the Alzheimer Disease Neuroimaging Initiative cohort (mean [SD] age, 72.4 [5.4] years; 43.4% women), where the IP-MS-WashU assay performed significantly better than the IP-MS-UGOT, IA-Elc, IA-N4PE, and IA-Quan assays but not the IP-MS-Shim assay.
Conclusions and Relevance: The results from 2 independent cohorts indicate that certain MS-based methods performed better than most of the immunoassays for plasma Aβ42/40 when detecting brain Aβ pathology.}, }
@article {pmid34542418, year = {2021}, author = {Saredakis, D and Keage, HA and Corlis, M and Ghezzi, ES and Loffler, H and Loetscher, T}, title = {The Effect of Reminiscence Therapy Using Virtual Reality on Apathy in Residential Aged Care: Multisite Nonrandomized Controlled Trial.}, journal = {Journal of medical Internet research}, volume = {23}, number = {9}, pages = {e29210}, doi = {10.2196/29210}, pmid = {34542418}, issn = {1438-8871}, abstract = {BACKGROUND: Apathy is a frequent and underrecognized neurological disorder symptom. Reduced goal-directed behavior caused by apathy is associated with poor outcomes for older adults in residential aged care. Recommended nonpharmacological treatments include person-centered therapy using information and communication technology. Virtual reality (VR) in the form of head-mounted displays (HMDs) is a fully immersive technology that provides access to a wide range of freely available content. The use of VR as a therapy tool has demonstrated promise in the treatment of posttraumatic stress disorder and anxiety. In addition, VR has been used to improve conditions including depression, anxiety, cognitive function, and balance in older adults with memory deficits, Alzheimer disease, and Parkinson disease. Research using VR for the symptoms of apathy in older adults living in residential aged care facilities is limited.
OBJECTIVE: This study aims to examine whether using HMDs as a tool for reminiscence therapy improves the symptoms of apathy compared with using a laptop computer and physical items with older adults living in residential aged care.
METHODS: In this multisite trial, 43 participants were allocated to one of three groups: reminiscence therapy intervention using VR in the form of HMDs, reminiscence therapy using a laptop computer supplemented by physical items if required (active control), and a usual care (passive control) group. The primary outcome was apathy, and the secondary outcomes included cognition and depression. The side effects of using HMDs were also measured in the VR group.
RESULTS: Mixed model analyses revealed no significant group interaction over time in outcomes between the VR and laptop groups (estimate=-2.24, SE 1.89; t40=-1.18; P=.24). Pooled apathy scores in the two intervention groups compared with the passive control group also revealed no significant group interaction over time (estimate=-0.26, SE 1.66; t40=-0.16; P=.88). There were no significant secondary outcomes. Most participants in the VR group stated that they would prefer to watch content in VR than on a flat screen (Χ22=11.2; P=.004), side effects from HMD use were negligible to minimal according to the Simulator Sickness Questionnaire cutoff scores.
CONCLUSIONS: Although there were no significant results in outcome measures, this study found that participants engaged in the research and enjoyed the process of reminiscing using both forms of technology. It was found that VR can be implemented in an aged care setting with correct protocols in place. Providing residents in aged care with a choice of technology may assist in increasing participation in activities. We cannot dismiss the importance of immediate effects while the therapy was in progress, and this is an avenue for future research.
TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12619001510134; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=378564.
RR2-DOI: 10.1136/bmjopen-2020-046030.}, }
@article {pmid34535787, year = {2021}, author = {Liu, KY and Howard, R}, title = {Can we learn lessons from the FDA's approval of aducanumab?.}, journal = {Nature reviews. Neurology}, volume = {}, number = {}, pages = {}, pmid = {34535787}, issn = {1759-4766}, abstract = {On 7 June 2021, aducanumab was granted accelerated approval for the treatment of Alzheimer disease (AD) by the FDA on the basis of amyloid-lowering effects considered reasonably likely to confer clinical benefit. This decision makes aducanumab the first new drug to be approved for the treatment of AD since 2003 and the first drug to ever be approved for modification of the course of AD. Many have questioned how scientific evidence, expert advice and the best interests of patients and families were considered in the approval decision. In this article, we argue that prior to approval, the FDA and Biogen's shared interpretation of clinical trial data - that high-dose aducanumab was substantially clinically effective - avoided conventional scientific scrutiny, was prominently advanced by patient representative groups who had been major recipients of Biogen funds, and raised concerns that safeguards were insufficient to mitigate regulatory capture within the FDA. Here, we reflect on events leading to the FDA's decision on 7 June 2021 and consider whether any lessons can be learned for the field.}, }
@article {pmid34531308, year = {2021}, author = {Lopez-Grancha, M and Bernardelli, P and Moindrot, N and Genet, E and Vincent, C and Roudieres, V and Krick, A and Sabuco, JF and Machnik, D and Ibghi, D and Pradier, L and Taupin, V}, title = {A Novel Selective PKR Inhibitor Restores Cognitive Deficits and Neurodegeneration in Alzheimer Disease Experimental Models.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {378}, number = {3}, pages = {262-275}, doi = {10.1124/jpet.121.000590}, pmid = {34531308}, issn = {1521-0103}, abstract = {In Alzheimer disease (AD), the double-strand RNA-dependent kinase protein kinase R (PKR)/EIF2AK2 is activated in brain with increased phosphorylation of its substrate eukaryotic initiation factor 2α (eIF2α). AD risk-promoting factors, such as ApoE4 allele or the accumulation of neurotoxic amyloid-β oligomers (AβOs), have been associated with activation of PKR-dependent signaling. Here, we report the discovery of a novel potent and selective PKR inhibitor (SAR439883) and demonstrate its neuroprotective pharmacological activity in AD experimental models. In ApoE4 human replacement male mice, 1-week oral treatment with SAR439883 rescued short-term memory impairment in the spatial object recognition test and dose-dependently reduced learning and memory deficits in the Barnes maze test. Moreover, in AβO-injected male mice, a 2-week administration of SAR439883 in diet dose-dependently ameliorated the AβO-induced cognitive impairment in both Y-maze and Morris Water Maze, prevented loss of synaptic proteins, and reduced levels of the proinflammatory cytokine interleukin-1β In both mouse models, these effects were associated with a dose-dependent inhibition of brain PKR activity as measured by both PKR occupancy and partial lowering of peIF2α levels. Our results provide evidence that selective pharmacological inhibition of PKR by a small selective molecule can rescue memory deficits and prevent neurodegeneration in animal models of AD-like pathology, suggesting that inhibition of PKR is a potential therapeutic approach for AD. SIGNIFICANCE STATEMENT: This study reports the identification of a new small molecule potent and selective protein kinase R (PKR) inhibitor that can prevent cognitive deficits and neurodegeneration in Alzheimer disease (AD) experimental models, including a mouse model expressing the most prevalent AD genetic risk factor ApoE4. With high potency and selectivity, this PKR inhibitor represents a unique tool for investigating the physiological role of PKR and a starting point for developing new drug candidates for AD.}, }
@article {pmid34530925, year = {2021}, author = {Marazuela, P and Solé, M and Bonaterra-Pastra, A and Pizarro, J and Camacho, J and Martínez-Sáez, E and Kuiperij, HB and Verbeek, MM and de Kort, AM and Schreuder, FHBM and Klijn, CJM and Castillo-Ribelles, L and Pancorbo, O and Rodríguez-Luna, D and Pujadas, F and Delgado, P and Hernández-Guillamon, M}, title = {MFG-E8 (LACTADHERIN): a novel marker associated with cerebral amyloid angiopathy.}, journal = {Acta neuropathologica communications}, volume = {9}, number = {1}, pages = {154}, pmid = {34530925}, issn = {2051-5960}, support = {PI20/00465//instituto de salud carlos iii/ ; RD16/0019/0021//invictus/ ; Predoctoral Fellowship//fundació institut de recerca hospital universitari vall d'hebron/ ; 733050822//bionic project/ ; 5R01NS104147-02//foundation for the national institutes of health/ ; NR170024//selfridges group foundation/ ; }, abstract = {Brain accumulation of amyloid-beta (Aβ) is a crucial feature in Alzheimer´s disease (AD) and cerebral amyloid angiopathy (CAA), although the pathophysiological relationship between these diseases remains unclear. Numerous proteins are associated with Aβ deposited in parenchymal plaques and/or cerebral vessels. We hypothesized that the study of these proteins would increase our understanding of the overlap and biological differences between these two pathologies and may yield new diagnostic tools and specific therapeutic targets. We used a laser capture microdissection approach combined with mass spectrometry in the APP23 transgenic mouse model of cerebral-β-amyloidosis to specifically identify vascular Aβ-associated proteins. We focused on one of the main proteins detected in the Aβ-affected cerebrovasculature: MFG-E8 (milk fat globule-EGF factor 8), also known as lactadherin. We first validated the presence of MFG-E8 in mouse and human brains. Immunofluorescence and immunoblotting studies revealed that MFG-E8 brain levels were higher in APP23 mice than in WT mice. Furthermore, MFG-E8 was strongly detected in Aβ-positive vessels in human postmortem CAA brains, whereas MFG-E8 was not present in parenchymal Aβ deposits. Levels of MFG-E8 were additionally analysed in serum and cerebrospinal fluid (CSF) from patients diagnosed with CAA, patients with AD and control subjects. Whereas no differences were found in MFG-E8 serum levels between groups, MFG-E8 concentration was significantly lower in the CSF of CAA patients compared to controls and AD patients. Finally, in human vascular smooth muscle cells MFG-E8 was protective against the toxic effects of the treatment with the Aβ40 peptide containing the Dutch mutation. In summary, our study shows that MFG-E8 is highly associated with CAA pathology and highlights MFG-E8 as a new CSF biomarker that could potentially be used to differentiate cerebrovascular Aβ pathology from parenchymal Aβ deposition.}, }
@article {pmid34530113, year = {2021}, author = {Gao, F and Liu, T and Tuo, M and Chi, S}, title = {The Role of Orexin in Alzheimer Disease: From Sleep-wake Disturbance to Therapeutic Target.}, journal = {Neuroscience letters}, volume = {}, number = {}, pages = {136247}, doi = {10.1016/j.neulet.2021.136247}, pmid = {34530113}, issn = {1872-7972}, abstract = {Accumulating evidence has shown that sleep disturbance is a common symptom in Alzheimer's disease (AD), which is regarded as a modifiable risk factor for AD. Orexin is a key modulator of the sleep-wake cycle and has been found to be dysregulated in AD patients. The increased orexin in cerebrospinal fluid (CSF) is associated with decreased sleep efficiency and REM sleep, as well as cognitive impairment in AD patients. The orexin system has profuse projections to brain regions that are implicated in arousal and cognition and has been found to participate in the progression of AD pathology. Conversely the orexin receptor antagonists are able to consolidate sleep and reduce AD pathology. Therefore, improved understanding of the mechanisms linking orexin system, sleep disturbance and AD could make orexin receptor antagonists a promising target for the prevention or treatment of AD.}, }
@article {pmid34524654, year = {2021}, author = {Parker, K and Vincent, B and Rhee, Y and Choi, BJ and Robinson-Lane, SG and Hamm, JM and Klawitter, L and Jurivich, DA and McGrath, R}, title = {The estimated prevalence of no reported dementia-related diagnosis in older Americans living with possible dementia by healthcare utilization.}, journal = {Aging clinical and experimental research}, volume = {}, number = {}, pages = {}, pmid = {34524654}, issn = {1720-8319}, abstract = {BACKGROUND: Screening for dementia in relevant healthcare settings may help in identifying low cognitive functioning for comprehensive cognitive assessments and subsequent dementia treatment after diagnosis.
AIMS: This study sought to estimate the prevalence of no reported dementia-related diagnosis in a nationally-representative sample of older Americans with a cognitive impairment consistent with dementia (CICD) by healthcare utilization.
METHODS: The unweighted analytical sample included 1514 Americans aged ≥ 65 years that were identified as having a CICD without history of stroke, cancers, neurological conditions, or brain damage who participated in at least one-wave of the 2010-2016 waves of the Health and Retirement Study. An adapted Telephone Interview of Cognitive Status assessed cognitive functioning. Those with scores ≤ 6 had a CICD. Dementia-related diagnosis was self-reported. Respondents indicated if they visited a physician, received home healthcare, or experienced an overnight nursing home stay in the previous two years.
RESULTS: The prevalence of no reported dementia-related diagnosis in persons with a CICD who visited a physician was 89.9% (95% confidence interval (CI): 85.4%-93.1%). Likewise, the prevalence of no reported diagnosis in those with a CICD who received home healthcare was 84.3% (CI: 75.1-90.5%). For persons with a CICD that had an overnight nursing home stay, the prevalence of no reported dementia-related diagnosis was 83.0% (CI: 69.1-91.4%).
DISCUSSION: Although the prevalence of no reported dementia-related diagnosis in individuals with a CICD differed across healthcare settings, the prevalence was generally high nonetheless.
CONCLUSIONS: We recommend increased awareness and efforts be given to dementia screenings in various clinical settings.}, }
@article {pmid34521342, year = {2021}, author = {Wen, J and Zhao, M and Sun, W and Cheng, X and Yu, L and Cao, D and Li, P}, title = {Uptake of Aβ by OATPs might be a new pathophysiological mechanism of Alzheimer disease.}, journal = {BMC neuroscience}, volume = {22}, number = {1}, pages = {53}, pmid = {34521342}, issn = {1471-2202}, support = {81660620//National Natural Science Foundation/ ; }, abstract = {BACKGROUND: The accumulation of neurotoxic amyloid-beta (Aβ) in the brain is a characteristic of Alzheimer's disease (AD), at the same time, it is possible alterations of liver function could affect brain Aβ levels through changes in blood Aβ concentration. Over the last decade, a number of reports have shown that P-glycoprotein (encoded by ABC1B1) actively mediates the efflux transport of Aβ peptides. However, the mechanism by which Aβ peptides enter the cells is not clear. In the preliminary study, we found that the protein expression of organic anion transporting Polypeptide 1a4 (OATP1B1) in the liver tissue of mice with AD was significantly higher than that in the normal mice. In contrast, the protein expression of Oatp1a4 in the brain significantly decreased in mice with AD. OATP1B1, an important drug transporter might be related to the pathophysiology of AD.
RESULTS: In this study, we established an OATP1B1-GFP-HEK293T cell model to confirm the OATP1B1 mediated transport of Aβ1-42. Compared to the control group of GFP-HEK293Tcells, the uptake of Aβ1-42 protein in the OATP1B1-GFP-HEK293T group increased significantly with the increase in concentration of Aβ1-42, and also increased significantly with an increase in the duration of incubation. Similar results were observed in the flow cytometry experiment, and the uptake of Aβ1-42in HEK293T-OATP1B1 cells was almost twice that in the control group. These results indicate that OATPs may act as an important "carrier" for the transport of Aβ1-42 from the blood to the tissues, including liver and brain.
CONCLUSIONS: This is a novel and interesting finding and OATP1B1 can be investigated as a new treatment target for AD.}, }
@article {pmid34519052, year = {2021}, author = {Kozlowska, U and Nichols, C and Wiatr, K and Figiel, M}, title = {From Psychiatry to Neurology: Psychedelics as Prospective Therapeutics for Neurodegenerative Disorders.}, journal = {Journal of neurochemistry}, volume = {}, number = {}, pages = {}, doi = {10.1111/jnc.15509}, pmid = {34519052}, issn = {1471-4159}, abstract = {The studies of psychedelics, especially psychedelic tryptamines like psilocybin, are rapidly gaining interest in neuroscience research. Much of this interest stems from recent clinical studies demonstrating that they have a unique ability to improve the debilitating symptoms of major depressive disorder (MDD) long-term after only a single treatment. Indeed, the Food and Drug Administration (FDA) has recently designated two Phase III clinical trials studying the ability of psilocybin to treat forms of MDD with "Breakthrough Therapy" status. If successful, the use of psychedelics to treat psychiatric diseases like depression would be revolutionary. As more evidence appears in the scientific literature to support their use in psychiatry to treat MDD on and substance use disorders (SUD), recent studies with rodents revealed that their therapeutic effects might extend beyond treating MDD and SUD. For example, psychedelics may have efficacy in the treatment and prevention of brain injury and neurodegenerative diseases such as Alzheimer Disease. Preclinical work has highlighted psychedelics' ability to induce neuroplasticity and synaptogenesis, and neural progenitor cell proliferation. Psychedelics may also act as immunomodulators by reducing levels of proinflammatory biomarkers, including IL-1β, IL-6, Tumor Necrosis Factor-α (TNF-α). Their exact molecular mechanisms, and induction of cellular interactions, especially between neural and glial cells, leading to therapeutic efficacy, remain to be determined. In this review, we discuss recent findings and information on how psychedelics may act therapeutically on cells within the Central Nervous System (CNS) during brain injuries and neurodegenerative diseases.}, }
@article {pmid34515788, year = {2021}, author = {Schwartz, JB and Weintraub, S}, title = {Treatment for Alzheimer Disease-Sex and Gender Effects Need to Be Explicitly Analyzed and Reported in Clinical Trials.}, journal = {JAMA network open}, volume = {4}, number = {9}, pages = {e2124386}, doi = {10.1001/jamanetworkopen.2021.24386}, pmid = {34515788}, issn = {2574-3805}, }
@article {pmid34512506, year = {2021}, author = {Tsolaki, M and Tsatali, M and Gkioka, M and Poptsi, E and Tsolaki, A and Papaliagkas, V and Tabakis, IM and Lazarou, I and Makri, M and Kazis, D and Papagiannopoulos, S and Kiryttopoulos, A and Koutsouraki, E and Tegos, T}, title = {Memory Clinics and Day Care Centers in Thessaloniki, Northern Greece: 30 Years of Clinical Practice and Experience.}, journal = {Frontiers in neurology}, volume = {12}, number = {}, pages = {683131}, doi = {10.3389/fneur.2021.683131}, pmid = {34512506}, issn = {1664-2295}, abstract = {Background: This review describes the diagnostic and interventional procedures conducted in two university memory clinics (established network of G. Papanikolaou Hospital: 1988-2017 and AHEPA hospital: 2017-today) and 2 day care centers (established network of DCCs: 2005-today) in North Greece and their contribution in the scientific field of dementia. The aims of this work are (1) to provide a diagnosis and treatment protocol established in the network of memory clinics and DCCs and (2) to present further research conducted in the aforementioned network during the last 30 years of clinical practice. Methods: The guidelines to set a protocol demand a series of actions as follows: (1) set the diagnosis criteria, neuropsychological assessment, laboratory examinations, and examination of neurophysiological, neuroimaging, cerebrospinal fluid, blood, and genetic markers; and (2) apply non-pharmacological interventions according to the needs and specialized psychosocial interventions of the patient to the caregivers of the patient. Results: In addition to the guidelines followed in memory clinics at the 1st and 3rd Department of Neurology and two DCCs, a database of patients, educational programs, and further participation in international research programs, including clinical trials, make our contribution in the dementia field strong. Conclusion: In the current paper, we provide useful guidelines on how major and minor neurocognitive disorders are being treated in Thessaloniki, Greece, describing successful practices which have been adapted in the last 30 years.}, }
@article {pmid34508753, year = {2021}, author = {Baldinotti, R and Fronza, MG and Silva, L and Bender, CB and Lüdtke, DS and Seixas, FK and Collares, T and Alves, D and Savegnago, L}, title = {Protective effects of octylseleno-xylofuranoside in a streptozotocin-induced mouse model of Alzheimer's disease.}, journal = {European journal of pharmacology}, volume = {}, number = {}, pages = {174499}, doi = {10.1016/j.ejphar.2021.174499}, pmid = {34508753}, issn = {1879-0712}, abstract = {Octylseleno-xylofuranoside (OSX) is an organic selenium compound which has previously shown antioxidant and antidepressant-like activities, trough the modulation of monoaminergic system and synaptic plasticity pathways. Since recent studies have suggested Major Depressive Disorder (MDD) as a potential risk factor or condition that precedes and correlates with Alzheimer's Disease (AD), this study aimed to evaluate the protective effects of OSX in an AD mouse model induced by intracerebroventricular injection of STZ. To address this protective effect, mice were pre-treated with intragastrical OSX (0.1 mg/kg) or vehicle for 20 days. After the pre-treatment, mice were submitted to two alternated icv infusions of STZ (days 21 and 23) or saline. 15 days after the last STZ injection, cognitive and memory skills of the treated mice were evaluated on object recognition test, Y-maze, stepdown passive avoidance and social recognition paradigms. Added to that, measurements of oxidative stress markers and gene expression were evaluated in brain samples of the same mice groups. Mice pre-treatment with OSX protected mice from cognitive and memory decline elicited by STZ. This effect was attributed to the prevention of lipid peroxidation and modulation of acetylcholinesterase and monoamine oxidase activities in cerebral cortices and hippocampi by OSX treatment. Furthermore, OSX treatment demonstrated reduction of amyloidogenic pathway genes expression when compared to the control groups. Besides that, OSX treatment showed no hepatic and renal toxicity in the protocol used for treatment. Considering the antidepressant-like effect of OSX, together with the ability to prevent memory and cognitive impairment, this new compound may be an interesting strategy for targeting the comorbidity between MDD and AD, in a multitarget drug paradigm.}, }
@article {pmid34507318, year = {2021}, author = {Brenowitz, WD and Xiang, Y and McEvoy, CT and Yang, C and Yaffe, K and Le, WD and Leng, Y}, title = {Current Alzheimer disease research highlights: evidence for novel risk factors.}, journal = {Chinese medical journal}, volume = {}, number = {}, pages = {}, doi = {10.1097/CM9.0000000000001706}, pmid = {34507318}, issn = {2542-5641}, abstract = {ABSTRACT: Alzheimer disease (AD) is the most common type of dementia characterized by the progressive cognitive and social decline. Clinical drug targets have heavily focused on the amyloid hypothesis, with amyloid beta (Aβ), and tau proteins as key pathophysiologic markers of AD. However, no effective treatment has been developed so far, which prompts researchers to focus on other aspects of AD beyond Aβ, and tau proteins. Additionally, there is a mounting epidemiologic evidence that various environmental factors influence the development of dementia and that dementia etiology is likely heterogenous. In the past decades, new risk factors or potential etiologies have been widely studied. Here, we review several novel epidemiologic and clinical research developments that focus on sleep, hypoxia, diet, gut microbiota, and hearing impairment and their links to AD published in recent years. At the frontiers of AD research, these findings and updates could be worthy of further attention.}, }
@article {pmid34506904, year = {2021}, author = {Sanders, OD and Rajagopal, L and Rajagopal, JA}, title = {The oxidatively damaged DNA and amyloid-β oligomer hypothesis of Alzheimer's disease?.}, journal = {Free radical biology & medicine}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.freeradbiomed.2021.08.019}, pmid = {34506904}, issn = {1873-4596}, abstract = {The amyloid-β (Aβ) oligomer hypothesis of Alzheimer's disease (AD) still dominates the field, yet the clinical trial evidence does not robustly support it. A falsifiable prediction of the hypothesis is that Aβ oligomer levels should be elevated in the brain regions and at the disease stages where and when neuron death and synaptic protein loss begin and are the most severe, but we review previous evidence to demonstrate that this is not consistently the case. To rescue the Aβ oligomer hypothesis from falsification, we propose the novel ad-hoc hypothesis that the exceptionally vulnerable hippocampus may normally produce Aβ peptides even in healthily aging individuals, and hippocampal oxidatively damaged DNA, pathogen DNA, and metal ions such as zinc may initiate and drive Aβ peptide aggregation into oligomers and spreading, neuron death, synaptic dysfunction, and other aspects of AD neurodegeneration. We highlight additional evidence consistent with the underwhelming efficacy of Aβ oligomer-lowering agents, such as aducanumab, and of antioxidants, such as vitamin E, versus the so far isolated case report that DNase-I treatment for 2 months resulted in a severe AD patient's Mini-Mental State Exam score increasing from 3 to 18, reversing his diagnosis to moderate AD, according to the Mini-Mental State Exam.}, }
@article {pmid34496627, year = {2021}, author = {Lee, SR and Choi, EK and Park, SH and Jung, JH and Han, KD and Oh, S and Lip, GYH}, title = {Comparing Warfarin and 4 Direct Oral Anticoagulants for the Risk of Dementia in Patients With Atrial Fibrillation.}, journal = {Stroke}, volume = {}, number = {}, pages = {STROKEAHA120033338}, doi = {10.1161/STROKEAHA.120.033338}, pmid = {34496627}, issn = {1524-4628}, abstract = {BACKGROUND AND PURPOSE: Atrial fibrillation is a risk factor for dementia, and oral anticoagulant use is associated with a decreased risk of dementia in patients with atrial fibrillation. We aimed to investigate whether the risk of dementia would be different between patients treated with direct oral anticoagulants (DOACs) compared with those with warfarin.
METHODS: Using the Korean nationwide claims database from January 2014 to December 2017, we identified oral anticoagulant-naive nonvalvular atrial fibrillation patients aged ≥40 years. For the comparisons, warfarin and DOAC groups were balanced using the inverse probability of treatment weighting method. The primary outcome was incident dementia.
RESULTS: Among 72 846 of total study patients, 25 948 were treated with warfarin, and 46 898 were treated with DOAC (17 193 with rivaroxaban, 9882 with dabigatran, 11 992 with apixaban, and 7831 with edoxaban). During mean 1.3±1.1 years of follow-up, crude incidence of dementia was 4.87 per 100 person-years (1.20 per 100 person-years for vascular dementia and 3.30 per 100 person-years for Alzheimer dementia). Compared with warfarin, DOAC showed a comparable risks of dementia, vascular dementia, and Alzheimer dementia. In subgroup analyses, DOAC was associated with a lower risk of dementia than warfarin, particularly in patients aged 65 to 74 years (hazard ratio, 0.815 [95% CI, 0.709-0.936]) and in patients with prior stroke (hazard ratio, 0.891 [95% CI, 0.820-0.968]). When comparing individual DOACs with warfarin, edoxaban was associated with a lower risk of dementia (hazard ratio, 0.830 [95% CI, 0.740-0.931]).
CONCLUSIONS: In this large Asian population with atrial fibrillation, DOAC showed a comparable risk of dementia with warfarin overall. DOACs appeared more beneficial than warfarin, in those aged 65 to 74 years or with a history of stroke. For specific DOACs, only edoxaban was associated with a lower risk of dementia than warfarin.}, }
@article {pmid34489674, year = {2021}, author = {Ou, H and Chien, WC and Chung, CH and Chang, HA and Kao, YC and Wu, PC and Tzeng, NS}, title = {Association Between Antibiotic Treatment of Chlamydia pneumoniae and Reduced Risk of Alzheimer Dementia: A Nationwide Cohort Study in Taiwan.}, journal = {Frontiers in aging neuroscience}, volume = {13}, number = {}, pages = {701899}, doi = {10.3389/fnagi.2021.701899}, pmid = {34489674}, issn = {1663-4365}, abstract = {Background: Chlamydia pneumoniae (CPn) is a common community-acquired pneumonia. In the literature, CPn infection is demonstrated to exhibit an association with Alzheimer dementia (AD). We executed the present nationwide, population-based research with the goal of probing the association of CPn infection and antibiotic therapy with AD risk. Methods: We conducted a cohort study using a database extracted from Taiwan's National Health Insurance Research Database (NHIRD). All medical conditions for each enrolled individuals were categorized using the International Classification of Diseases, ninth Revision classifications. Hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between CPn pneumonia-associated hospitalizations and AD were estimated using Fine and Gray's survival analysis and adjusted for comorbidities. The effects of the antibiotics on the HRs for AD in the patients with CPn pneumonia-associated hospitalization were also analyzed. Results: Our analyses included 6,628 individuals, including 1,657 CPn-infected patients, as well as 4,971 controls matched by age, index date, and sex (1:3). In this study, patients hospitalized for CPn pneumonia exhibited a significantly higher AD risk (adjusted HR = 1.599, 95% CI = 1.284-1.971, p < 0.001). We also noted an association of macrolide use (≥15 days) and fluoroquinolone use (≥15 days) with decreased AD risk. Conclusions: We determined CPn pneumonia to be associated with a relatively high AD risk. The result in this study confirmed the findings from previous literatures, by using a large, nationwide, population-based database. Appropriate macrolide and fluoroquinolone treatment may attenuate this risk.}, }
@article {pmid34489627, year = {2021}, author = {Sim, AY and Barua, S and Kim, JY and Lee, YH and Lee, JE}, title = {Role of DPP-4 and SGLT2 Inhibitors Connected to Alzheimer Disease in Type 2 Diabetes Mellitus.}, journal = {Frontiers in neuroscience}, volume = {15}, number = {}, pages = {708547}, doi = {10.3389/fnins.2021.708547}, pmid = {34489627}, issn = {1662-4548}, abstract = {Alzheimer's disease (AD) is characterized by memory loss and cognitive decline. Additionally, abnormal extracellular amyloid plaques accumulation and nerve damage caused by intracellular neurofibrillary tangles, and tau protein are characteristic of AD. Furthermore, AD is associated with oxidative stress, impaired mitochondrial structure and function, denormalization, and inflammatory responses. Recently, besides the amyloid β hypothesis, another hypothesis linking AD to systemic diseases has been put forth by multiple studies as a probable cause for AD. Particularly, type 2 diabetes mellitus (T2DM) and its features, including hyperinsulinemia, and chronic hyperglycemia with an inflammatory response, have been shown to be closely related to AD through insulin resistance. The brain cannot synthesize or store glucose, but it does require glucose, and the use of glucose in the brain is higher than that in any other organ in the mammalian body. One of the therapeutic drugs for T2DM, dipeptidyl peptidase-4 (DPP-4) inhibitor, suppresses the degradation of incretins, glucagon-like peptides and glucose-dependent insulinotropic peptide. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, recently used in T2DM treatment, have a unique mechanism of action via inhibition of renal glucose reabsorption, and which is different from the mechanisms of previously used medications. This manuscript reviews the pathophysiological relationship between the two diseases, AD and T2DM, and the pharmacological effects of therapeutic T2DM drugs, especially DPP-4 inhibitors, and SGLT2 inhibitors.}, }
@article {pmid34329605, year = {2021}, author = {Procter, TV and Williams, A and Montagne, A}, title = {Interplay between Brain Pericytes and Endothelial Cells in Dementia.}, journal = {The American journal of pathology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ajpath.2021.07.003}, pmid = {34329605}, issn = {1525-2191}, abstract = {Dementia is becoming an increasingly important disease because of the aging population and limited treatment options. Cerebral small vessel disease and Alzheimer disease are the two most common causes of dementia with vascular dysfunction being a large component of both their pathophysiologies. The neurogliovascular unit and in particular the blood-brain barrier (BBB) are required for maintaining brain homeostasis. A complex interaction exists between the endothelial cells, which line the blood vessels and pericytes, which surround them in the neurogliovascular unit. Disruption of the BBB occurs in dementia, precipitating cognitive decline. In this review, we highlight how dysfunction of the endothelial-pericyte crosstalk contributes to dementia, focusing on cerebral small vessel disease and Alzheimer disease. This review examines how loss of pericyte coverage occurs and subsequent downstream changes. Furthermore, it examines how disruption to intimate crosstalk between endothelial cells and pericytes leads to alterations in cerebral blood flow, transcription, neuroinflammation, and transcytosis, contributing to breakdown of the BBB. This review illustrates how cumulation of loss of endothelial-pericyte crosstalk is a major driving force in dementia pathology.}, }
@article {pmid34088880, year = {2021}, author = {Grill, JD and Karlawish, J}, title = {Implications of FDA Approval of a First Disease-Modifying Therapy for a Neurodegenerative Disease on the Design of Subsequent Clinical Trials.}, journal = {Neurology}, volume = {97}, number = {10}, pages = {496-500}, doi = {10.1212/WNL.0000000000012329}, pmid = {34088880}, issn = {1526-632X}, abstract = {The goal of clinical research is to improve clinical practice. In progressive neurodegenerative conditions without any disease-slowing therapies, this will result in eventual approval of a first disease-modifying treatment. Clinical trials will still be needed to discover treatments that are more effective, safer, or more convenient. This will generate controversies over how to design these trials; specifically, controversies about the use of a placebo control. We consider ethical guidance for these studies with attention to 3 designs: placebo-controlled trials in the absence of the new drug, placebo-controlled trials with the approved drug as background therapy, and trials with the new drug as an active control. To understand the practical implications of these designs, we examine experiences in drug development in multiple sclerosis. We conclude by contemplating the future of clinical trials in Alzheimer disease.}, }
@article {pmid34484904, year = {2021}, author = {Mahdavi, KD and Jordan, SE and Barrows, HR and Pravdic, M and Habelhah, B and Evans, NE and Blades, RB and Iovine, JJ and Becerra, SA and Steiner, RA and Chang, M and Kesari, S and Bystritsky, A and O'Connor, E and Gross, H and Pereles, FS and Whitney, M and Kuhn, T}, title = {Treatment of Dementia With Bosutinib: An Open-Label Study of a Tyrosine Kinase Inhibitor.}, journal = {Neurology. Clinical practice}, volume = {11}, number = {3}, pages = {e294-e302}, doi = {10.1212/CPJ.0000000000000918}, pmid = {34484904}, issn = {2163-0402}, abstract = {Objective: The pursuit of an effective therapeutic intervention for dementia has inspired interest in the class of medications known as tyrosine kinase inhibitors such as bosutinib.
Methods: Thirty-one patients with probable Alzheimer dementia or Parkinson spectrum disorder with dementia completed 12 months of bosutinib therapy and an additional 12 months of follow-up. The Clinical Dementia Rating scale (as estimated by the Quick Dementia Rating System [QDRS]) was the primary cognitive status outcome measure. Secondary outcome measures included the Repeatable Battery Assessment of Neuropsychological Status (RBANS) and the Montreal Cognitive Assessment. Cox regression methods were used to compare results with population-based estimates of cognitive decline.
Results: The present article reports on cognitive outcomes obtained at 12 months for 31 participants and up to 24 months for a 16-participant subset. Safety and tolerability of bosutinib were confirmed among the study population (Mage = 73.7 years, SDage = 14 years). Bosutinib was associated with less worsening in Clinical Dementia Rating (CDR) scores (hazard ratio = -0.62, p < 0.001, 95% confidence interval [CI]: -1.02 to -0.30) and less decline in RBANS performance (hazard ratio = -3.42, p < 0.001, 95% CI: -3.59 to -3.72) during the year of treatment than population-based estimates of decline. In the 24-month follow-up, wherein 16 patients were observed after 1 year postintervention, 31.2% of participants exhibited worsened CDR levels compared with their 12-month performances.
Conclusions: Results support an overall positive outcome after 1 year of bosutinib. Future studies should explore the relationship between tyrosine kinases and neurodegenerative pathology as well as related avenues of treatment.}, }
@article {pmid34478861, year = {2021}, author = {Taheri, M and Oryan, SH and Eslimi Esfahani, D and Mohseni Kouchesfahani, H and Salari, A}, title = {Artemisia Absinthium improves spatial performance and neuronal injury induced by amyloid- beta in the CA1 hippocampal area of male Wistar rats.}, journal = {Neurobiology of learning and memory}, volume = {}, number = {}, pages = {107506}, doi = {10.1016/j.nlm.2021.107506}, pmid = {34478861}, issn = {1095-9564}, abstract = {Alzheimer's disease is a neurodegenerative disorder. It is characterized by the presence of two aberrant structures in the brain, those are, amyloid plaques and neurofibrillary tangles, along with neuronal death. Amyloid-beta further exacerbates the metabolic decline and results in cognitive impairments. Because of the favorable antioxidant and anti-inflammatory activities of Artemisia absinthium (wormwood), this study aimed to evaluate the effects of hydroalcoholic extract of this plant on spatial memory performance, neuronal injury, and apoptosis induced by amyloid-beta. Forty-eight male Wistar rats (220-250 g) were divided into the following groups: 1) control; 2) sham (solvent; ICV); 3) amyloid-beta 1-40 (ICV); and 4) amyloid-beta plus A. absinthium (10, 50, and 100 mg/kg/day; gavage). Congo red and TUNEL staining were performed to investigate the neuronal injury. Also, the Morris water maze (MWM) test was used to evaluate the spatial memory of the experimental groups. The results showed that spatial memory for finding the hidden platform in the MWM task decreased significantly in the amyloid-beta group, compared to the control and sham groups. In contrast, treatment with A. absinthium improved spatial memory dose-dependently and reduced tissue degeneration, amyloid plaques, and apoptosis. It seems that the hydroalcoholic extract of A. absinthium, due to its antioxidant and anti-inflammatory activities, can effectively reverse spatial memory deficits and reduce amyloid-beta plaques.}, }
@article {pmid34466513, year = {2019}, author = {Zarifkar, AH and Zarifkar, A and Nami, M and Rafati, A and Aligholi, H and Vafaee, F}, title = {Ameliorative Effects of Different Transcranial Electrical Stimulation Paradigms on the Novel Object Recognition Task in a Rat Model of Alzheimer Disease.}, journal = {Galen medical journal}, volume = {8}, number = {}, pages = {e1440}, doi = {10.31661/gmj.v8i0.1440}, pmid = {34466513}, issn = {2322-2379}, abstract = {Background: Treatment of Alzheimer as a disease that is associated with cognitive impairment has been associated with some restrictions. Recently, researchers have focused on non-pharmacological treatments, including non-invasive stimulation of the brain by transcranial electrical stimulation (tES). Four main paradigms of transcranial electrical current include transcranial direct current stimulation (tDCS), transcranial alternative current stimulation (tACS), transcranial random noise stimulation (tRNS), transcranial pulse current stimulation (tPCS). The tDCS is a possible new therapeutic option for patients with cognitive impairment, including Alzheimer disease.
Materials and Methods: The study was done on Sprague-Dawley male rats weighing 250-270 g. to develop Alzheimer's model, the cannula was implanted bilaterally into the hippocampus. Aβ 25-35 (5μg/ 2.5µl/day) was microinjected bilaterally for 4 days. Then, an electrical stimulation paradigm was applied to the animal for 6 days. Animal cognitive capacity was evaluated on day 11 and 12 by novel object recognition (NOR) test.
Results: Our results showed that application of tDCS; tACS; tRNS and tPCS reversed beta-amyloid-induced impairment (P<0.05). The tRNS Group spent total exploration time around the objects compared to other groups (P<0.05). There was no significant difference between the four different paradigms in discrimination ratio and the percentage of total exploration time.
Conclusion: The results of this study showed that the use of multiple sessions of different tES paradigms could improve Aβ-induced memory impairment in the NOR test. Therefore, based on evidence, it can be expected that in addition to using tDCS, other stimulatory paradigms may also be considered in the treatment of AD.}, }
@article {pmid34463981, year = {2021}, author = {Ryder, MI and Xenoudi, P}, title = {Alzheimer disease and the periodontal patient: New insights, connections, and therapies.}, journal = {Periodontology 2000}, volume = {87}, number = {1}, pages = {32-42}, doi = {10.1111/prd.12389}, pmid = {34463981}, issn = {1600-0757}, abstract = {Loss of cognitive function in the aging population, particular those with Alzheimer disease, presents unique challenges to health practitioners. For the dental practitioner these include management of periodontal diseases, caries, and other dental conditions in this special population. It is well established in the cognitively impaired patient that a lack of adherence to dental hygiene routines and professional care leads to increases in the prevalence and severity of these dental conditions, leading to increased loss of teeth. More recent evidence has indicated a possible role of the microbiota of dental plaque associated with periodontal diseases in the development and progression of Alzheimer disease, thereby supporting a two-way interaction of these two diseases. New therapies are needed to address the potential upstream events that may precede overt signs of Alzheimer disease. One of these approaches would be to target these various bacterial, viral, and other microbial pathogens associated with periodontal disease that can translocate into the bloodstream and then to distal sites, such as the brain. Such microbial translocation would lead to local inflammation and buildup of the hallmark signs of Alzheimer disease, including amyloid beta deposits, tau fragmentation and tangles, breakdown of host protective molecules, such as the apolipoproteins, and neuron toxicity. In this review, evidence for the biological basis of the role of the periodontal disease microflora on the initiation and progression of Alzheimer disease will be presented with a focus on the potential role of the keystone pathogen Porphyromonas gingivalis with its family of gingipain enzymes. The various mechanisms for which P. gingivalis gingipains may contribute to the initiation and progression of Alzheimer disease are presented. Small-molecule inhibitors of these gingipains and their effects on reducing biological markers of Alzheimer disease may have beneficial effects for the initiation and progression of loss of cognitive function in Alzheimer disease. In addition to these targeted therapies for specific periodontal pathogens, considerations for the dental practitioner in applying more general approaches to reducing the periodontal plaque microflora in the management of the cognitively impaired patient are discussed for this special population.}, }
@article {pmid34459862, year = {2021}, author = {Winer, JR and Deters, KD and Kennedy, G and Jin, M and Goldstein-Piekarski, A and Poston, KL and Mormino, EC}, title = {Association of Short and Long Sleep Duration With Amyloid-β Burden and Cognition in Aging.}, journal = {JAMA neurology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaneurol.2021.2876}, pmid = {34459862}, issn = {2168-6157}, abstract = {Importance: Disrupted sleep is common in aging and is associated with cognition. Age-related changes to sleep are associated with multiple causes, including early Alzheimer disease pathology (amyloid β [Aβ]), depression, and cardiovascular disease.
Objective: To investigate the associations between self-reported sleep duration and brain Aβ burden as well as the demographic, cognitive, and lifestyle variables in adults with normal cognition.
This cross-sectional study obtained data from participants in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study, which is being conducted in 67 sites in the United States, Canada, Australia, and Japan. The sample for this analysis consisted of individuals aged 65 to 85 years who underwent an Aβ positron emission tomography (PET) scan, had complete apolipoprotein E (APOE) genotype data, and were identified as clinically normal (per a Clinical Dementia Rating score of 0) and cognitively unimpaired (per a Mini-Mental State Examination score of 25 to 30 and Logical Memory Delayed Recall test score of 6 to 18). Data were analyzed from April 3, 2020, to June 20, 2021.
Main Outcomes and Measures: The outcome was self-reported nightly sleep duration (grouped by short sleep duration: ≤6 hours, normal sleep duration: 7-8 hours, and long sleep duration: ≥9 hours) compared with demographic characteristics, Aβ burden (as measured with a fluorine 18-labeled-florbetapir PET scan), objective and subjective cognitive function measures, and lifestyle variables.
Results: The 4417 participants in the study included 2618 women (59%) and had a mean (SD) age of 71.3 (4.7) years. Self-reported shorter sleep duration was linearly associated with higher Aβ burden (β [SE] = -0.01 [0.00]; P = .005), and short sleep duration was associated with reduced cognition that was mostly in memory domains. No difference in Aβ was found between long and normal sleep duration groups (β [SE] = 0.00 [0.01]; P = .99). However, compared with normal sleep duration, both short and long sleep durations were associated with higher body mass index (short vs normal sleep duration: β [SE] = 0.48 [0.17], P = .01; long vs normal sleep duration: β [SE] = 0.97 [0.31], P = .002), depressive symptoms (short vs normal sleep duration: β [SE] = 0.31 [0.05], P < .001; long vs normal sleep duration: β [SE] = 0.39 [0.09], P < .001), and daytime napping (short vs normal sleep duration: β [SE] = 2.66 [0.77], P = .001; long vs normal sleep duration: β [SE] = 3.62 [1.38], P = .01). Long sleep duration was associated with worse performance across multiple cognitive domains.
Conclusions and Relevance: In this cross-sectional study, both short and long sleep durations were associated with worse outcomes for older adults, such as greater Aβ burden, greater depressive symptoms, higher body mass index, and cognitive decline, emphasizing the importance of maintaining adequate sleep.}, }
@article {pmid34451840, year = {2021}, author = {Thakur, A and Moyo, P and van der Westhuizen, CJ and Yang, HO and Maharaj, V}, title = {A Novel Cardenolide Glycoside Isolated from Xysmalobium undulatum Reduces Levels of the Alzheimer's Disease-Associated β-Amyloid Peptides Aβ42 In Vitro.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {14}, number = {8}, pages = {}, pmid = {34451840}, issn = {1424-8247}, support = {NRF-2015M3A9A5030735//Bio & Medical Technology Development Program/ ; }, abstract = {Elevated levels of the amylo β-proteins (Aβ), particularly Aβ42, are associated with a high risk of Alzheimer's disease (AD). The Aβ proteins are produced from cellular processing of the amyloid precursor proteins (APPs). To identify natural products that block the formation of Aβ-proteins from APPs, we previously screened a library of plant extracts and identified Xysmalobium undulaum (Apocynaceae) as a potential plant for further research. Here, we provide a report on the isolation and identification of the active principles from the plant species using a bioassay-guided fractionation. Fractions and resulting pure compounds from the purification process of the extract of X. undulatum were screened in vitro against APPs transfected HeLa cell lines. Three compounds, acetylated glycosydated crotoxogenin (1), xysmalogenin-3, β-d-glucopyranoside (2), and crotoxigenin 3-O-glucopyranoside (3), were subsequently isolated and their structures elucidated using NMR and mass spectrometry. Compound 1, a novel cardenolide, and 2 significantly decreased the Aβ42 levels in a dose-dependent manner while compound 3 was inactive. In silico investigations identified the AD's β-secretase enzyme, BACE1, as a potential target for these compounds with the glycoside moiety being of significance in binding to the enzyme active site. Our study provides the first report of a novel cardenolide and the potential of cardenolides as chemical scaffolds for developing AD treatment drugs.}, }
@article {pmid34449462, year = {2021}, author = {Liang, Z and Wu, L and Gong, S and Liu, X}, title = {The cognitive dysfunction related to Alzheimer disease or cerebral small vessel disease: What's the differences.}, journal = {Medicine}, volume = {100}, number = {34}, pages = {e26967}, doi = {10.1097/MD.0000000000026967}, pmid = {34449462}, issn = {1536-5964}, support = {LY13G030020//natural science foundation of zhejiang province/ ; }, abstract = {ABSTRACT: Alzheimer disease (AD) and sporadic cerebral small vessel disease (CSVD) are common cognitive disorders. Both AD and CSVD have mental symptoms including chronic progressive cognitive impairment, dysfunction, and behavioral abnormalities. However, the differences on the cognitive dysfunction of AD and CSVD remain unclear. It is necessary to elucidate the cognitive dysfunction differences of AD and CSVD, and to identify the potential risk factors.AD or sporadic CSVD patients treated in our hospital from December 1, 2018 to May 31, 2019 were included. And we selected healthy participants as controls. The mini-mental state examination and Montreal Cognitive Assessment Scale were used for neuropsychological assessment, and related medical information were collected and compared.A total of 190 patients were included. The total mini-mental state examination scores in AD, CSVD group were significantly less than that of control group, there were significant differences in the domains of directional ability, attention and computing ability, delayed recall, and visual perception (all P < .05); the total Montreal Cognitive Assessment Scale scores in AD, CSVD group were significantly less than that of control group. There were significant differences in the domains of visual space and execution, immediate remember, attention and computing ability, language, delayed recall, and directional ability (all P < .05); diabetes was a risk factor both for AD (hazard ratio = 1.63, 95% confidence interval: 1.35-1.97) and CSVD (hazard ratio = 1.15, 95% confidence interval: 1.08-1.27).The cognitive dysfunctions of AD are difference to that of CSVD patients, and diabetes is the risk factor both for AD and CSVD, future studies are needed to further identify the prevention and treatment of AD and CSVD.}, }
@article {pmid34447508, year = {2021}, author = {Soureshjani, FH and Kheirollahi, M and Yaghmaei, P and Fattahjadnematalahi, S}, title = {Possible Preventive Effect of Donepezil and Hyoscyamoside by Reduction of Plaque Formation and Neuroinflammation in Alzheimer's Disease.}, journal = {International journal of preventive medicine}, volume = {12}, number = {}, pages = {66}, pmid = {34447508}, issn = {2008-7802}, abstract = {Background: Alzheimer disease (AD) is the most common age-dependent dementia. The complex natural accumulation of amyloid beta (Aβ) precursor protein in hippocampus neurons is regarded as the earliest pathological feature of AD, although there are cholinergic assumptions and effective inflammation in AD. In this animal experimental study, we evaluated the preventive effect of hyoscyamoside (Hyo) and donepezil (Dz) on plaque formation and improvement of neurogenic inflammation in AD rats.
Methods: Dz was prepared and Hyo (steroidal saponin) was isolated from Hyoscymus niger. Then, Wistar rats divided into five groups including negative and positive controls, AD, Dz, and Hyo treatment groups based on the drug exposure and their behavioral alternation was examined using Morris water maze (MWM) test. Bielschowsky staining was used to detect the nerve fibers. Serum levels of interleukin (IL)-4 and IL-6 were evaluated by ELISA. The RNA expression of cyclin-dependent kinase CDK11-P58 in peripheral blood lymphocytes was performed using quantitative PCR.
Results: The MWM test showed significant changes in time the models spent to find the hidden platform. The Hyo treatment group showed a notable speed change (P < 0.01). The histopathological analysis of the hippocampal tissue revealed the inhibition of Aβ formation in the treatment groups. The treatment groups had a significant decline in the serum level of IL-6, and the IL-4 serum level was increased in the Hyo and Dz treated groups. The expression levels of CDK11-P58 was significantly decreased in the treatment groups.
Conclusions: In sum, the therapeutic effects of Hyo is comparable with that of Dz in AD rats by suppressing neuroinflammation. Thus, these compounds could be considered as a preventive agent in the AD therapy.}, }
@article {pmid34447243, year = {2021}, author = {Wang, S and Ma, J and Zeng, Y and Zhou, G and Wang, Y and Zhou, W and Sun, X and Wu, M}, title = {Icariin, an Up-and-Coming Bioactive Compound Against Neurological Diseases: Network Pharmacology-Based Study and Literature Review.}, journal = {Drug design, development and therapy}, volume = {15}, number = {}, pages = {3619-3641}, pmid = {34447243}, issn = {1177-8881}, abstract = {Icariin is a biologically active substance in Epimedii herba that is used for the treatment of neurologic disorders. However, a comprehensive analysis of the molecular mechanisms of icariin is lacking. In this review, we present a brief history of the use of icariin for medicinal purposes; describe the active chemical components of Epimedii herba; and examine the evidence from experimental studies that have uncovered molecular targets of icariin in different diseases. We also constructed a protein-protein interaction network and carried out Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional enrichment analyses to predict the therapeutic actions of icariin in nervous system diseases including Alzheimer disease, Parkinson disease, ischemic stroke, depressive disorder, multiple sclerosis, glioblastoma, and hereditary spastic paraplegias. The results of our analyses can guide future studies on the application of icariin to the treatment of neurologic disorders.}, }
@article {pmid34445613, year = {2021}, author = {Oleksak, P and Novotny, M and Patocka, J and Nepovimova, E and Hort, J and Pavlik, J and Klimova, B and Valis, M and Kuca, K}, title = {Neuropharmacology of Cevimeline and Muscarinic Drugs-Focus on Cognition and Neurodegeneration.}, journal = {International journal of molecular sciences}, volume = {22}, number = {16}, pages = {}, pmid = {34445613}, issn = {1422-0067}, support = {VT2019-2021//UHK/ ; }, abstract = {At present, Alzheimer's disease (AD) and related dementias cannot be cured. Therefore, scientists all over the world are trying to find a new approach to prolong an active life of patients with initial dementia. Both pharmacological and non-pharmacological pathways are investigated to improve the key symptom of the disease, memory loss. In this respect, influencing the neuromodulator acetylcholine via muscarinic receptors, such as cevimeline, might be one of the therapeutic alternatives. The purpose of this study is to explore the potential of cevimeline on the cognitive functions of AD patients. The methodology is based on a systematic literature review of available studies found in Web of Science, PubMed, Springer, and Scopus on the research topic. The findings indicate that cevimeline has shown an improvement in experimentally induced cognitive deficits in animal models. Furthermore, it has demonstrated to positively influence tau pathology and reduce the levels of amyloid-β (Aβ) peptide in the cerebral spinal fluid of Alzheimer's patients. Although this drug has not been approved by the FDA for its use among AD patients and there is a lack of clinical studies confirming and extending this finding, cevimeline might represent a breakthrough in the treatment of AD.}, }
@article {pmid34440421, year = {2021}, author = {Ibanez, L and Cruchaga, C and Fernández, MV}, title = {Advances in Genetic and Molecular Understanding of Alzheimer's Disease.}, journal = {Genes}, volume = {12}, number = {8}, pages = {}, pmid = {34440421}, issn = {2073-4425}, abstract = {Alzheimer's disease (AD) has become a common disease of the elderly for which no cure currently exists. After over 30 years of intensive research, we have gained extensive knowledge of the genetic and molecular factors involved and their interplay in disease. These findings suggest that different subgroups of AD may exist. Not only are we starting to treat autosomal dominant cases differently from sporadic cases, but we could be observing different underlying pathological mechanisms related to the amyloid cascade hypothesis, immune dysfunction, and a tau-dependent pathology. Genetic, molecular, and, more recently, multi-omic evidence support each of these scenarios, which are highly interconnected but can also point to the different subgroups of AD. The identification of the pathologic triggers and order of events in the disease processes are key to the design of treatments and therapies. Prevention and treatment of AD cannot be attempted using a single approach; different therapeutic strategies at specific disease stages may be appropriate. For successful prevention and treatment, biomarker assays must be designed so that patients can be more accurately monitored at specific points during the course of the disease and potential treatment. In addition, to advance the development of therapeutic drugs, models that better mimic the complexity of the human brain are needed; there have been several advances in this arena. Here, we review significant, recent developments in genetics, omics, and molecular studies that have contributed to the understanding of this disease. We also discuss the implications that these contributions have on medicine.}, }
@article {pmid34425883, year = {2021}, author = {Vijverberg, EGB and Axelsen, TM and Bihlet, AR and Henriksen, K and Weber, F and Fuchs, K and Harrison, JE and Kühn-Wache, K and Alexandersen, P and Prins, ND and Scheltens, P}, title = {Rationale and study design of a randomized, placebo-controlled, double-blind phase 2b trial to evaluate efficacy, safety, and tolerability of an oral glutaminyl cyclase inhibitor varoglutamstat (PQ912) in study participants with MCI and mild AD-VIVIAD.}, journal = {Alzheimer's research & therapy}, volume = {13}, number = {1}, pages = {142}, pmid = {34425883}, issn = {1758-9193}, abstract = {BACKGROUND: Varoglutamstat (formerly PQ912) is a small molecule that inhibits the activity of the glutaminyl cyclase to reduce the level of pyroglutamate-A-beta (pGluAB42). Recent studies confirm that pGluAB42 is a particular amyloid form that is highly synaptotoxic and plays a significant role in the development of AD.
METHODS: This paper describes the design and methodology behind the phase 2b VIVIAD-trial in AD. The aim of this study is to evaluate varoglutamstat in a state-of-the-art designed, placebo-controlled, double-blind, randomized clinical trial for safety and tolerability, efficacy on cognition, and effects on brain activity and AD biomarkers. In addition to its main purpose, the trial will explore potential associations between novel and established biomarkers and their individual and composite relation to disease characteristics.
RESULTS: To be expected early 2023 CONCLUSION: This state of the art phase 2b study will yield important results for the field with respect to trial methodology and for the treatment of AD with a small molecule directed against pyroglutamate-A-beta.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04498650.}, }
@article {pmid34425652, year = {2020}, author = {Sedighi, M and Baluchnejadmojarad, T and Roghani, M}, title = {Linagliptin Protects Human SH-SY5Y Neuroblastoma Cells against Amyloid-β Cytotoxicity via the Activation of Wnt1 and Suppression of IL-6 Release.}, journal = {Iranian biomedical journal}, volume = {25}, number = {5}, pages = {343-348}, doi = {10.52547/ibj.25.5.343}, pmid = {34425652}, issn = {2008-823X}, abstract = {Background: Alzheimer's disease is one of the neurodegenerative disorders typified by the aggregate of Aβ and phosphorylated tau protein. Oxidative stress and neuroinflammation, because of Aβ peptides, are strongly involved in the pathophysiology of AD. Linagliptin shows neuroprotective properties against AD pathological processes through alleviation of neural inflammation and AMPK activation.
Methods: We assessed the benefits of linagliptin pretreatment (at 10, 20, and 50 nM concentrations), against Aβ1-42 toxicity (20 μM) in SH-SY5Y cells. The concentrations of secreted cytokines, such as TNF-α, IL-6, and IL-1β, and signaling proteins, including pCREB, Wnt1, and PKCε, were quantified by ELISA.
Results: We observed that Aβ led to cellular inflammation, which was assessed by measuring inflammatory cytokines (TNF-α, IL-1β, and IL-6). Moreover, Aβ1-42 treatment impaired pCREB, PKCε, and Wnt1 signaling in human SH-SY5Y neuroblastoma cells. Addition of Linagliptin significantly reduced IL-6 levels in the lysates of cells, treated with Aβ1-42. Furthermore, linagliptin prevented the downregulation of Wnt1 in Aβ1-42-treated cells exposed.
Conclusion: The current findings reveal that linagliptin alleviates Aβ1-42-induced inflammation in SH-SY5Y cells, probably through the suppression of IL-6 release, and some of its benefits are mediated through the activation of the Wnt1 signaling pathway.}, }
@article {pmid34403885, year = {2021}, author = {Shi, S and Li, J and Zhao, X and Liu, Q and Song, SJ}, title = {A comprehensive review: Biological activity, modification and synthetic methodologies of prenylated flavonoids.}, journal = {Phytochemistry}, volume = {191}, number = {}, pages = {112895}, doi = {10.1016/j.phytochem.2021.112895}, pmid = {34403885}, issn = {1873-3700}, abstract = {Prenylated flavonoids, a unique class of flavonoids which combine a flavonoid skeleton and a lipophilic prenyl side-chain, possess great potential biological activities including cytotoxicity, anti-inflammation, anti-Alzheimer, anti-microbial, anti-oxidant, anti-diabetes, estrogenic, vasorelaxant and enzyme inhibition. Recently, prenylated flavonoids have become an indispensable anchor for the development of new therapeutic agents, and have received increasing from medicinal chemists. The prenylated flavonoids have been outstanding developed through isolation, semi or fully synthesis in a very short period of time, which proves the great value in medicinal chemistry researches. In this review, research progress of prenylated flavonoids including natural prenylated flavonoids, structural modification, synthetic methodologies and pharmacological activities was summarized comprehensively. Furthermore, the structure-activity relationships (SARs) of prenylated flavonoids were summarized which provided a basis for the selective design and optimization of multifunctional prenylated flavonoid derivatives for the treatment of multi-factorial diseases in clinic.}, }
@article {pmid34403652, year = {2021}, author = {Puris, E and Auriola, S and Korhonen, P and Loppi, S and Kanninen, KM and Malm, T and Koistinaho, J and Gynther, M}, title = {Systemic inflammation induced changes in protein expression of ABC transporters and ionotropic glutamate receptor subunit 1 in the cerebral cortex of familial Alzheimer`s disease mouse model.}, journal = {Journal of pharmaceutical sciences}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.xphs.2021.08.013}, pmid = {34403652}, issn = {1520-6017}, abstract = {Alzheimer's disease (AD) is an incurable disease, with complex pathophysiology and a myriad of proteins involved in its development. In this study, we applied quantitative targeted absolute proteomic analysis for investigation of changes in potential AD drug targets, biomarkers, and transporters in cerebral cortices of lipopolysaccharide (LPS)-induced neuroinflammation mouse model, familial AD mice (APdE9) with and without LPS treatment as compared to age-matched wild type (WT) mice. The ABCB1, ABCG2 and GluN1 protein expression ratios between LPS treated APdE9 and WT control mice were 0.58 (95% CI 0.44 - 0.72), 0.65 (95% CI 0.53 - 0.77) and 0.61 (95% CI 0.52 - 0.69), respectively. The protein expression levels of other proteins such as MGLL, COX-2, CytC, ABCC1, ABCC4, SLC2A1 and SLC7A5 did not differ between the study groups. Overall, the study revealed that systemic inflammation can alter ABCB1 and ABCG2 protein expression in brain in AD, which can affect intra-brain drug distribution and play a role in AD development. Moreover, the inflammatory insult caused by peripheral infection in AD may be important factor triggering changes in GluN1 protein expression. However, more studies need to be performed in order to confirm these findings. The quantitative information about the expression of selected proteins provides important knowledge, which may help in the optimal use of the mouse models in AD drug development and better translation of preclinical data to humans.}, }
@article {pmid34402024, year = {2021}, author = {Gu, J and Li, Z and Chen, H and Xu, X and Li, Y and Gui, Y}, title = {Neuroprotective Effect of Trans-Resveratrol in Mild to Moderate Alzheimer Disease: A Randomized, Double-Blind Trial.}, journal = {Neurology and therapy}, volume = {}, number = {}, pages = {}, pmid = {34402024}, issn = {2193-8253}, abstract = {INTRODUCTION: Amyloid-beta (Aβ) protein is a major component of the extracellular plaque found in the brains of individuals with Alzheimer's disease (AD). In this study, we investigated the effect of trans-resveratrol as an antagonist treatment for moderate to mild AD, as well as its safety and tolerability.
METHODS: This was a case-control study that enrolled 30 selected patients who had been clinically diagnosed with moderate to mild AD. These patients were randomly divided into two groups, namely, a placebo group (n = 15) and a trans-resveratrol group (n = 15) who received 500 mg trans-resveratrol orally once daily for 52 weeks. Brain magnetic resonance imaging (MRI) examinations were performed on and cerebrospinal fluid (CSF) samples were obtained from all participants before (baseline) and after the study (52 weeks). Enzyme-linked immunosorbent assays were used to determine the levels of plasma Aβ40 and Aβ42 and CSF Aβ40 and Aβ42.
RESULTS: The results showed that the changes over the study period in the levels of Aβ40 in the blood and CSF of the patients treated with trans-resveratrol were not statistically significant (P > 0.05). In contrast, patients who received placebo showed a significant decrease in Aβ40 levels compared with that at the beginning of the study (CSF Aβ40: P = 0.024, plasma Aβ40: P = 0.036). Analysis of the images on the brain MRI scans revealed that the brain volume of the patients treated with trans-resveratrol was significantly reduced at 52 weeks (P = 0.011) compared with that of patients in the placebo treatment group, Further analysis indicated that the level of matrix metallopeptidase 9 in the CSF of the patients treated with trans-resveratrol at 52 weeks decreased by 46% compared with that of patients in the placebo group (P = 0.033).
CONCLUSION: These results indicate that trans-resveratrol has potential neuroprotective roles in the treatment of moderate to mild AD and that its mechanism may involve a reduction in the accumulation and toxicity of Aβ in the brain of patients, thereby reducing neuroinflammation.
TRIAL REGISTRATION: Chinese clinical trial registry: CTR20151780X.}, }
@article {pmid34393775, year = {2021}, author = {Ning, F and Chen, L and Chen, L and Liu, X and Zhu, Y and Hu, J and Xie, G and Xia, J and Shi, K and Lan, Z and Wang, P}, title = {Combination of Polygoni Multiflori Radix Praeparata and Acori Tatarinowii Rhizoma Alleviates Learning and Memory Impairment in Scopolamine-Treated Mice by Regulating Synaptic-Related Proteins.}, journal = {Frontiers in pharmacology}, volume = {12}, number = {}, pages = {679573}, pmid = {34393775}, issn = {1663-9812}, abstract = {Polygoni Multiflori Radix Praeparata (ZhiHeShouWu, PMRP) and Acori Tatarinowii Rhizoma (ShiChangPu, ATR) and their traditional combination (PA) are frequently used in traditional Chinese medicine to prevent and treat Alzheimer disease (AD) based on the theory that PMRP tonifies the kidney and ATR dissipates phlegm. However, the components of PA and their mechanisms of action are not known. The present study analyzed the active components of PA, and investigated the protective effect of PA against cognitive impairment induced by scopolamine in mice along with the underlying mechanism.The aqueous extract of PA was analyzed by high-performance liquid chromatography-mass spectrometry (HPLC-MS) and gas chromatography (GC)-MS in order to identify the major components. To evaluate the protective effect of PA against cognitive dysfunction, mice were orally administered PA, PMRP, or ATR for 30 days before treatment with scopolamine. Learning and memory were assessed in mice with the Morris water maze test; neurotransmitter levels in the hippocampus were analyzed by HPLC-MS; and the expression of synapse-related proteins in the hippocampus was detected by western blotting and immunohistochemistry. Eight active compounds in PA and rat plasma were identified by HPLC-MS and GC-MS. Plasma concentrations of 2,3,5,4'-tetrahydroxystilbene-2-O-β-d-glucoside, emodin, α-asarone, and asarylaldehyde were increased following PA administration; meanwhile, gallic acid, emodin-8-O-β-d-glucopyranoside, β-asarone, and cis-methyl isoeugenol concentrations were similar in rats treated with PA, PMRP, and ATR. In scopolamine-treated mice, PA increased the concentrations of neurotransmitters in the hippocampus, activated the brain-derived neurotrophic factor (BDNF)/extracellular signal-regulated kinase (ERK)/cAMP response element binding protein (CREB) signaling pathway, and increased the expression of p90 ribosomal S6 kinase (p90RSK) and postsynaptic density (PSD)95 proteins. Thus, PA alleviates cognitive deficits by enhancing synaptic-related proteins, suggesting that it has therapeutic potential for the treatment of aging-related diseases such as AD.}, }
@article {pmid34391822, year = {2021}, author = {Mosaferi, B and Jand, Y and Salari, AA}, title = {Antibiotic-induced gut microbiota depletion from early adolescence exacerbates spatial but not recognition memory impairment in adult male C57BL/6 mice with Alzheimer-like disease.}, journal = {Brain research bulletin}, volume = {176}, number = {}, pages = {8-17}, doi = {10.1016/j.brainresbull.2021.08.004}, pmid = {34391822}, issn = {1873-2747}, abstract = {Gut microbiota dysbiosis is associated with cognitive dysfunctions and Alzheimer's disease (AD). This study set out to better understand the relationship between gut microbiota depletion and cognitive abilities in mice with or without Alzheimer-like disease. Male C57BL/6 mice from early adolescence received an antibiotic cocktail, and then in adulthood, animals were subjected to a stereotaxic surgery to induce Alzheimer-like disease using amyloid-beta (Aβ) 1-42 microinjection. To assess cognitive functions in mice, three behavioural tests including the Y maze, object recognition, and Morris water maze were used. We also measured brain-derived-neurotrophic factor (BDNF), tumour-necrosis factor (TNF)-α, interleukin (IL)-6, and Aβ42 in the brain. Our findings showed that antibiotics treatment impaired object recognition memory, whereas did not alter spatial memory in healthy mice. Antibiotics treatment in mice significantly exacerbated spatial memory impairment following the induction of AD in both the Y maze and Morris water maze test. There were significant correlations between these behavioural tests. In addition, healthy animals treated with antibiotics displayed a significant reduction in brain IL-6. We observed that antibiotics treatment significantly decreased both cytokines TNF-α and IL-6 in the brain of AD-induced mice. However, no alterations were found in brain BDNF levels following both antibiotics treatment and AD induction. These findings show that antibiotic-induced gut microbiota depletion from early adolescence to adulthood can impair cognitive abilities in mice with or without Alzheimer-like disease. Overall, this study suggests that gut microbiota manipulation from early adolescence to adulthood may adversely affect the normal development of cognitive functions.}, }
@article {pmid34383681, year = {2021}, author = {Moussavi, Z and Koski, L and Fitzgerald, PB and Millikin, C and Lithgow, B and Jafari-Jozani, M and Wang, X}, title = {Repeated Transcranial Magnetic Stimulation for Improving Cognition in Alzheimer Disease: Protocol for an Interim Analysis of a Randomized Controlled Trial.}, journal = {JMIR research protocols}, volume = {10}, number = {8}, pages = {e31183}, doi = {10.2196/31183}, pmid = {34383681}, issn = {1929-0748}, abstract = {BACKGROUND: Many clinical trials investigating treatment efficacy require an interim analysis. Recently we have been running a large, multisite, randomized, placebo-controlled, double-blind clinical trial investigating the effect of repetitive transcranial magnetic stimulation (rTMS) treatment for improving or stabilizing the cognition of patients diagnosed with Alzheimer disease.
OBJECTIVE: The objectives of this paper are to report on recruitment, adherence, and adverse events (AEs) to date, and to describe in detail the protocol for interim analysis of the clinical trial data. The protocol will investigate whether the trial is likely to reach its objectives if continued to the planned maximum sample size.
METHODS: The specific requirements of the analytic protocol are to (1) ensure the double-blind nature of the data while doing the analysis, (2) estimate the predictive probabilities of success (PPoSs), (3) estimate the numbers needed to treat, (4) re-estimate the initial required sample size. The initial estimate of sample size was 208. The interim analysis will be based on 150 patients who will be enrolled in the study and finish at least 8 weeks of the study. Our protocol for interim analysis, at the very first stage, is to determine the response rate for each participant to the treatment (either sham or active), while ensuring the double-blind nature of the data. The blinded data will be analyzed by a statistician to investigate the treatment efficacy. We will use Bayesian PPoS to predict the success rate and determine whether the study should continue.
RESULTS: The enrollment has been slowed significantly due to the COVID-19 pandemic and lockdown. Nevertheless, so far 133 participants have been enrolled, while 22 of these have been withdrawn or dropped out for various reasons. In general, rTMS has been found tolerable with no serious AE. Only 2 patients dropped out of the study due to their intolerability to rTMS pulses.
CONCLUSIONS: Overall, the study with the same protocol is going as expected with no serious AE or any major protocol deviation.
TRIAL REGISTRATION: ClinicalTrials.gov NCT02908815; https://clinicaltrials.gov/ct2/show/NCT02908815.
DERR1-10.2196/31183.}, }
@article {pmid34382514, year = {2021}, author = {Ahmad, SS and Younis, K and Philippe, J and Aschner, M and Khan, H}, title = {Strategic approaches to target the enzymes using natural compounds for the management of Alzheimer's disease: A review.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/1871527320666210811160007}, pmid = {34382514}, issn = {1996-3181}, abstract = {Alzheimer's disease (AD) is a chronic neurodegenerative disease. It is clinically characterized by memory loss and intellectual decrease, among other neurological deficits. The etiology of AD is not completely understood but includes amyloid plaques and intracellular helical filaments as well as neurofibrillary tangles with hyperphosphorylated tau protein. AD is also associated with alterations in amyloid processing genes, such as PSEN1 or PSEN2 and APP. The modulation immune system, cholesterol metabolism, and synaptic vesicle endocytosis have all been shown to remediate AD. In this review, enzymes such as AChE, BuChE, β-secretase, γ-secretase, MAO, and RAGE are discussed as potential targets for AD treatment. The aim of this review was to addresses the molecular mechanisms as well as various genetic factors in AD etiology. The use of natural compounds against these targets might be beneficial for the management of AD.}, }
@article {pmid34378891, year = {2021}, author = {Pierzynowska, K and Cyske, Z and Gaffke, L and Rintz, E and Mantej, J and Podlacha, M and Wiśniewska, K and Ĺťabińska, M and Sochocka, M and Lorenc, P and Bielańska, P and Giecewicz, I and Węgrzyn, G}, title = {Potential of genistein-induced autophagy in the treatment of neurodegenerative diseases.}, journal = {Postepy biochemii}, volume = {67}, number = {2}, pages = {117-129}, doi = {10.18388/pb.2021_380}, pmid = {34378891}, issn = {0032-5422}, mesh = {*Alzheimer Disease/drug therapy ; Animals ; Autophagy ; Genistein/pharmacology/therapeutic use ; *Huntington Disease ; *Neurodegenerative Diseases/drug therapy ; }, abstract = {Development of therapies for neurodegenerative diseases, disorders characterized by progressing loss of neurons, is a great challenge for current medicine. Searching for drugs for these diseases is being proceeded in many laboratories in the world. To date, several therapeutical strategies have been proposed which, however, are either of insufficient efficacy or at the early preclinical stages. One of the newest concepts is elevated efficiency of degradation of protein aggregates which are causes of 70% of these diseases. Autophagy, i.e. lysosomal degradation of macromolecules, is a process which could be employed in such a strategy Searching for a compound which would not only stimulate autophagy but also reveal safety in a long-term usage and be able to cross the blood-brain-barrier led to studies on one of flavonoids, genistein which occurs at high concentrations in soy. Experiments with this compound indicated its enormous efficiency in removing protein aggregated formed by beta-amyloid, hyperphosphorylated tau protein, and mutant huntingtin. Moreover, using animal models of these diseases, correction of cognitive and motoric symptoms was demonstrated. Considering safety of genistein as well as its ability to crossing the blood-brain-barrier, one may assume that this molecule is a candidate for an effective drug in therapies of not only Alzheimer disease and Huntington disease, but also other disorders caused be protein aggregates. In this article, recent results of studies on the use of genistein in different models of neurodegenerative diseases are summarized, with special emphasis on its autophagy-dependent action.}, }
@article {pmid34378237, year = {2021}, author = {Gove, D and Nielsen, TR and Smits, C and Plejert, C and Rauf, MA and Parveen, S and Jaakson, S and Golan-Shemesh, D and Lahav, D and Kaur, R and Herz, MK and Monsees, J and Thyrian, JR and Georges, J}, title = {The challenges of achieving timely diagnosis and culturally appropriate care of people with dementia from minority ethnic groups in Europe.}, journal = {International journal of geriatric psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1002/gps.5614}, pmid = {34378237}, issn = {1099-1166}, support = {//European Commission/ ; //Robert Bosch Stiftung/ ; }, abstract = {In a just society, everyone should have equal access to healthcare in terms of prevention, assessment, diagnosis, treatment and care. Europe is a multicultural society made up of people who identify with a wide range of ethnic groups. Many older people from minority ethnic groups also have a direct migration background. Several studies have shown that there is a lack of equity in relation to dementia diagnoses and care because equal opportunities do not necessarily translate into equal outcomes. An expert ethics working group led by Alzheimer Europe has produced an extensive report on this issue, a policy brief and a guide for health and social care workers. In this brief summary, the authors/members of the expert working group present some of the key challenges and recommendations for healthcare clinicians striving to provide timely diagnosis and good quality care and treatment to people with dementia from all ethnic groups.}, }
@article {pmid34367470, year = {2021}, author = {Zhang, T and Liu, N and Wei, W and Zhang, Z and Li, H}, title = {Integrated Analysis of Weighted Gene Coexpression Network Analysis Identifying Six Genes as Novel Biomarkers for Alzheimer's Disease.}, journal = {Oxidative medicine and cellular longevity}, volume = {2021}, number = {}, pages = {9918498}, pmid = {34367470}, issn = {1942-0994}, abstract = {Background: Alzheimer's disease (AD) is a chronic progressive neurodegenerative disease; however, there are no comprehensive therapeutic interventions. Therefore, this study is aimed at identifying novel molecular targets that may improve the diagnosis and treatment of patients with AD.
Methods: In our study, GSE5281 microarray dataset from the GEO database was collected and screened for differential expression analysis. Genes with a P value of <0.05 and ∣log2FoldChange | >0.5 were considered differentially expressed genes (DEGs). We further profiled and identified AD-related coexpression genes using weighted gene coexpression network analysis (WGCNA). Functional enrichment analysis was performed to determine the characteristics and pathways of the key modules. We constructed an AD-related model based on hub genes by logistic regression and least absolute shrinkage and selection operator (LASSO) analyses, which was also verified by the receiver operating characteristic (ROC) curve.
Results: In total, 4674 DEGs were identified. Nine distinct coexpression modules were identified via WGCNA; among these modules, the blue module showed the highest positive correlation with AD (r = 0.64, P = 3e - 20), and it was visualized by establishing a protein-protein interaction network. Moreover, this module was particularly enriched in "pathways of neurodegeneration-multiple diseases," "Alzheimer disease," "oxidative phosphorylation," and "proteasome." Sixteen genes were identified as hub genes and further submitted to a LASSO regression model, and six genes (EIF3H, RAD51C, FAM162A, BLVRA, ATP6V1H, and BRAF) were identified based on the model index. Additionally, we assessed the accuracy of the LASSO model by plotting an ROC curve (AUC = 0.940).
Conclusions: Using the WGCNA and LASSO models, our findings provide a better understanding of the role of biomarkers EIF3H, RAD51C, FAM162A, BLVRA, ATP6V1H, and BRAF and provide a basis for further studies on AD progression.}, }
@article {pmid34362303, year = {2021}, author = {Kile, S and Au, W and Parise, C and Rose, K and Donnel, T and Hankins, A and Au, Y and Chan, M and Ghassemi, A}, title = {Five-year outcomes after IVIG for mild cognitive impairment due to alzheimer disease.}, journal = {BMC neuroscience}, volume = {22}, number = {1}, pages = {49}, pmid = {34362303}, issn = {1471-2202}, support = {9471100-1107542//Sutter Health/ ; }, abstract = {BACKGROUND: The purpose of this study was to assess the five-year treatment effects of a short course of intravenous immunoglobulin (IVIG) in subjects with mild cognitive impairment (MCI) due to Alzheimer disease (AD).
METHODS: Fifty subjects 50 to 84 years of age with MCI due to AD were administered 0.4 g/kg 10% IVIG or 0.9% saline every two weeks x five doses in a randomized double-blinded design as part of a two-year study. Twenty-seven subjects completed an additional three-year extension study. MRI brain imaging, cognitive testing, and conversion to dementia were assessed annually. Participants were stratified into early MCI (E-MCI) and late MCI (L-MCI). The primary endpoint was brain atrophy measured as annualized percent change in ventricular volume (APCV) annually for five years. ANOVA was used to compare annualized percent change in ventricular volume from baseline between the groups adjusting for MCI status (E-MCI, L-MCI).
RESULTS: Differences in brain atrophy between the groups, which were statistically significant after one year, were no longer significant after five years. IVIG-treated L-MCI subjects did demonstrate a delay in conversion to dementia of 21.4 weeks.
CONCLUSION: An eight-week course of IVIG totaling 2 g/kg in MCI is safe but is not sufficient to sustain an initial reduction in brain atrophy or a temporary delay in conversion to dementia at five years. Other dosing strategies of IVIG in the early stages of AD should be investigated to assess more sustainable disease-modifying effects. Trial registration ClinicalTrials.gov NCT01300728. Registered 23 February 2011.}, }
@article {pmid34361099, year = {2021}, author = {Esselun, C and Theyssen, E and Eckert, GP}, title = {Effects of Urolithin A on Mitochondrial Parameters in a Cellular Model of Early Alzheimer Disease.}, journal = {International journal of molecular sciences}, volume = {22}, number = {15}, pages = {}, pmid = {34361099}, issn = {1422-0067}, mesh = {Adenosine Triphosphate/*metabolism ; Alzheimer Disease/drug therapy/*metabolism/pathology ; Autophagy ; Coumarins/*pharmacology ; Energy Metabolism ; Humans ; Membrane Potential, Mitochondrial ; Mitochondria/drug effects/*metabolism ; Neuroblastoma/drug therapy/*metabolism/pathology ; *Organelle Biogenesis ; Reactive Oxygen Species/metabolism ; Tumor Cells, Cultured ; }, abstract = {(1) Background: Ellagitannins are natural products occurring in pomegranate and walnuts. They are hydrolyzed in the gut to release ellagic acid, which is further metabolized by the microflora into urolithins, such as urolithin A (UA). Accumulation of damaged mitochondria is a hallmark of aging and age-related neurodegenerative diseases. In this study, we investigated the neuroprotective activity of the metabolite UA against mitochondrial dysfunction in a cellular model of early Alzheimer disease (AD). (2) Methods: In the present study we used SH-SY5Y-APP695 cells and its corresponding controls (SH-SY5Ymock) to assess UA's effect on mitochondrial function. Using these cells we investigated mitochondrial respiration (OXPHOS), mitochondrial membrane potential (MMP), adenosine triphosphate (ATP) production, autophagy and levels of reactive oxygen species (ROS) in cells treated with UA. Furthermore, we assessed UA's effect on the expression of genes related to mitochondrial bioenergetics, mitochondrial biogenesis, and autophagy via quantitative real-time PCR (qRT-PCR). (3) Results: Treatment of SH-SY5Y-APP695 cells suggests changes to autophagy corresponding with qRT-PCR results. However, LC3B-I, LC3B-II, and p62 levels were unchanged. UA (10 µM) reduced MMP, and ATP-levels. Treatment of cells with UA (1 µM) for 24 h did not affect ROS production or levels of Aβ, but significantly increased expression of genes for mitochondrial biogenesis and OXPHOS. Mitochondrial Transcription Factor A (TFAM) expression was specifically increased in SH-SY5Y-APP695. Both cell lines showed unaltered levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), which is commonly associated with mitochondrial biogenesis. Results imply that biogenesis might be facilitated by estrogen-related receptor (ESRR) genes. (4) Conclusion: Urolithin A shows no effect on autophagy in SH-SY5Y-APP695 cells and its effect on mitochondrial function is limited. Instead, data suggests that UA treatment induces hormetic effects as it induces transcription of several genes related to mitochondrial biogenesis.}, }
@article {pmid34360133, year = {2021}, author = {Godefroy, V and Levy, R and Bouzigues, A and Rametti-Lacroux, A and Migliaccio, R and Batrancourt, B}, title = {ECOCAPTURE@HOME: Protocol for the Remote Assessment of Apathy and Its Everyday-Life Consequences.}, journal = {International journal of environmental research and public health}, volume = {18}, number = {15}, pages = {}, pmid = {34360133}, issn = {1660-4601}, mesh = {*Alzheimer Disease/diagnosis ; *Apathy ; Caregivers ; Humans ; Observational Studies as Topic ; Quality of Life ; Surveys and Questionnaires ; }, abstract = {Apathy, a common neuropsychiatric symptom associated with dementia, has a strong impact on patients' and caregivers' quality of life. However, it is still poorly understood and hard to define. The main objective of the ECOCAPTURE programme is to define a behavioural signature of apathy using an ecological approach. Within this program, ECOCAPTURE@HOME is an observational study which aims to validate a method based on new technologies for the remote monitoring of apathy in real life. For this study, we plan to recruit 60 couples: 20 patient-caregiver dyads in which patients suffer from behavioral variant Fronto-Temporal Dementia, 20 patient-caregiver dyads in which patients suffer from Alzheimer Disease and 20 healthy control couples. These dyads will be followed for 28 consecutive days via multi-sensor bracelets collecting passive data (acceleration, electrodermal activity, blood volume pulse). Active data will also be collected by questionnaires on a smartphone application. Using a pool of metrics extracted from these passive and active data, we will validate a measurement model for three behavioural markers of apathy (i.e., daytime activity, quality of sleep, and emotional arousal). The final purpose is to facilitate the follow-up and precise diagnosis of apathy, towards a personalised treatment of this condition within everyday life.}, }
@article {pmid34357949, year = {2021}, author = {Arce-López, B and Alvarez-Erviti, L and De Santis, B and Izco, M and López-Calvo, S and Marzo-Sola, ME and Debegnach, F and Lizarraga, E and López de Cerain, A and González-Peñas, E and Vettorazzi, A}, title = {Biomonitoring of Mycotoxins in Plasma of Patients with Alzheimer's and Parkinson's Disease.}, journal = {Toxins}, volume = {13}, number = {7}, pages = {}, pmid = {34357949}, issn = {2072-6651}, support = {Project-43, 2019 modality A//Departamento de Salud, Gobierno de Navarra/ ; AGL2017-85732-R//Ministerio de Economía, Industria y Competitividad, Gobierno de España/ ; }, abstract = {Exposure to environmental contaminants might play an important role in neurodegenerative disease pathogenesis, such as Parkinson´s disease (PD) and Alzheimer´s disease (AD). For the first time in Spain, the plasmatic levels of 19 mycotoxins from patients diagnosed with a neurodegenerative disease (44 PD and 24 AD) and from their healthy companions (25) from La Rioja region were analyzed. The studied mycotoxins were aflatoxins B1, B2, G1, G2 and M1, T-2 and HT-2, ochratoxins A (OTA) and B (OTB), zearalenone, sterigmatocystin (STER), nivalenol, deoxynivalenol, 3-acetyldeoxynivalenol, 15-acetyldeoxynivalenol, deepoxy-deoxynivalenol, neosolaniol, diacetoxyscirpenol and fusarenon-X. Samples were analyzed by LC-MS/MS before and after treatment with β-glucuronidase/arylsulfatase in order to detect potential metabolites. Only OTA, OTB and STER were detected in the samples. OTA was present before (77% of the samples) and after (89%) the enzymatic treatment, while OTB was only detectable before (13%). Statistically significant differences in OTA between healthy companions and patients were observed but the observed differences might seem more related to gender (OTA levels higher in men, p-value = 0.0014) than the disease itself. STER appeared only after enzymatic treatment (88%). Statistical analysis on STER, showed distributions always different between healthy controls and patients (patients' group > controls, p-value < 0.0001). Surprisingly, STER levels weakly correlated positively with age in women (rho = 0.3384), while OTA correlation showed a decrease of levels with age especially in the men with PD (rho = -0.4643).}, }
@article {pmid34338566, year = {2021}, author = {Boada, M and Martínez-Lage, P and Serrano-Castro, P and Costa, M and Páez, A}, title = {Therapeutic plasma exchange with albumin: a new approach to treat Alzheimer's disease.}, journal = {Expert review of neurotherapeutics}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/14737175.2021.1960823}, pmid = {34338566}, issn = {1744-8360}, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a chronic neurodegenerative disease and the most common cause of dementia. It has a complex pathophysiology that is not yet completely understood, where multiple central, systemic, and environmental factors play a key role in disease progression. Understanding the multifactorial nature of AD is paramount to formulate new therapies.
AREAS COVERED: The authors reviewed the role of the amyloid-β-binding, antioxidant, and immunomodulatory properties of albumin in AD and the use of therapeutic plasma exchange (PE) in neurology. The results from the Alzheimer Management By Albumin Replacement (AMBAR) trial that combined the use of PE with albumin replacement in patients with mild-to-moderate AD, are also analyzed.
EXPERT OPINION: Findings from the AMBAR study provide encouraging results in the treatment of AD with PE and albumin replacement, especially in patients at the moderate stage of the disease, who showed less cognitive decline from baseline compared with placebo in most of the variables analyzed. Further research is warranted to ascertain the possible mechanisms of action underlying these results. Different cohorts of patients that may also benefit from this treatment, such as those with mild cognitive impairment or other types of dementia, could also be the target of additional studies.}, }
@article {pmid34338277, year = {2021}, author = {Tsuji, K and Ishii, T and Kobayakawa, T and Ohashi, N and Nomura, W and Tamamura, H}, title = {Fluorescence resonance energy transfer-based screening for protein kinase C ligands using 6-methoxynaphthalene-labeled 1,2-diacylglycerol-lactones.}, journal = {Organic & biomolecular chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1039/d1ob00814e}, pmid = {34338277}, issn = {1477-0539}, abstract = {Protein kinase C (PKC) is associated with a central cellular signal transduction pathway and disorders such as cancer and Alzheimer-type dementia and is therefore a target for the treatment of these diseases. The development of simple methods suitable for high-throughput screening to find potent PKC ligands is desirable. We have developed an assay based on fluorescence-quenching screening with a solvatochromic fluorophore attached to a competitive probe and its alternative method based on Förster/fluorescence resonance energy transfer (FRET) phenomena. Here, an improved FRET-based PKC binding assay using a diacylglycerol (DAG) lactone labeled with a donor fluorescent dye, 6-methoxynaphthalene (6MN), was developed. The 6MN-labeled DAG-lactone has a higher binding affinity for the PKCδ C1b domain and the fluorescent PKCδ C1b domain labeled by fluorescein as an acceptor fluorescent dye (Fl-δC1b) than the diethylaminocoumarin (DEAC)-labeled DAG-lactone. The combination of the 6MN-labeled DAG-lactone and Fl-δC1b showed a change in fluorescence response larger than that of the DEAC-labeled DAG-lactone and Fl-δC1b. The IC50 values of known PKC ligands calculated by the present FRET-based method using 6MN-labeled DAG-lactone agree well with the Ki values obtained by the conventional radioisotope-based assays. Some false positive compounds, identified by the previous solvatochromic fluorophore-based method, were found to be negative by this method. The present FRET-based PKC binding assay is more sensitive and could be more useful.}, }
@article {pmid34333330, year = {2021}, author = {Zhang, YM and Zheng, T and Huang, TT and Gu, PP and Gou, LS and Ma, TF and Liu, YW}, title = {Sarsasapogenin attenuates Alzheimer-like encephalopathy in diabetes.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {91}, number = {}, pages = {153686}, doi = {10.1016/j.phymed.2021.153686}, pmid = {34333330}, issn = {1618-095X}, abstract = {BACKGROUND: A crosstalk exists between diabetes and Alzheimer's disease (AD), and diabetic encephalopathy displays AD-like disorders. Sarsasapogenin (Sar) has strong anti-inflammatory efficacy, showing neuroprotection and memory-enhancement effects.
PURPOSE: This study aims to verify the ameliorative effects of Sar on diabetic encephalopathy in vivo and in vitro, and to clarify the mechanisms from attenuation of AD-like pathology.
METHODS: Streptozotocin-induced type 1 diabetic rats and high glucose-cultured SH-SY5Y cells were used in this study. After Sar treatment (20 and 60 mg/kg) for consecutive 9 weeks, Morris water maze and novel object recognition tasks were performed. Hematoxylin-eosin staining was used for examining loss of neurons in CA1 area and ki67 expression for reflecting neurogenesis in DG area of hippocampus. Aβ production pathway and tau phosphorylation kinase cascade were examined in these two models.
RESULTS: Sar improved learning and memory ability, loss of neurons and reduction of neurogenesis in the hippocampus of diabetic rats. Moreover, Sar suppressed Aβ overproduction due to up-regulation of BACE1 in protein and mRNA and tau hyperphosphorylation from inactivation of AKT/GSK-3β cascade in the hippocampus and cerebral cortex of diabetic rats and high glucose-cultured SH-SY5Y cells, and PPARγ antagonism abolished the effects of Sar on key molecules in the two pathways. Additionally, it was found that high glucose-stimulated Aβ overproduction was prior to tau hyperphosphorylation in neurons.
CONCLUSION: Sar alleviated diabetic encephalopathy, which was obtained through inhibitions of Aβ overproduction and tau hyperphosphorylation mediated by the activation of PPARγ signaling. Hence, Sar is a good candidate compound for AD-like disorders.}, }
@article {pmid34322508, year = {2021}, author = {Sukkar, SG and Muscaritoli, M}, title = {A Clinical Perspective of Low Carbohydrate Ketogenic Diets: A Narrative Review.}, journal = {Frontiers in nutrition}, volume = {8}, number = {}, pages = {642628}, pmid = {34322508}, issn = {2296-861X}, abstract = {Low carbohydrates diets (LCDs), which provide 20-120 g of carbohydrates per day, have long been used as therapeutic options in the treatment of severe obesity, type 2 diabetes mellitus and other morbid conditions, with good results in terms of weight loss and control of the main metabolic parameters, at least in the short and medium term. According to the caloric content and the macronutrient composition, we can classify LCDs in hypocaloric, normoproteic diets [such as the Very Low-Calorie Ketogenic Diet (VLCKD) or the protein-sparing modified fasting (PSMF)], hypocaloric, hyperproteic and hyperlipidic diets (e.g., Atkins, Paleo diets…) and normocaloric, normo-/hyperproteic diets (eucaloric KD), the latter mainly used in patients with brain tumors (gliomas) and refractory epilepsy. In addition to LCD diets, another interesting dietary approach which gained attention in the last few decades is fasting and its beneficial effects in terms of modulation of metabolic pathways, cellular processes and hormonal secretions. Due to the impossibility of using fasting regimens for long periods of time, several alternative strategies have been proposed that can mimic the effects, including calorie restriction, intermittent or alternating fasting, and the so-called fasting mimicking diets (FMDs). Recent preclinical studies have shown positive effects of FMDs in various experimental models of tumors, diabetes, Alzheimer Disease, and other morbid conditions, but to date, the scientific evidence in humans is limited to some opens studies and case reports. The purpose of our narrative review is to offer an overview of the characteristics of the main dietary regimens applied in the treatment of different clinical conditions as well as of the scientific evidence that justifies their use, focusing on low and zero-carb diets and on the different types of fasting.}, }
@article {pmid34315132, year = {2021}, author = {Zeng, P and Fang, M and Zhao, H and Guo, J}, title = {A network pharmacology approach to uncover the key ingredients in Ginkgo Folium and their anti-Alzheimer's disease mechanisms.}, journal = {Aging}, volume = {13}, number = {14}, pages = {18993-19012}, pmid = {34315132}, issn = {1945-4589}, abstract = {This study aimed to identify potential anti-Alzheimer's disease (AD) targets and action mechanisms of Ginkgo Folium (GF) through a network pharmacology approach. Eighty-four potential targets of 10 active anti-AD ingredients of GF were identified, among which genkwanin (GK) had the greatest number of AD-related targets. KEGG pathway enrichment analysis showed that the most significantly enriched signaling pathway of GF against AD was Alzheimer disease (hsa05010). More importantly, 29 of the 84 targets were significantly correlated with tau, Aβ or both Aβ and tau pathology. In addition, GO analysis suggested that the main biological processes of GF in AD treatment were the regulation of chemical synaptic transmission (GO:0007268), neuron death (GO:0070997), amyloid-beta metabolic process (GO:0050435), etc. We further investigated the anti-AD effects of GK using N2A-APP cells (a classical cellular model of AD). Treatment N2A-APP cells with 100 μM GK for 48 h affected core targets related to tau pathology (such as CDK5 and GSK3β). In conclusion, these findings indicate that GF exerts its therapeutic effects on AD by acting directly on multiple pathological processes of AD.}, }
@article {pmid34299575, year = {2021}, author = {Huang, Y and Chang, Y and Liu, L and Wang, J}, title = {Nanomaterials for Modulating the Aggregation of β-Amyloid Peptides.}, journal = {Molecules (Basel, Switzerland)}, volume = {26}, number = {14}, pages = {}, pmid = {34299575}, issn = {1420-3049}, support = {22076221//National Natural Science Foundation of China/ ; 21IRTSTHN005//Program for Innovative Research Team of Science and Technology in the University of Henan Province/ ; }, abstract = {The aberrant aggregation of amyloid-β (Aβ) peptides in the brain has been recognized as the major hallmark of Alzheimer's disease (AD). Thus, the inhibition and dissociation of Aβ aggregation are believed to be effective therapeutic strategiesforthe prevention and treatment of AD. When integrated with traditional agents and biomolecules, nanomaterials can overcome their intrinsic shortcomings and boost their efficiency via synergistic effects. This article provides an overview of recent efforts to utilize nanomaterials with superior properties to propose effective platforms for AD treatment. The underlying mechanismsthat are involved in modulating Aβ aggregation are discussed. The summary of nanomaterials-based modulation of Aβ aggregation may help researchers to understand the critical roles in therapeutic agents and provide new insight into the exploration of more promising anti-amyloid agents and tactics in AD theranostics.}, }
@article {pmid34297074, year = {2021}, author = {Insel, PS and Mohlenhoff, BS and Neylan, TC and Krystal, AD and Mackin, RS}, title = {Association of Sleep and β-Amyloid Pathology Among Older Cognitively Unimpaired Adults.}, journal = {JAMA network open}, volume = {4}, number = {7}, pages = {e2117573}, pmid = {34297074}, issn = {2574-3805}, abstract = {Importance: Disrupted sleep commonly occurs with progressing neurodegenerative disease. Large, well-characterized neuroimaging studies of cognitively unimpaired adults are warranted to clarify the magnitude and onset of the association between sleep and emerging β-amyloid (Aβ) pathology.
Objective: To evaluate the associations between daytime and nighttime sleep duration with regional Aβ pathology in older cognitively unimpaired adults.
In this cross-sectional study, screening data were collected between April 1, 2014, and December 31, 2017, from healthy, cognitively unimpaired adults 65 to 85 years of age who underwent florbetapir F 18 positron emission tomography (PET), had APOE genotype information, scored between 25 and 30 on the Mini-Mental State Examination, and had a Clinical Dementia Rating of 0 for the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study. Data analysis was performed from December 1, 2019, to May 10, 2021.
Exposures: Self-reported daytime and nighttime sleep duration.
Main Outcomes and Measures: Regional Aβ pathology, measured by florbetapir PET standardized uptake value ratio.
Results: Amyloid PET and sleep duration information was acquired on 4425 cognitively unimpaired participants (mean [SD] age, 71.3 [4.7] years; 2628 [59.4%] female; 1509 [34.1%] tested Aβ positive). Each additional hour of nighttime sleep was associated with a 0.005 reduction of global Aβ standardized uptake value ratio (F1, 4419 = 5.0; P = .03), a 0.009 reduction of medial orbitofrontal Aβ (F1, 4419 = 17.4; P < .001), and a 0.011 reduction of anterior cingulate Aβ (F1, 4419 = 15.9; P < .001). When restricting analyses to participants who tested Aβ negative, nighttime sleep was associated with a 0.006 reduction of medial orbitofrontal Aβ (F1,2910 = 16.9; P < .001) and a 0.005 reduction of anterior cingulate Aβ (F1,2910 = 7.6; P = .03). Daytime sleep was associated with a 0.013 increase of precuneus Aβ (F1,2910 = 7.3; P = .03) and a 0.024 increase of posterior cingulate Aβ (F1,2910 = 14.2; P = .001) in participants who tested Aβ negative.
Conclusions and Relevance: In this cross-sectional study, the increased risk of Aβ deposition with reduced nighttime sleep duration occurred early, before cognitive impairment or significant Aβ deposition. Daytime sleep may be associated with an increase in risk for early Aβ accumulation and did not appear to be corrective for loss of nighttime sleep, demonstrating a circadian rhythm dependence of sleep in preventing Aβ accumulation. Treatments that improve sleep may reduce early Aβ accumulation and aid in delaying the onset of cognitive dysfunction associated with early Alzheimer disease.}, }
@article {pmid34295207, year = {2021}, author = {Kwan, KKL and Yun, H and Dong, TTX and Tsim, KWK}, title = {Ginsenosides attenuate bioenergetics and morphology of mitochondria in cultured PC12 cells under the insult of amyloid beta-peptide.}, journal = {Journal of ginseng research}, volume = {45}, number = {4}, pages = {473-481}, pmid = {34295207}, issn = {1226-8453}, abstract = {Background: Mitochondrial dysfunction is one of the significant reasons for Alzheimer's disease (AD). Ginsenosides, natural molecules extracted from Panax ginseng, have been demonstrated to exert essential neuroprotective functions, which can ascribe to its anti-oxidative effect, enhancing central metabolism and improving mitochondrial function. However, a comprehensive analysis of cellular mitochondrial bioenergetics after ginsenoside treatment under Aβ-oxidative stress is missing.
Methods: The antioxidant activities of ginsenoside Rb1, Rd, Re, Rg1 were compared by measuring the cell survival and reactive oxygen species (ROS) formation. Next, the protective effects of ginsenosides of mitochondrial bioenergetics were examined by measuring oxygen consumption rate (OCR) in PC12 cells under Aβ-oxidative stress with an extracellular flux analyzer. Meanwhile, mitochondrial membrane potential (MMP) and mitochondrial dynamics were evaluated by confocal laser scanning microscopy.
Results: Ginsenoside Rg1 possessed the strongest anti-oxidative property, and which therefore provided the best protective function to PC12 cells under the Aβ oxidative stress by increasing ATP production to 3 folds, spare capacity to 2 folds, maximal respiration to 2 folds and non-mitochondrial respiration to 1.5 folds, as compared to Aβ cell model. Furthermore, ginsenoside Rg1 enhanced MMP and mitochondrial interconnectivity, and simultaneously reduced mitochondrial circularity.
Conclusion: In the present study, these results demonstrated that ginsenoside Rg1 could be the best natural compound, as compared with other ginsenosides, by modulating the OCR of cultured PC12 cells during oxidative phosphorylation, in regulating MMP and in improving mitochondria dynamics under Aβ-induced oxidative stress.}, }
@article {pmid34294612, year = {2021}, author = {Chiang, TI and Yu, YH and Lin, CH and Lane, HY}, title = {Novel Biomarkers of Alzheimer's Disease: Based Upon N-methyl-D-aspartate Receptor Hypoactivation and Oxidative Stress.}, journal = {Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology}, volume = {19}, number = {3}, pages = {423-433}, pmid = {34294612}, issn = {1738-1088}, abstract = {Early detection and prevention of Alzheimer's disease (AD) is important. The current treatment for early AD is acetylcholine esterase inhibitors (AChEIs); however, the efficacy is poor. Besides, AChEI did not show efficacy in mild cognitive impairment (MCI). Beta-amyloid (A) deposits have been regarded to be highly related to the pathogenesis of AD. However, many clinical trials aiming at the clearance of A deposits failed to improve the cognitive decline of AD, even at its early phase. There should be other important mechanisms unproven in the course of AD and MCI. Feasible biomarkers for the diagnosis and treatment response of AD are lacking to date. The N-methyl-D-aspartate receptor (NMDAR) activation plays an important role in learning and memory. On the other hand, oxidative stress has been regarded to contribute to aging with the assumption that free radicals damage cell constituents and connective tissues. Our recent study found that an NMDAR enhancer, sodium benzoate (the pivotal inhibitor of D-amino acid oxidase [DAAO]), improved the cognitive and global function of patients with early-phase AD. Further, we found that peripheral DAAO levels were higher in patients with MCI and AD than healthy controls. We also found that sodium benzoate was able to change the activity of antioxidant. These pieces of evidence suggest that the NMDAR function is associated with anti-oxidation, and have potential to be biomarkers for the diagnosis and treatment response of AD.}, }
@article {pmid34294142, year = {2021}, author = {Ettcheto, M and Sánchez-Lopez, E and Cano, A and Carrasco, M and Herrera, K and Manzine, PR and Espinosa-Jimenez, T and Busquets, O and Verdaguer, E and Olloquequi, J and Auladell, C and Folch, J and Camins, A}, title = {Dexibuprofen ameliorates peripheral and central risk factors associated with Alzheimer's disease in metabolically stressed APPswe/PS1dE9 mice.}, journal = {Cell & bioscience}, volume = {11}, number = {1}, pages = {141}, pmid = {34294142}, issn = {2045-3701}, support = {SAF2017-84283-R//I+D+I RETOS/ ; CB06/05/0024//CIBERNED/ ; 2015/26084-1//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; 2017/13224-5//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; }, abstract = {BACKGROUND: Several studies stablished a relationship between metabolic disturbances and Alzheimer´s disease (AD) where inflammation plays a pivotal role. However, mechanisms involved still remain unclear. In the present study, we aimed to evaluate central and peripheral effects of dexibuprofen (DXI) in the progression of AD in APPswe/PS1dE9 (APP/PS1) female mice, a familial AD model, fed with high fat diet (HFD). Animals were fed either with conventional chow or with HFD, from their weaning until their sacrifice, at 6 months. Moreover, mice were divided into subgroups to which were administered drinking water or water supplemented with DXI (20 mg kg-1 d-1) for 3 months. Before sacrifice, body weight, intraperitoneal glucose and insulin tolerance test (IP-ITT) were performed to evaluate peripheral parameters and also behavioral tests to determine cognitive decline. Moreover, molecular studies such as Western blot and RT-PCR were carried out in liver to confirm metabolic effects and in hippocampus to analyze several pathways considered hallmarks in AD.
RESULTS: Our studies demonstrate that DXI improved metabolic alterations observed in transgenic animals fed with HFD in vivo, data in accordance with those obtained at molecular level. Moreover, an improvement of cognitive decline and neuroinflammation among other alterations associated with AD were observed such as beta-amyloid plaque accumulation and unfolded protein response.
CONCLUSIONS: Collectively, evidence suggest that chronic administration of DXI prevents the progression of AD through the regulation of inflammation which contribute to improve hallmarks of this pathology. Thus, this compound could constitute a novel therapeutic approach in the treatment of AD in a combined therapy.}, }
@article {pmid34282704, year = {2021}, author = {Sanders, OD and Rajagopal, L and Rajagopal, JA}, title = {Does oxidatively damaged DNA drive amyloid-β generation in Alzheimer's disease? A hypothesis.}, journal = {Journal of neurogenetics}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/01677063.2021.1954641}, pmid = {34282704}, issn = {1563-5260}, abstract = {In Alzheimer's disease (AD), amyloid-β (Aβ) generation and upstream β-secretase 1 (BACE1) expression appear to be driven by oxidative stress via c-Jun N-terminal kinase (JNK), p38, and Interferon-Induced, Double-Stranded RNA-Activated Protein Kinase (PKR). In addition, inflammatory molecules, including lipopolysaccharide (LPS), induce genes central to Aβ genesis, such as BACE1, via nuclear factor-κB (NFκB). However, additional triggers of Aβ generation remain poorly understood and might represent novel opportunities for therapeutic intervention. Based on mechanistic studies and elevated ectopic oxidatively damaged DNA (oxoDNA) levels in preclinical AD, mild cognitive impairment, and AD patients, we hypothesize oxoDNA contributes to β-amyloidosis starting from the earliest stages of AD through multiple pathways. OxoDNA induces mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), thereby sensitizing the brain to oxidative stress-induced JNK activation and BACE1 transcription. It also induces myeloid differentiation primary response 88 (MyD88) and activates protein kinase CK2, thereby increasing NFκB activation and BACE1 induction. OxoDNA increases oxidative stress via nuclear factor erythroid 2-related factor 2 (Nrf2) ectopic localization, likely augmenting JNK-mediated BACE1 induction. OxoDNA likely also promotes β-amyloidosis via absent in melanoma 2 (AIM2) induction. Falsifiable predictions of this hypothesis include that deoxyribonuclease treatment should decrease Aβ and possibly slow cognitive decline in AD patients. While formal testing of this hypothesis remains to be performed, a case report has found deoxyribonuclease I treatment improved a severely demented AD patient's Mini-Mental Status Exam score from 3 to 18 at 2 months. There is preliminary preclinical and clinical evidence suggesting that ectopic oxidatively damaged DNA may act as an inflammatory damage-associated molecular pattern contributing to Aβ generation in AD, and deoxyribonuclease I should be formally evaluated to test whether it can decrease Aβ levels and slow cognitive decline in AD patients.}, }
@article {pmid34276768, year = {2021}, author = {Liu, Z and Li, H and Pan, S}, title = {Discovery and Validation of Key Biomarkers Based on Immune Infiltrates in Alzheimer's Disease.}, journal = {Frontiers in genetics}, volume = {12}, number = {}, pages = {658323}, pmid = {34276768}, issn = {1664-8021}, abstract = {Background: As the most common neurodegenerative disease, Alzheimer's disease (AD) leads to progressive loss of cognition and memory. Presently, the underlying pathogenic genes of AD patients remain elusive, and effective disease-modifying therapy is not available. This study explored novel biomarkers that can affect diagnosis and treatment in AD based on immune infiltration.
Methods: The gene expression profiles of 139 AD cases and 134 normal controls were obtained from the NCBI GEO public database. We applied the computational method CIBERSORT to bulk gene expression profiles of AD to quantify 22 subsets of immune cells. Besides, based on the use of the Least Absolute Shrinkage Selection Operator (LASSO), this study also applied SVM-RFE analysis to screen key genes. GO-based semantic similarity and logistic regression model analyses were applied to explore hub genes further.
Results: There was a remarkable significance in the infiltration of immune cells between the subgroups. The proportions for monocytes, M0 macrophages, and dendritic cells in the AD group were significantly higher than those in the normal group, while the proportion of some cells was lower than that of the normal group, such as NK cell resting, T-cell CD4 naive, T-cell CD4 memory activation, and eosinophils. Additionally, seven genes (ABCA2, CREBRF, CD72, CETN2, KCNG1, NDUFA2, and RPL36AL) were identified as hub genes. Then we performed the analysis of immune factor correlation, gene set enrichment analysis (GSEA), and GO based on seven hub genes. The AUC of ROC prediction model in test and validation sets were 0.845 and 0.839, respectively. Eventually, the mRNA expression analysis of ABCA2, NDUFA2, CREBRF, and CD72 revealed significant differences among the seven hub genes and then was confirmed by RT-PCR.
Conclusion: A model based on immune cell infiltration might be used to forecast AD patients' diagnosis, and it provided a new perspective for AD treatment targets.}, }
@article {pmid34276536, year = {2021}, author = {Song, Y and Chen, S and Gao, J and Lu, J and Xu, W and Lin, X and Chen, J}, title = {Case Report: Coexistence of Anti-AMPA Receptor Encephalitis and Positive Biomarkers of Alzheimer's Disease.}, journal = {Frontiers in neurology}, volume = {12}, number = {}, pages = {673347}, pmid = {34276536}, issn = {1664-2295}, abstract = {Anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor encephalitis is a rare autoimmune disease that is characterized by acute cognitive impairment, mental symptoms, and seizures. The high comorbidity rate between anti-AMPA receptor (AMPAR) encephalitis and other somatic diseases, such as malignancy, has revealed the possibility of potential copathogenesis. However, there have not yet been reports about anti-AMPAR encephalitis with concomitant cerebrospinal fluid (CSF) biomarkers consistent with Alzheimer disease (AD). Herein, we present the case of an elderly male patient with autoimmune encephalitis (AE) presenting with anti-AMPA1-R and anti-AMPA2-R antibodies, as well as CSF biomarkers of AD. The patient was hospitalized with acute memory decline for 1 week. Anti-AMPA1-R and anti-AMPA2-R antibodies were positively detected in CSF, and the anti-AMPA2-R antibody was also present in the serum. Additionally, the biomarkers of AD were concurrently present in CSF (Aβ1-42 = 245.70 pg/mL, t-Tau = 894.48 pg/mL, p-Tau = 78.66 pg/mL). After administering a combined treatment of intravenous immunoglobulin and glucocorticoids, the patient recovered significantly, and his cognitive function achieved a sustained remission during 2 months' follow-up. This case raises the awareness of a possible interaction between AE and changes of CSF biomarkers. We speculated that the existence of AMPAR antibodies can induce changes of CSF, and other pathological alterations. This present report highlights that a potential relationship exists among AE and provides a warning when making the diagnosis of AD.}, }
@article {pmid34274727, year = {2021}, author = {Ritwiset, A and Khajonrit, J and Krongsuk, S and Maensiri, S}, title = {Molecular insight on the formation structure and dynamics of melatonin in an aqueous solution and at the Water-Air interface: A molecular dynamics study.}, journal = {Journal of molecular graphics & modelling}, volume = {108}, number = {}, pages = {107983}, doi = {10.1016/j.jmgm.2021.107983}, pmid = {34274727}, issn = {1873-4243}, abstract = {Melatonin is a natural hormone that has been shown highly antioxidant effects. Consequently, it has been extensively studied for its therapeutic potential in several diseases such as insomnia, cardiovascular, Alzheimer, and certain types of cancers. Recently, it has been used to adjuvant treatment for COVID-19 patients. It is well-known that melatonin is highly hydrophobic, resulting in lower solubility. However, the molecular structure and dynamic behavior of the formation of melatonin in an aqueous solution and at the water-air interface have not yet been clearly explained. This information is necessary for the melatonin formulation in drug delivery systems. The present work focuses on the molecular structure and dynamics of melatonin molecules in the aqueous solution and at the water-air interface based on using a molecular dynamics simulation study. The results showed that most melatonin molecules were aggregated in an aqueous solution while they were formed a self-assembled monolayer with the ordered structure at the water-air interface. The strong interaction of melatonin depends on their functional group which showed a similar trend for both systems and was sequenced as follows: carbonyl O > indole NH > amide NH > methoxy OA, respectively. However, the carbonyl O and the indole NH groups exhibit strong interactions with water molecules at the interface. Consequently, the two preferred orientations of the melatonin head group can be observed at the water-air interface (i.e., one is to turn the head group to the water surface with the tilted angle of ~40°-60° and the second one is to turn the head group away from the water surface with the tilted angle of ~130°). The longer lifetime of hydrogen bonds formed between melatonin themselves in the bulk water reveals that the stability of melatonin aggregation in an aqueous solution is more stable. Therefore, melatonin has less soluble in an aqueous solution.}, }
@article {pmid34268646, year = {2021}, author = {Ousta, A and Piao, L and Fang, YH and Vera, A and Nallamothu, T and Garcia, AJ and Sharp, WW}, title = {Microglial Activation and Neurological Outcomes in a Murine Model of Cardiac Arrest.}, journal = {Neurocritical care}, volume = {}, number = {}, pages = {}, pmid = {34268646}, issn = {1556-0961}, support = {R01 HL133675/HL/NHLBI NIH HHS/United States ; RO1HL133675/NH/NIH HHS/United States ; T32HL007381/HL/NHLBI NIH HHS/United States ; R01NS10742101/NH/NIH HHS/United States ; }, abstract = {BACKGROUND: Neurological injury following successful resuscitation from sudden cardiac arrest (CA) is common. The pathophysiological basis of this injury remains poorly understood, and treatment options are limited. Microglial activation and neuroinflammation are established contributors to many neuropathologies, such as Alzheimer disease and traumatic brain injury, but their potential role in post-CA injury has only recently been recognized. Here, we hypothesize that microglial activation that occurs following brief asystolic CA is associated with neurological injury and represents a potential therapeutic target.
METHODS: Adult C57BL/6 male and female mice were randomly assigned to 12-min, KCl-induced asystolic CA, under anesthesia and ventilation, followed by successful cardiopulmonary resuscitation (n = 19) or sham intervention (n = 11). Neurological assessments of mice were performed using standardized neurological scoring, video motion tracking, and sensory/motor testing. Mice were killed at 72 h for histological studies; neuronal degeneration was assessed using Fluoro-Jade C staining. Microglial characteristics were assessed by immunohistochemistry using the marker of ionized calcium binding adaptor molecule 1, followed by ImageJ analyses for cell integrity density and skeletal analyses.
RESULTS: Neurological injury in post-cardiopulmonary-resuscitation mice vs. sham mice was evident by poorer neurological scores (difference of 3.626 ± 0.4921, 95% confidence interval 2.618-4.634), sensory and motor functions (worsened by sixfold and sevenfold, respectively, compared with baseline), and locomotion (75% slower with a 76% decrease in total distance traveled). Post-CA brains demonstrated evidence of neurodegeneration and neuroinflammatory microglial activation.
CONCLUSIONS: Extensive microglial activation and neurodegeneration in the CA1 region and the dentate gyrus of the hippocampus are evident following brief asystolic CA and are associated with severe neurological injury.}, }
@article {pmid34262831, year = {2021}, author = {Qi, X and Nizamutdinov, D and Berman, MH and Dougal, G and Chazot, PL and Wu, E and Stevens, AB and Yi, SS and Huang, JH}, title = {Gender Differences of Dementia in Response to Intensive Self-Administered Transcranial and Intraocular Near-Infrared Stimulation.}, journal = {Cureus}, volume = {13}, number = {7}, pages = {e16188}, pmid = {34262831}, issn = {2168-8184}, abstract = {Background Transcranial near-infrared (tNIR) stimulation was proven to be a safe, reliable, and effective treatment for cognitive and behavioral symptoms of dementia. Dementia patients of different genders differ in terms of gross anatomy, biochemistry, genetic profile, clinical presentations, and socio-psychological status. Studies of the tNIR effect on dementia have thus far been gender-neutral, with dementia subjects being grouped based on diagnoses or dementia severity. This trial hereby investigated how dementia subjects of different sex respond to tNIR treatment. Methods A total of 60 patient-caregiver dyads were enrolled and randomized to this double-blind, sham-controlled clinical trial. The tNIR light has a wavelength of 1,060 nm to 1,080 nm and was delivered via a photobiomodulation (PBM) unit. The active PBM unit emits near-infrared (NIR) light while the sham unit does not. The treatment consists of a six-minute tNIR light stimulation session twice daily for eight weeks. Neuropsychological assessments conducted at baseline (week 0) and endline (week 8) were compared within the female and male group and between different sex, respectively. Results Over the course of treatment, active-arm female subjects had a 20.2% improvement in Mini-Mental State Exam (MMSE) (mean 4.8 points increase, p < 0.001) and active-arm male cohort had 19.3% improvement (p < 0.001). Control-arm female subjects had a 6.5% improvement in MMSE (mean 1.5 points increase, p < 0.03) and control-arm male subjects had 5.9% improvement (p = 0.35) with no significant differences in the mean MMSE between female and male subjects in both arms respectively. Other comparison of assessments including Clock Copying and Drawing Test, Logical Memory Test - immediate and delayed recall yielded nominal but not statistically significant differences. No significant differences were observed in the mean MMSE between female and male subjects in both arms respectively before treatment implementation (active arm, p = 0.12; control arm, p = 0.50) at week 0, or after treatment completion (active arm, p = 0.11; control arm, p = 0.74) at week 8. Conclusion Despite differences between female and male dementia subjects, the response to tNIR light stimulation does not demonstrate gender-based differences. Further studies are warranted to refine the tNIR treatment protocol for subjects suffering from dementia or dementia-related symptoms.}, }
@article {pmid34258377, year = {2021}, author = {Keret, O and Staffaroni, AM and Ringman, JM and Cobigo, Y and Goh, SM and Wolf, A and Allen, IE and Salloway, S and Chhatwal, J and Brickman, AM and Reyes-Dumeyer, D and Bateman, RJ and Benzinger, TLS and Morris, JC and Ances, BM and Joseph-Mathurin, N and Perrin, RJ and Gordon, BA and Levin, J and Vöglein, J and Jucker, M and la Fougère, C and Martins, RN and Sohrabi, HR and Taddei, K and Villemagne, VL and Schofield, PR and Brooks, WS and Fulham, M and Masters, CL and Ghetti, B and Saykin, AJ and Jack, CR and Graff-Radford, NR and Weiner, M and Cash, DM and Allegri, RF and Chrem, P and Yi, S and Miller, BL and Rabinovici, GD and Rosen, HJ and , }, title = {Pattern and degree of individual brain atrophy predicts dementia onset in dominantly inherited Alzheimer's disease.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {13}, number = {1}, pages = {e12197}, pmid = {34258377}, issn = {2352-8729}, support = {P01 AG003991/AG/NIA NIH HHS/United States ; P30 AG066444/AG/NIA NIH HHS/United States ; P50 AG005681/AG/NIA NIH HHS/United States ; U19 AG032438/AG/NIA NIH HHS/United States ; }, abstract = {Introduction: Asymptomatic and mildly symptomatic dominantly inherited Alzheimer's disease mutation carriers (DIAD-MC) are ideal candidates for preventative treatment trials aimed at delaying or preventing dementia onset. Brain atrophy is an early feature of DIAD-MC and could help predict risk for dementia during trial enrollment.
Methods: We created a dementia risk score by entering standardized gray-matter volumes from 231 DIAD-MC into a logistic regression to classify participants with and without dementia. The score's predictive utility was assessed using Cox models and receiver operating curves on a separate group of 65 DIAD-MC followed longitudinally.
Results: Our risk score separated asymptomatic versus demented DIAD-MC with 96.4% (standard error = 0.02) and predicted conversion to dementia at next visit (hazard ratio = 1.32, 95% confidence interval [CI: 1.15, 1.49]) and within 2 years (area under the curve = 90.3%, 95% CI [82.3%-98.2%]) and improved prediction beyond established methods based on familial age of onset.
Discussion: Individualized risk scores based on brain atrophy could be useful for establishing enrollment criteria and stratifying DIAD-MC participants for prevention trials.}, }
@article {pmid34255194, year = {2021}, author = {Isik, AT and Erken, N and Yavuz, I and Kaya, D and Ontan, MS and Ates Bulut, E and Dost, FS}, title = {Orthostatic hypotension in patients with Alzheimer's disease: a meta-analysis of prospective studies.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {}, number = {}, pages = {}, pmid = {34255194}, issn = {1590-3478}, abstract = {BACKGROUND: Orthostatic hypotension (OH) is a clinical sign associated with severe adverse health outcomes in older adults. It has been reported to be common in patients with Alzheimer's disease (AD). The present meta-analysis aimed to investigate the prevalence and risk of OH in AD patients.
METHODS: English-language articles published from January 1990 to August 2020 were searched in PubMed, ScienceDirect, Cochrane, and Web of Science with the keywords "Alzheimer" and "autonomic dysfunction" or "dysautonomia" or "postural hypotension" or "orthostatic hypotension." All prospective clinical studies (case-control, cohort, and cross-sectional studies, and randomized controlled trials) that were regarded as pertinent were included in this study. For quality assessment, the Newcastle-Ottawa Scale was used. Odds ratios (OR) and risk ratios (RR) were extracted with 95% confidence intervals (CI) and combined using the random effects model after logarithmic transformation. The prevalence in the AD patients was also combined using the random effects model.
RESULTS: The meta-analysis involved 11 studies (7 case-control and 4 case series) to assess the risk of OH in AD. It was found that AD increased the risk of OH with an RR of 1.98 (95% CI: 0.97-4.04) and an OR of 2.53 (95% CI:1.10-5.86) compared to healthy controls, and OH was present in 28% (95% CI: 0.17-0.40) of 500 AD patients.
CONCLUSION: There is an elevated risk of OH in AD by nearly 2.5-fold. Therefore, the evaluation of postural blood pressure changes should definitely be among the follow-up and treatment goals of AD.}, }
@article {pmid34254991, year = {2021}, author = {Steinbrook, R}, title = {The Accelerated Approval of Aducanumab for Treatment of Patients With Alzheimer Disease.}, journal = {JAMA internal medicine}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamainternmed.2021.4622}, pmid = {34254991}, issn = {2168-6114}, }
@article {pmid34251396, year = {2021}, author = {Mitchell, SL and D'Agata, EMC and Hanson, LC and Loizeau, AJ and Habtemariam, DA and Tsai, T and Anderson, RA and Shaffer, ML}, title = {The Trial to Reduce Antimicrobial Use in Nursing Home Residents With Alzheimer Disease and Other Dementias (TRAIN-AD): A Cluster Randomized Clinical Trial.}, journal = {JAMA internal medicine}, volume = {}, number = {}, pages = {}, pmid = {34251396}, issn = {2168-6114}, abstract = {Importance: Antimicrobials are extensively prescribed to nursing home residents with advanced dementia, often without evidence of infection or consideration of the goals of care.
Objective: To test the effectiveness of a multicomponent intervention to improve the management of suspected urinary tract infections (UTIs) and lower respiratory infections (LRIs) for nursing home residents with advanced dementia.
A cluster randomized clinical trial of 28 Boston-area nursing homes (14 per arm) and 426 residents with advanced dementia (intervention arm, 199 residents; control arm, 227 residents) was conducted from August 1, 2017, to April 30, 2020.
Interventions: The intervention content integrated best practices from infectious diseases and palliative care for management of suspected UTIs and LRIs in residents with advanced dementia. Components targeting nursing home practitioners (physicians, physician assistants, nurse practitioners, and nurses) included an in-person seminar, an online course, management algorithms (posters, pocket cards), communication tips (pocket cards), and feedback reports on prescribing of antimicrobials. The residents' health care proxies received a booklet about infections in advanced dementia. Nursing homes in the control arm continued routine care.
Main Outcomes and Measures: The primary outcome was antimicrobial treatment courses for suspected UTIs or LRIs per person-year. Outcomes were measured for as many as 12 months. Secondary outcomes were antimicrobial courses for suspected UTIs and LRIs when minimal criteria for treatment were absent per person-year and burdensome procedures used to manage these episodes (bladder catherization, chest radiography, venous blood sampling, or hospital transfer) per person-year.
Results: The intervention arm had 199 residents (mean [SD] age, 87.7 [8.0] years; 163 [81.9%] women; 36 [18.1%] men), of which 163 (81.9%) were White and 27 (13.6%) were Black. The control arm had 227 residents (mean [SD] age, 85.3 [8.6] years; 190 [83.7%] women; 37 [16.3%] men), of which 200 (88.1%) were White and 22 (9.7%) were Black. There was a 33% (nonsignificant) reduction in antimicrobial treatment courses for suspected UTIs or LRIs per person-year in the intervention vs control arm (adjusted marginal rate difference, -0.27 [95% CI, -0.71 to 0.17]). This reduction was primarily attributable to reduced antimicrobial use for LRIs. The following secondary outcomes did not differ significantly between arms: antimicrobials initiated when minimal criteria were absent, bladder catheterizations, venous blood sampling, and hospital transfers. Chest radiography use was significantly lower in the intervention arm (adjusted marginal rate difference, -0.56 [95% CI, -1.10 to -0.03]). In-person or online training was completed by 88% of the targeted nursing home practitioners.
Conclusions and Relevance: This cluster randomized clinical trial found that despite high adherence to the training, a multicomponent intervention promoting goal-directed care for suspected UTIs and LRIs did not significantly reduce antimicrobial use among nursing home residents with advanced dementia.
Trial Registration: ClinicalTrials.gov Identifier: NCT03244917.}, }
@article {pmid34246109, year = {2021}, author = {Moghadam, B and Ashouri, M and Roohi, H and Karimi-Jafari, MH}, title = {Computational evidence of new putative allosteric sites in the acetylcholinesterase receptor.}, journal = {Journal of molecular graphics & modelling}, volume = {107}, number = {}, pages = {107981}, doi = {10.1016/j.jmgm.2021.107981}, pmid = {34246109}, issn = {1873-4243}, mesh = {*Acetylcholinesterase/metabolism ; Allosteric Site ; Binding Sites ; *Cholinesterase Inhibitors/pharmacology ; Molecular Docking Simulation ; }, abstract = {Acetylcholinesterase (AChE), with a rigid structure and buried active site at the end of a deep narrow gorge, is interesting enough to solve the paradox between high catalytic activity and unavailability of the active site in treatment of Alzheimer's disease (AD). In this way, the blind docking process is performed on an ensemble of AChE structures created with molecular dynamics (MD) simulations to survey the whole space of AChE to find multiple access pathways to the active site and ranking them based on their affinity scores. Our results show that there are other allosteric binding sites in the protein structure whose inhibition, can affect protein function by disrupting the release of the Acetylcholine (AC) degradation products. In this study, inhibitory activities of Hybride14 and two natural compounds (Papaverine and Palmatine) were evaluated for all possible allosteric sites via docking method. The results confirmed the non-competitive inhibition mechanism. The best binding mode for these inhibitors and efficacy of hydrogen bonds and hydrophobic interactions on inhibitory activities of ligands were also disclosed. Furthermore, our studies provide significant molecular insight for AChE inhibition that could aid in the development of new drugs for AD's treatment.}, }
@article {pmid34245772, year = {2021}, author = {Patwardhan, AG and Belemkar, S}, title = {An update on Alzheimer's disease: Immunotherapeutic agents, stem cell therapy and gene editing.}, journal = {Life sciences}, volume = {282}, number = {}, pages = {119790}, doi = {10.1016/j.lfs.2021.119790}, pmid = {34245772}, issn = {1879-0631}, mesh = {Alzheimer Disease/genetics/immunology/*therapy ; Animals ; Gene Editing/methods ; Genetic Therapy/methods ; Humans ; Immunotherapy/methods ; Stem Cell Transplantation/methods ; }, abstract = {Alzheimer's disease is a chronic lifestyle ailment whose occurrence has come to light with the increasing life expectancy due to better healthcare. The patient burden for AD is set to double by the year 2060 and advancement in research is of utmost importance to combat this problem. AD is characterized by the pathological hallmarks of amyloid plaques and neurofibrillary tangles. The disease has been implicated to have a genetic predisposition. The current treatment strategies are at best ameliorative in nature and offer no substantive cure. Immunotherapeutic approaches employed have shown few therapeutic benefits but the accelerated approval of aducanumab by the US-FDA shows clinical benefit merit. In addition, newer therapeutic approaches are the need of the hour. This review aims to highlight the pathology of the disease, followed by an insight into newer approaches like stem cell therapy and gene editing, focusing on possible CRISPR mediated targets.}, }
@article {pmid34242671, year = {2021}, author = {Ilieva, K and Atanasova, M and Atanasova, D and Kortenska, L and Tchekalarova, J}, title = {Chronic agomelatine treatment alleviates icvAβ-induced anxiety and depressive-like behavior through affecting Aβ metabolism in the hippocampus in a rat model of Alzheimer's disease.}, journal = {Physiology & behavior}, volume = {239}, number = {}, pages = {113525}, doi = {10.1016/j.physbeh.2021.113525}, pmid = {34242671}, issn = {1873-507X}, abstract = {Recently, we reported that the atypical antidepressant agomelatine (Ago) exerted a beneficial impact on behavioral changes and concomitant neuropathological events in icvSTZ rat model of sporadic Alzheimer diseases (AD). In the present study, we aimed to explore the effect of Ago (40 mg/kg, i.p. for 30 days) on beta-amyloid (Aβ) metabolism in icvAβ1-42 rat model of AD. The melatonin analogue was administered either simultaneously with Aβ1-42 (AβAgo1) or 30 days later during the late stage of the progression of AD (AβAgo2). Treatment with Ago in the early stage of AD attenuated anxiety and depressive-like responses but was inefficient against Aβ-induced impairment of hippocampus-dependent spatial memory. The melatonin analogue, administered both during the early and the late stage of AD, corrected to control level the elevated Aβ1-42 in the frontal cortex (FC) and the hippocampus. The concentration of α-secretase was enhanced by AβAgo1 compared to the sham- and Aβ-veh groups in the hippocampus. No changes in the concentration of β-secretase in the FC and the hippocampus as well as of γ-secretase in the FC were observed among groups. Both the AβAgo1 and AβAgo2 attenuated to control level the Aβ-induced increased concentration of γ-secretase in the hippocampus. AβAgo1 exerted also structure-specific neuroprotection observed mainly in the CA1, septal CA3b subfield of the dorsal hippocampus and septo-temporal piriform cortex (Pir) and partially in the temporal CA3c, septal and temporal Pir. These findings suggest that Ago treatment in the early stage of AD can exert beneficial effects on concomitant behavioral impairments and neuroprotection in associated brain structures. The antidepressant administration both in the early stage and after the progression of AD affected Aβ metabolism via decreasing of γ-secretase concentration in the hippocampus.}, }
@article {pmid34238525, year = {2021}, author = {Jorge, C and Cetó, M and Arias, A and Blasco, E and Gil, MP and López, R and Dakterzada, F and Purroy, F and Piñol-Ripoll, G}, title = {Level of understanding of Alzheimer disease among caregivers and the general population.}, journal = {Neurologia (Barcelona, Spain)}, volume = {36}, number = {6}, pages = {426-432}, doi = {10.1016/j.nrleng.2018.03.004}, pmid = {34238525}, issn = {2173-5808}, abstract = {INTRODUCTION: Understanding of Alzheimer disease (AD) is fundamental for early diagnosis and to reduce caregiver burden. The objective of this study is to evaluate the degree of understanding of AD among informal caregivers and different segments of the general population through the Alzheimer's Disease Knowledge Scale (ADKS).
PATIENTS AND METHODS: We assessed the knowledge of caregivers in different follow-up periods (less than one year, between 1 and 5 years, and over 5 years since diagnosis) and individuals from the general population. ADKS scores were grouped into different items: life impact, risk factors, symptoms, diagnosis, treatment, disease progression, and caregiving.
RESULTS: A total of 419 people (215 caregivers and 204 individuals from the general population) were included in the study. No significant differences were found between groups for overall ADKS score (19.1 vs 18.8, P = .9). There is a scarce knowledge of disease risk factors (49.3%) or the care needed (51.2%), while symptoms (78.6%) and course of the disease (77.2%) were the best understood aspects. Older caregiver age was correlated with worse ADKS scores overall and for life impact, symptoms, treatment, and disease progression (P < .05). Time since diagnosis improved caregivers' knowledge of AD symptoms (P = .00) and diagnosis (P = .05).
CONCLUSION: Assessing the degree of understanding of AD is essential to the development of health education strategies both in the general population and among caregivers.}, }
@article {pmid34238048, year = {2021}, author = {He, Y and Li, H and Huang, J and Huang, S and Bai, Y and Li, Y and Huang, W}, title = {Efficacy of antidepressant drugs in the treatment of depression in Alzheimer disease patients: A systematic review and network meta-analysis.}, journal = {Journal of psychopharmacology (Oxford, England)}, volume = {35}, number = {8}, pages = {901-909}, doi = {10.1177/02698811211030181}, pmid = {34238048}, issn = {1461-7285}, abstract = {BACKGROUND: Depression is considered as one of the most common neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) patients. Prescription of antidepressants is a current clinical practice well-established as the first-line treatment for such patients. Our study was aimed at systematically examining the evidence on the efficacy of antidepressants in the treatment of depression in AD patients.
METHODS: We conducted a network meta-analysis of randomized controlled trials retrieved by systematic search of the Cochrane Central Register of Controlled Trials, PubMed, Embase, and CNKI databases. Primary outcomes included mean depression score and safety. Secondary outcomes were cognition. The surface under the cumulative ranking curve was performed to estimate a ranking probability for different treatments.
RESULTS: A total of 25 studies including 14 medications met the inclusion criteria. Compared with placebo, only mirtazapine (standard mean deviation [SMD], -1.94; 95% confidence interval [CI], -3.53 to -0.36; p < 0.05) and sertraline (SMD, -1.16; 95% CI, -2.17 to -0.15; p < 0.05) showed a slightly better effect in treating symptoms of depression. Clomipramine increased risk of adverse events than placebo (odds ratio, 3.01; 95% CI, 1.45 to 4.57; p < 0.05). In terms of cognitive function, there was no statistically significant difference between antidepressants and placebo.
CONCLUSION: Overall, in the short-term treatment, these data suggest that commonly used antidepressants sertraline and mirtazapine should be considered as an alternative treatment for depression in AD patients. However, more high-quality trials with large samples and longer following-up are proposed.}, }
@article {pmid34224891, year = {2021}, author = {Lin, F and Zhang, H and Bao, J and Li, L}, title = {Identification of Potential Diagnostic miRNAs Biomarkers for Alzheimer Disease Based on Weighted Gene Coexpression Network Analysis.}, journal = {World neurosurgery}, volume = {153}, number = {}, pages = {e315-e328}, doi = {10.1016/j.wneu.2021.06.118}, pmid = {34224891}, issn = {1878-8769}, abstract = {BACKGROUND: Alzheimer disease (AD) is an age-related neurodegenerative disease that accounts for nearly three fourths of dementia cases. Searching for potential biomarkers will help clinicians in the early diagnosis and treatment of AD.
METHODS: Firstly, we downloaded detailed AD data from the Gene Expression Omnibus (GEO) database for identification of differentially expressed microribonucleic acids (DEmiRNAs) and differentially expressed messenger ribonucleic acids (DEmRNAs). Secondly, functional enrichment analysis was used to identify the biological functions of DEmRNAs. Thirdly, weighted gene coexpression network analysis was used to identify important modules and hub miRNAs. In addition, the miRNA-mRNA regulatory network was constructed. Fourthly, the GSE120584 dataset was used for electronic expression verification and diagnostic analysis. Finally, real-time polymerase chain reaction in vitro verification was performed.
RESULTS: We obtained 1005 DEmiRNAs and 97 DEmRNAs, respectively. Functional enrichment found that DEmRNAs was enriched in the N-glycan biosynthesis pathway, which was associated with AD. In the weighted gene coexpression network analysis, we found that the brown module was the optimal module. Moreover, 11 hub miRNAs were identified. A total of 216 negatively regulated miRNA-mRNA regulation effects are involved. Hub miRNAs were found to have potential diagnostic value in the receiver operating characteristic analysis.
CONCLUSION: Eleven hub miRNAs were identified, and DEmRNAs was found to be significantly enriched in the N-glycan biosynthesis pathway, which contributes to the early diagnosis and treatment of AD.}, }
@article {pmid34224083, year = {2021}, author = {Chen, X and Li, L and Sharma, A and Dhiman, G and Vimal, S}, title = {The Application of Convolutional Neural Network Model in Diagnosis and Nursing of MR Imaging in Alzheimer's Disease.}, journal = {Interdisciplinary sciences, computational life sciences}, volume = {}, number = {}, pages = {}, pmid = {34224083}, issn = {1867-1462}, abstract = {The disease Alzheimer is an irrepressible neurologicalbrain disorder. Earlier detection and proper treatment of Alzheimer's disease can help for brain tissue damage prevention. The study was intended to explore the segmentation effects of convolutional neural network (CNN) model on Magnetic Resonance (MR) imaging for Alzheimer's diagnosis and nursing. Specifically, 18 Alzheimer's patients admitted to Indira Gandhi Medical College (IGMC) hospital were selected as the experimental group, with 18 healthy volunteers in the Ctrl group. Furthermore, the CNN model was applied to segment the MR imaging of Alzheimer's patients, and its segmentation effects were compared with those of the fully convolutional neural network (FCNN) and support vector machine (SVM) algorithms. It was found that the CNN model demonstrated higher segmentation precision, and the experimental group showed a higher clinical dementia rating (CDR) score and a lower mini-mental state examination (MMSE) score (P < 0.05). The size of parahippocompalgyrus and putamen was bigger in the Ctrl (P < 0.05). In experimental group, the amplitude of low-frequency fluctuation (ALFF) was positively correlated with the MMSE score in areas of bilateral cingulum gyri (r = 0.65) and precuneus (r = 0.59). In conclusion, the grey matter structure is damaged in Alzheimer's patients, and hippocampus ALFF and regional homogeneity (ReHo) is involved in the neuronal compensation mechanism of hippocampal damage, and the caregivers should take an active nursing method.}, }
@article {pmid34221150, year = {2021}, author = {Cotoban, AG and Udroiu, CA and Vina, R and Vinereanu, D}, title = {Antithrombotic Strategies in Invasively Managed Patients with Non-ST Elevation Acute Coronary Syndromes and Non-Valvular Atrial Fibrillation in Romania.}, journal = {Maedica}, volume = {16}, number = {1}, pages = {6-15}, pmid = {34221150}, issn = {1841-9038}, abstract = {Introduction: Concomitant atrial fibrillation (AF) in non-ST segment elevation acute coronary syndrome (NSTE-ACS) patients complicates the decision-making process regarding short- and long-term antithrombotic strategies. Patient profiles and usage rates of different antithrombotic combinations in this patient subgroup in Romania are poorly described. Premises and objectives: To describe the characteristics of invasively managed NSTE-ACS patients with AF (either known or newly diagnosed) compared to patients with no oral anticoagulation (OAC) indications, and analyze the rates and factors that influence the different antithrombotic regimens at discharge in AF patients. Material and methods: The Romanian National NSTE-ACS Registry allows the enrollment of invasively managed NSTE-ACS patients admitted in 11 interventional centers. Patients with non-valvular AF and no other OAC indication were identified and compared with patients with no indication for OAC. The antithrombotic strategy at discharge was analyzed based on demographic, clinical, and invasive management characteristics. Outcomes:A total of 1418 patients were enrolled between 2016 and 2019 out of which, 175 AF subjects and 1159 patients with no OAC indication were included in the analysis. Subjects with AF were older (70 ± 8.3 vs 62.9 ± 10.4 years, p <0.001) and more likely to have a GRACE score >140 (aOR 2.28, 95% CI 1.58-3.31, p<0.001), a history of heart failure (aOR 3.07, 95% CI 2.14-4.41, p <0.001), dementia or Alzheimer disease (aOR 3.45, 95% CI 1.11-10.68, p 0.032), and non-fatal major cardiovascular (CV) events during admission (aOR 6.71, 95% CI 1.61-27.94, p 0.009). Globally, triple antithrombotic therapy (TAT) was used in 52.5% of AF patients. 69% of PCI patients received TAT. One in four patients with AF did not receive OAC at discharge. Prior treatment with OAC was the strongest predictor for OAC usage at discharge (aOR 12.34, 95% CI 3.21-47.61, p<0.001). Conclusion: More than one in 10 NSTE-ACS patients have a concomitant non-valvular AF diagnosis. These patients are significantly older and are more likely to have significant CV and non-CV disease. Triple antithrombotic therapy is the most used antithrombotic strategy, especially in the PCI subgroup. One in four NSTE-ACS AF patients do not receive OAC at discharge.}, }
@article {pmid34210995, year = {2021}, author = {Aarsland, D and Batzu, L and Halliday, GM and Geurtsen, GJ and Ballard, C and Ray Chaudhuri, K and Weintraub, D}, title = {Parkinson disease-associated cognitive impairment.}, journal = {Nature reviews. Disease primers}, volume = {7}, number = {1}, pages = {47}, pmid = {34210995}, issn = {2056-676X}, abstract = {Parkinson disease (PD) is the second most common neurodegenerative disorder, affecting >1% of the population ≥65 years of age and with a prevalence set to double by 2030. In addition to the defining motor symptoms of PD, multiple non-motor symptoms occur; among them, cognitive impairment is common and can potentially occur at any disease stage. Cognitive decline is usually slow and insidious, but rapid in some cases. Recently, the focus has been on the early cognitive changes, where executive and visuospatial impairments are typical and can be accompanied by memory impairment, increasing the risk for early progression to dementia. Other risk factors for early progression to dementia include visual hallucinations, older age and biomarker changes such as cortical atrophy, as well as Alzheimer-type changes on functional imaging and in cerebrospinal fluid, and slowing and frequency variation on EEG. However, the mechanisms underlying cognitive decline in PD remain largely unclear. Cortical involvement of Lewy body and Alzheimer-type pathologies are key features, but multiple mechanisms are likely involved. Cholinesterase inhibition is the only high-level evidence-based treatment available, but other pharmacological and non-pharmacological strategies are being tested. Challenges include the identification of disease-modifying therapies as well as finding biomarkers to better predict cognitive decline and identify patients at high risk for early and rapid cognitive impairment.}, }
@article {pmid34207410, year = {2021}, author = {Bures, J and Tacheci, I and Kvetina, J and Radochova, V and Kohoutova, D and Valis, M and Rejchrt, S and Knoblochova, V and Zdarova Karasova, J}, title = {Dextran Sodium Sulphate-Induced Gastrointestinal Injury Further Aggravates the Impact of Galantamine on the Gastric Myoelectric Activity in Experimental Pigs.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {14}, number = {6}, pages = {}, pmid = {34207410}, issn = {1424-8247}, support = {18-13283S//Grantová Agentura České Republiky/ ; }, abstract = {Galantamine has been used as a treatment for Alzheimer disease. It has a unique, dual mode of action (inhibitor of acetylcholinesterase and allosteric modulator of nicotinic acetylcholine receptors). Nausea (in about 20%), vomiting (10%) and diarrhoea (5-7%) are the most common side effects. The aim of this study was to assess the effect of galantamine on porcine gastric myoelectric activity without (Group A) and with (Group B) dextran sodium sulphate (DSS)-induced gastrointestinal injury. Galantamine hydrobromide was administrated to twelve pigs as a single intragastric dose (24 mg). Gastric myoelectric activity was investigated by electrogastrography (EGG). Basal (15 min before galantamine administration) and study recordings after galantamine administration (300 min) were evaluated using a running spectral analysis. Results were expressed as dominant frequency of gastric slow waves and power analysis (areas of amplitudes). Altogether, 3780 one-minute EGG recordings were evaluated. In Group A, power was steady from basal values for 180 min, then gradually decreased till 270 min (p = 0.007). In Group B, there was a rapid gradual fall from basal values to those after 120 min (p = 0.007) till 300 min (p ˂ 0.001). In conclusion, galantamine alone revealed an unfavourable effect on porcine myoelectric activity assessed by gastric power. It can be a plausible explanation of galantamine-associated dyspepsia in humans. DSS caused further profound decrease of EGG power. That may indicate that underlying inflammatory, ischaemic or NSAIDs-induced condition of the intestine in humans can have aggravated the effect of galantamine on gastric myoelectric activity.}, }
@article {pmid34206776, year = {2021}, author = {Benito-Cuesta, I and Ordoñez-Gutierrez, L and Wandosell, F}, title = {Trehalose Reduces the Secreted Beta-Amyloid Levels in Primary Neurons Independently of Autophagy Induction.}, journal = {Metabolites}, volume = {11}, number = {7}, pages = {}, pmid = {34206776}, issn = {2218-1989}, support = {RTI 2018-096303-B-C1//Spanish Ministry of Science, Innovation and University/ ; CAM-Biomedicina, B2017/BMD-3700//Comunidad de Madrid/ ; CIBERNED [PI2016/01].//Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas/ ; }, abstract = {The disaccharide trehalose was described as possessing relevant neuroprotective properties as an mTORC1-independent inducer of autophagy, with the ability to protect cellular membranes and denaturation, resulting from desiccation, and preventing the cellular accumulation of protein aggregates. These properties make trehalose an interesting therapeutic candidate against proteinopathies such as Alzheimer's disease (AD), which is characterized by deposits of aggregated amyloid-beta (Aβ) and hyperphosphorylated tau. In this study, we observed that trehalose was able to induce autophagy in neurons only in the short-term, whereas long-term treatment with trehalose provoked a relevant anti-amyloidogenic effect in neurons from an AD mouse model that was not mediated by autophagy. Trehalose treatment reduced secreted Aβ levels in a manner unrelated to its intracellular accumulation or its elimination through endocytosis or enzymatic degradation. Moreover, the levels of Aβ precursor protein (APP) and beta-secretase (BACE1) remained unaltered, as well as the proper acidic condition of the endo-lysosome system. Instead, our results support that the neuroprotective effect of trehalose was mediated by a reduced colocalization of APP and BACE1 in the cell, and, therefore, a lower amyloidogenic processing of APP. This observation illustrates that the determination of the mechanism, or mechanisms, that associate APP and BACE is a relevant therapeutic target to investigate.}, }
@article {pmid34206456, year = {2021}, author = {Milán-Tomás, Á and Fernández-Matarrubia, M and Rodríguez-Oroz, MC}, title = {Lewy Body Dementias: A Coin with Two Sides?.}, journal = {Behavioral sciences (Basel, Switzerland)}, volume = {11}, number = {7}, pages = {}, pmid = {34206456}, issn = {2076-328X}, abstract = {Lewy body dementias (LBDs) consist of dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), which are clinically similar syndromes that share neuropathological findings with widespread cortical Lewy body deposition, often with a variable degree of concomitant Alzheimer pathology. The objective of this article is to provide an overview of the neuropathological and clinical features, current diagnostic criteria, biomarkers, and management of LBD. Literature research was performed using the PubMed database, and the most pertinent articles were read and are discussed in this paper. The diagnostic criteria for DLB have recently been updated, with the addition of indicative and supportive biomarker information. The time interval of dementia onset relative to parkinsonism remains the major distinction between DLB and PDD, underpinning controversy about whether they are the same illness in a different spectrum of the disease or two separate neurodegenerative disorders. The treatment for LBD is only symptomatic, but the expected progression and prognosis differ between the two entities. Diagnosis in prodromal stages should be of the utmost importance, because implementing early treatment might change the course of the illness if disease-modifying therapies are developed in the future. Thus, the identification of novel biomarkers constitutes an area of active research, with a special focus on α-synuclein markers.}, }
@article {pmid34203763, year = {2021}, author = {Forés-Martos, J and Boullosa, C and Rodrigo-Domínguez, D and Sánchez-Valle, J and Suay-García, B and Climent, J and Falcó, A and Valencia, A and Puig-Butillé, JA and Puig, S and Tabarés-Seisdedos, R}, title = {Transcriptomic and Genetic Associations between Alzheimer's Disease, Parkinson's Disease, and Cancer.}, journal = {Cancers}, volume = {13}, number = {12}, pages = {}, pmid = {34203763}, issn = {2072-6694}, support = {PROMETEOII/2015/021//Generalitat Valenciana/ ; PI17/00719//ISCIII-FEDER/ ; }, abstract = {Alzheimer's (AD) and Parkinson's diseases (PD) are the two most prevalent neurodegenerative disorders in human populations. Epidemiological studies have shown that patients suffering from either condition present a reduced overall risk of cancer than controls (i.e., inverse comorbidity), suggesting that neurodegeneration provides a protective effect against cancer. Reduced risks of several site-specific tumors, including colorectal, lung, and prostate cancers, have also been observed in AD and PD. By contrast, an increased risk of melanoma has been described in PD patients (i.e., direct comorbidity). Therefore, a fundamental question to address is whether these associations are due to shared genetic and molecular factors or are explained by other phenomena, such as flaws in epidemiological studies, exposure to shared risk factors, or the effect of medications. To this end, we first evaluated the transcriptomes of AD and PD post-mortem brain tissues derived from the hippocampus and the substantia nigra and analyzed their similarities to those of a large panel of 22 site-specific cancers, which were obtained through differential gene expression meta-analyses of array-based studies available in public repositories. Genes and pathways that were deregulated in both disorders in each analyzed pair were examined. Second, we assessed potential genetic links between AD, PD, and the selected cancers by establishing interactome-based overlaps of genes previously linked to each disorder. Then, their genetic correlations were computed using cross-trait LD score regression and GWAS summary statistics data. Finally, the potential role of medications in the reported comorbidities was assessed by comparing disease-specific differential gene expression profiles to an extensive collection of differential gene expression signatures generated by exposing cell lines to drugs indicated for AD, PD, and cancer treatment (LINCS L1000). We identified significant inverse associations of transcriptomic deregulation between AD hippocampal tissues and breast, lung, liver, and prostate cancers, and between PD substantia nigra tissues and breast, lung, and prostate cancers. Moreover, significant direct (same direction) associations of deregulation were observed between AD and PD and brain and thyroid cancers, as well as between PD and kidney cancer. Several biological processes, including the immune system, oxidative phosphorylation, PI3K/AKT/mTOR signaling, and the cell cycle, were found to be deregulated in both cancer and neurodegenerative disorders. Significant genetic correlations were found between PD and melanoma and prostate cancers. Several drugs indicated for the treatment of neurodegenerative disorders and cancer, such as galantamine, selegiline, exemestane, and estradiol, were identified as potential modulators of the comorbidities observed between neurodegeneration and cancer.}, }
@article {pmid34191107, year = {2021}, author = {Farhat, A and Panchaud, A and Al-Hajje, A and Lang, PO and Csajka, C}, title = {Ability to detect potentially inappropriate prescribing in older patients: comparative analysis between PIM-Check and STOPP/STARTv2.}, journal = {European journal of clinical pharmacology}, volume = {}, number = {}, pages = {}, pmid = {34191107}, issn = {1432-1041}, abstract = {PURPOSE: Potentially inappropriate prescribing (PIP) is a source of preventable adverse drug events. The objective of this study was a comparative analysis (quantitative and qualitative) between two tools used to detect PIP, PIM-Check and STOPP/START.
METHODS: First, a qualitative analysis (QAC) was conducted to evaluate the concordance between the criteria, which constitute PIM-Check and the gold standard STOPP/START. Second, a retrospective comparative and observational study was performed on the list of treatment at the admission of 50 older patients hospitalized in an acute geriatric ward of a university hospital in Switzerland in 2016 using both tools.
RESULTS: The QAC has shown that 50% (57 criteria) of STOPP/START criteria are fully or partially concordant with those of PIM-Check. The retrospective study was performed on 50 patients aged 87 years, suffering from 5 co-morbidities (min-max 1-11) and treated by of 8 drugs (min-max 2-16), as medians. The prevalence of the detected PIP was 80% by PIM-Check and 90% by STOPP/START. Medication review shows that 4.2 PIP per patient were detected by PIM-Check and 3.5 PIP by STOPP/START among which 1.9 PIP was commonly detected by both tools, as means. PIM-Check detected more PIP related to cardiology, angiology, nephrology, and endocrinology in older patients but missed the PIP related to geriatric syndromes (e.g., fall, dementia, Alzheimer) detected by STOPP/START.
CONCLUSIONS: By using PIM-Check in geriatric settings, some PIP will not be detected. It is considered as a limitation for this tool in this frail population but brings a certain complementarity in other areas of therapy not covered by STOPP/START.}, }
@article {pmid34183022, year = {2021}, author = {Qiao, O and Zhang, X and Zhang, Y and Ji, H and Li, Z and Han, X and Wang, W and Li, X and Wang, J and Liu, C and Gao, W}, title = {Cerebralcare Granule® enhances memantine hydrochloride efficacy in APP/PS1 mice by ameliorating amyloid pathology and cognitive functions.}, journal = {Chinese medicine}, volume = {16}, number = {1}, pages = {47}, pmid = {34183022}, issn = {1749-8546}, support = {NO. 18ZXXYSY00080//the Science and Technology project of Tianjin/ ; No. 81673535//National Natural Science Foundation of China/ ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory deficits and cognitive decline. Current drugs can only relieve symptoms, but cannot really cure AD. Cerebralcare Granule® (CG) is a Traditional Chinese medicine (TCM) containing a variety of biologically active compounds. In our previous studies, CG has shown a beneficial effect against memory impairment in mice caused by D-galactose. However, whether CG can be used as a complementary medicine for the treatment of AD remains unexplored. Here, we use a combination of CG and memantine hydrochloride (Mm) to treat Alzheimer-like pathology and investigate the effects and mechanisms in vivo.
METHODS: The histology of brain was examined with Hematoxylin-eosin (HE) staining, Golgi staining and Thioflavin S staining. ELISA was applied to assess the expression levels or activities of CAT, SOD, GSH-Px, MDA, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (TBIL) in serum, as well as the levels of IL-6, IL-1β, and TNF-α in the mice brain. Western blotting was used to assess the expression of β-secretase (BACE1), amyloid precursor protein (APP), APPβ, APPα, synaptophysin (SYN), growth-associated protein 43 (GAP43), and postsynaptic density 95 (PSD95).
RESULTS: In the present study, the combination group (CG + Mm) significantly attenuated Alzheimer-like behavior without adverse effects in APP/PS1 mice, indicating its high degree of safety and efficacy after long-term treatment. CG + Mm reduced AD pathological biomarker Aβ plaque accumulation by inhibiting BACE1 and APP expression (P < 0.05 or P < 0.001). Besides, the combination group markedly inhibited the levels of IL-1β, IL-6, and TNF-α in hippocampus (P < 0.001), as well as activities of SOD, CAT, and GSH-Px in serum (P < 0.001). By contrast, the combination group improved synaptic plasticity by enhancing SYN, PSD95, and GAP43 expression.
CONCLUSIONS: Taken together, these data supported the notion that CG combined with Mm might ameliorate the cognitive impairment through multiple pathways, suggesting that CG could play a role as complementary medicine to increase anti-AD effect of chemical drugs by reducing Aβ deposition, neuroinflammation, oxidative damage, and improving synaptic plasticity.}, }
@article {pmid34182090, year = {2021}, author = {Abdelmeguid, NE and Khalil, MIM and Elhabet, R and Sultan, AS and Salam, SA}, title = {Combination of docosahexaenoic acid and Ginko biloba extract improves cognitive function and hippocampal tissue damages in a mouse model of Alzheimer's disease.}, journal = {Journal of chemical neuroanatomy}, volume = {116}, number = {}, pages = {101995}, doi = {10.1016/j.jchemneu.2021.101995}, pmid = {34182090}, issn = {1873-6300}, abstract = {Alzheimer's disease (AD) is one of the most common neurodegenerative diseases characterized by a progressive loss of memory and other cognitive functions among elder people. Nowadays, natural antioxidants have been used to recover the quality of life for those with AD. In this study, we investigated, for the first time, the combined effect of docosahexaenoic acid (DHA) and Ginkgo bilobastandardized extract (EGb761) on AD mice. AD was induced in adult male albino mice with AlCl3 (20 mg/kg b.w, i.g.) and D-galactose (D-gal; 120 mg/kg, i.p.) for 90 days. 30 days after induction, mice were treated with DHA (200 mg/kg b.w., i.g.) and EGb761 (200 mg/kg b.w., i.g.) for two months. Our data revealed that the dual treatment of DHA and EGb761 significantly improved cognitive memory and spatial learning abilities in AD-induced mice. The drug treatments preserved the hippocampal CA3 architecture and restored neuronal ultrastructural alterations. Expression of protein phosphatase 2A (PP2A), the most implicated protein phosphatase in AD neurodegeneration, was highly upregulated in the CA3 hippocampus of AD mice treated with DHA and EGb761. Intriguingly, TNF-α expression was significantly reduced in the same group. In conclusion, our findings proved that the combined effect of DHA and EGb761 tended to be potent against the neurodegenerative effect of AlCl3 and D-gal. The applied treatment enhanced neuronal survival and cognitive functions via upregulation of PP2A and restoration of TNF-α expression.}, }
@article {pmid34170456, year = {2021}, author = {Mandour, DA and Bendary, MA and Alsemeh, AE}, title = {Histological and imunohistochemical alterations of hippocampus and prefrontal cortex in a rat model of Alzheimer like-disease with a preferential role of the flavonoid "hesperidin".}, journal = {Journal of molecular histology}, volume = {}, number = {}, pages = {}, pmid = {34170456}, issn = {1567-2387}, abstract = {Alzheimer's disease (AD) is a chronic age-related neurodegenerative disease characterized by degeneration of the central cholinergic neurons, inflammation and oxidative stress in the basal forebrain, prefrontal cortex and hippocampus. Hesperidin (Hesp) is one of the flavonoids havinganti-inflammatory and anti-oxidative properties in some neurodegerative brain lesions. To investigate the possible neuroprotective role of Hespin an AD-like rat model induced experimentally by Scopolamine (Scop). Forty adult male Sprague Dawley rats were randomly allocated into four groups. Group I-(Control), group II-(Hesp) (supplemented orally with 100 mg/kg Hesp for 28 days), group III-(AD) (injected i.p with 1 mg/kg Scop for 9 days) and group IV-(Hesp/AD). At the end of the experiment, behavioral (Y-maze test) and biochemical analysis were carried out along with histological, immunohistochemical and morphometric studies of the hippocampus and prefrontal cortex. AD rats displayed memory impairment in the behavioural paradigm with a concomitant increase of serum TNF-α and IL-1β, while IL-10 decreased significantly. Also, there was a rise of amyloid beta-42 (Aβ-42), acetylcholinesterase (AChE) activity and malondialdehyde (MDA) together with a decrease of reduced glutathione (GSH) in hippocampal and prefrontal homogenate. In addition, sections of the hippocampus and prefrontal cortex revealed obvious histopathological changes, overexpression of p-Tau protein and glial fibrillary acidic protein (GFAP) with a decrease in the expression of synaptophysin (SYN). Contradictorily, pre-treatment with Hesp offset the spatial memory deficits, redox imbalance, Aβ-42 and AChE over activity as well as preserved the histological architecture and attenuated the raised p-Tau protein and GFAP while upregulated SYN immuoreactivity of AD rats. Collectively, our results highlight the potential mitigating role of Hesp in AD-like state in rats and this may presumably raise the possibility of its future implementation as a prophylactic remedy against AD in humans.}, }
@article {pmid34169425, year = {2021}, author = {Zhang, Q and Wang, J and Zhu, L and Jiang, SJ and Liu, J and Wang, LX and Qin, XH}, title = {Ligustrazine Attenuates Hyperhomocysteinemia-induced Alzheimer-like Pathologies in Rats.}, journal = {Current medical science}, volume = {41}, number = {3}, pages = {548-554}, pmid = {34169425}, issn = {2523-899X}, abstract = {Ligustrazine, an alkaloid extracted from the traditional Chinese herbal medicine Ligusticum Chuanxiong Hort, has been clinically applied to treat the cerebrovascular diseases. Hyperhomocysteinemia (Hhcy) is an independent risk factor for Alzheimer's disease (AD). Memory deficits can be caused by Hhcy via pathologies of AD-like tau and amyloid-β (Aβ) in the hippocampus. Here, we investigated whether homocysteine (Hcy) can induce AD-like pathologies and the effects of ligustrazine on these pathologies. The Hcy rat model was constructed by 14-day Hcy injection via vena caudalis, and rats were treated with daily intragastric administration of ligustrazine at the same time. We found that the pathologies of tau and Aβ were induced by Hcy in the hippocampus, while the Hcy-induced tau hyperphosphorylation and Aβ accumulation could be markedly attenuated by simultaneous ligustrazine treatment. Our data demonstrate that ligustrazine may be used as a promising neuroprotective agent to treat the Hcy-induced AD-like pathologies.}, }
@article {pmid34160408, year = {2021}, author = {Lee, S and Kwon, DH and Kim, JY and Kim, Y and Cho, SH and Jung, IC}, title = {Efficacy of Yukmijihwang-tang on symptoms of Alzheimer disease: A protocol for systematic review and meta-analysis.}, journal = {Medicine}, volume = {100}, number = {25}, pages = {e26363}, pmid = {34160408}, issn = {1536-5964}, support = {KSN2021240//Korea Institute of Oriental Medicine/ ; HB16C0044//Ministry of Health and Welfare/ ; }, mesh = {Activities of Daily Living ; Alzheimer Disease/complications/diagnosis/*drug therapy ; Cognition/*drug effects ; Drugs, Chinese Herbal/*administration & dosage/adverse effects ; Humans ; Meta-Analysis as Topic ; Neuropsychological Tests ; Systematic Reviews as Topic ; Treatment Outcome ; }, abstract = {BACKGROUND: Alzheimer disease (AD) is the most common cause of dementia, which may lead to severe memory loss and other cognitive disorders. Yukmijihwang-tang (YMJ), a type of Korean traditional herbal medicine, has been shown to be effective against neurodegenerative diseases. Although a meta-analysis on the efficacy of YMJ on AD exists, the study had some limitations, and there have been several newly published studies assessing the effect of YMJ. Therefore, the purpose of this study is to evaluate the efficacy and safety of YMJ as a treatment for AD through a meta-analysis.
METHODS: A systematic search of the following electronic databases will be conducted to identify eligible studies: MEDLINE (PubMed), Elsevier (EMBASE), The Cochrane Central Register of Controlled Trials (CENTRAL), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Korean Medical Database (KMBASE), Oriental Medicine Advanced Searching Integrated System (OASIS), Korean Traditional Knowledge Portal, Citation Information by NII (CiNii), China National Knowledge Infrastructure (CNKI). All randomized controlled trials assessing the efficacy and safety of YMJ on the symptoms of AD will be included. Two independent reviewers will perform article retrieval, deduplication, data screening, data extraction, quality evaluation, and data analyses using RevMan version 5.4. The Cochrane risk of bias tool will be used to assess the quality of the trials.
RESULTS: This study will provide synthesis of the cognitive function measured with neuropsychological tests, behavioral and psychological symptoms of dementia (BPSD), and activities of daily living (ADL) measured using validated scales. The clinical effective rate and adverse events will also be analyzed to assess the efficacy and safety of YMJ for treating AD.
CONCLUSION: This systematic review will provide evidence for the efficacy and safety of YMJ in AD.
ETHICS AND DISSEMINATION: Ethical approval is not required because individual patient data will not be included in this study. The study findings will be disseminated through conference presentations.}, }
@article {pmid34158563, year = {2021}, author = {Puris, E and Kouřil, Š and Najdekr, L and Loppi, S and Korhonen, P and Kanninen, KM and Malm, T and Koistinaho, J and Friedecký, D and Gynther, M}, title = {Metabolomic and lipidomic changes triggered by lipopolysaccharide-induced systemic inflammation in transgenic APdE9 mice.}, journal = {Scientific reports}, volume = {11}, number = {1}, pages = {13076}, pmid = {34158563}, issn = {2045-2322}, support = {[18-12204S]//Czech Science Foundation Grant/ ; FNOL, 00098892//MH CZ-DRO/ ; }, abstract = {Peripheral infections followed by systemic inflammation may contribute to the onset of Alzheimer`s disease (AD) and accelerate the disease progression later in life. Yet, the impact of systemic inflammation on the plasma and brain tissue metabolome and lipidome in AD has not been investigated. In this study, targeted metabolomic and untargeted lipidomic profiling experiments were performed on the plasma, cortices, and hippocampi of wild-type (WT) mice and transgenic APdE9 mice after chronic lipopolysaccharide (LPS) treatment, as well as saline-treated APdE9 mice. The lipidome and the metabolome of these mice were compared to saline-treated WT animals. In the brain tissue of all three models, the lipidome was more influenced than the metabolome. The LPS-treated APdE9 mice had the highest number of changes in brain metabolic pathways with significant alterations in levels of lysine, myo-inositol, spermine, phosphocreatine, acylcarnitines and diacylglycerols, which were not observed in the saline-treated APdE9 mice. In the WT mice, the effect of the LPS administration on metabolome and lipidome was negligible. The study provided exciting information about the biochemical perturbations due to LPS-induced inflammation in the transgenic AD model, which can significantly enhance our understanding of the role of systemic inflammation in AD pathogenesis.}, }
@article {pmid34149418, year = {2021}, author = {Saleem, U and Hira, S and Anwar, F and Shah, MA and Bashir, S and Baty, RS and Badr, RH and Blundell, R and Batiha, GE and Ahmad, B}, title = {Pharmacological Screening of Viola odorata L. for Memory-Enhancing Effect via Modulation of Oxidative Stress and Inflammatory Biomarkers.}, journal = {Frontiers in pharmacology}, volume = {12}, number = {}, pages = {664832}, pmid = {34149418}, issn = {1663-9812}, abstract = {Purpose: Alzheimer disease (AD) is a progressive neurodegenerative disorder that is caused by neuroinflammation and oxidative stress. The present study aimed to characterize and then investigate the memory-enhancing potential of Viola odorata methanolic extract in lipopolysaccharide (LPS)-treated mice. Methods: V. odorata characterization was done by using the GCMS technique. Neuroinflammation was induced by the intracerebroventricular administration of LPS at a dose of 12 µg. Animals were divided randomly into six groups (n = 10). Group I was normal control, which was given vehicle. Group II was disease control, which received LPS (12 µg) via the intracerebroventricular route. Group III was standard, which was administered with donepezil (3 µg) orally for 21 days. Groups IV-VI were the treatment groups, which were administered with the extract at 100, 200, and 400 mg/kg dose levels orally respectively for 21 days. Groups III-VI received LPS (12 µg) on the first day along with their treatments. During the treatment, the animals were assessed for memory retention by employing different behavioral paradigms namely elevated plus maze, passive avoidance, foot shock and open field. Various mediators [endogenous antioxidants, neurotransmitters, and acetylcholinesterase (AChE)] involved in the pathogenesis of AD were quantified by using the UV spectrophotometric method. Results: Extract-treated groups showed a remarkable improvement in cognitive impairment in all behavioral paradigms. Oxidative stress biomarkers, that is, superoxide dismutase, catalase, and glutathione were raised dose-dependently in the treatment groups with a dose-dependent decrease in the malonaldehyde and AChE levels in the brains of the treated animals. The treatment groups showed decreased levels of inflammatory biomarkers, that is, tumor necrosis factor-alpha, nuclear factor kappa light-chain enhancer of activated β-cells, and cyclo-oxygenase, which supports the therapeutic effectiveness of the treatment. Conclusion: Based on behavioral, oxidative stress biomarker, and neuroinflammatory data, it is concluded that V. odorata possesses memory-enhancing activity and may prove a beneficial role in the management of AD.}, }
@article {pmid34147904, year = {2021}, author = {Gao, Y and Almalki, WH and Afzal, O and Panda, SK and Kazmi, I and Alrobaian, M and Katouah, HA and Altamimi, ASA and Al-Abbasi, FA and Alshehri, S and Soni, K and Ibrahim, IAA and Rahman, M and Beg, S}, title = {Systematic development of lectin conjugated microspheres for nose-to-brain delivery of rivastigmine for the treatment of Alzheimer's disease.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {141}, number = {}, pages = {111829}, doi = {10.1016/j.biopha.2021.111829}, pmid = {34147904}, issn = {1950-6007}, abstract = {The current study focuses on development of nasal mucoadhesive microspheres for nose-to-brain delivery of rivastigmine for Alzheimer treatment. A systematic development was employed for optimization of the formulation and process parameters influential on the quality attributes of the microspheres. The risk assessment study revealed major influence of the polymer concentration (ethylcellulose: chitosan), the concentration of surfactant solution (polyvinyl alcohol), and stirring speed as the critical factors for optimization of the microspheres. These factors were systematically optimized using Box-Behnken design and microspheres were evaluated for the particle size, entrapment efficiency, and in vitro drug release as the response variables. The optimized microspheres containing 4.4% wt/vol polymers, 1% wt/vol surfactant, and stirring speed at 1500 rpm showed particle size of 19.9 µm, entrapment efficiency of 77.8%, and drug release parameters as T80% of 7.3 h. The surface modification of microspheres was performed with lectin by carbodiimide activation reaction and confirmed by difference in surface charge before and after chemical functionalization by zeta potential measurement which was found to be - 25.7 mV and 20.5 mV, respectively. Ex vivo study for bioadhesion strength evaluation on goat nasal mucosa indicated a significant difference (p < 0.001) between the plain (29%) and lectin functionalized microspheres (64%). In vivo behavioral and biochemical studies in the rats treated with lectin functionalized microspheres showed markedly better memory-retention vis-à-vis test and pure drug solution treated rats (p < 0.001). In a nutshell, the present studies showed successful development of nasal microspheres for enhanced brain delivery of rivastigmine for Alzheimer's treatment.}, }
@article {pmid34144624, year = {2021}, author = {Brandt, MD}, title = {[Insomnia in the context of neurological diseases].}, journal = {Fortschritte der Neurologie-Psychiatrie}, volume = {89}, number = {6}, pages = {314-328}, doi = {10.1055/a-1309-0793}, pmid = {34144624}, issn = {1439-3522}, mesh = {Humans ; *Nervous System Diseases/complications/epidemiology/therapy ; Quality of Life ; *Restless Legs Syndrome ; *Sleep Initiation and Maintenance Disorders/complications/epidemiology/therapy ; *Sleep Wake Disorders/epidemiology/therapy ; }, abstract = {This article provides an overview of the prevalence, cause and treatment of insomnia in common neurological diseases (restless legs syndrome, stroke, multiple sclerosis, Parkinson´s disease and Alzheimer´s disease) with an additional focus on the bidirectional relationship between sleep and neurological disorders.Insomnia is prevalent, but frequently unrecognized in the context of neurological diseases. Although it is widely known that sleep has a relevant impact on quality of life in general and cerebral function in particular, sleep disorders receive little attention in the prevention and treatment of neurological diseases.}, }
@article {pmid34144146, year = {2021}, author = {Yang, EJ and Kim, H and Choi, Y and Kim, HJ and Kim, JH and Yoon, J and Seo, YS and Kim, HS}, title = {Modulation of Neuroinflammation by Low-Dose Radiation Therapy in an Animal Model of Alzheimer's Disease.}, journal = {International journal of radiation oncology, biology, physics}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ijrobp.2021.06.012}, pmid = {34144146}, issn = {1879-355X}, abstract = {PURPOSE: Recently, several studies have reported that low-dose radiation therapy (RT) suppresses the release of proinflammatory cytokines in inflammatory-degenerative disorders, including Alzheimer disease (AD). AD is the most common cause of dementia, and neuroinflammation is one of the major contributing factors in AD pathogenesis. Therefore, low-dose RT may be used clinically for treating AD. However, the appropriate doses, effects, and underlying mechanisms of RT in AD have not been determined. In this study, we aimed to determine the appropriate RT dose and schedule for AD treatment and to investigate the therapeutic effects and mechanisms of low-dose RT in AD.
METHODS AND MATERIALS: We first determined the proper dose and schedule for RT in late-stage AD using 8- to 9-month-old 5x Familial AD (5xFAD) mice, a well-known animal model of AD, by comparing the effects of a low total dose with low dose per fraction (LD-LDRT, 5 × 0.6 Gy) with those of a low moderate total dose with conventional dose per fraction (LMD-CDRT, 5 × 2 Gy).
RESULTS: LD-LDRT and LMD-CDRT were found to reduce the levels of the proinflammatory cytokines CD54, IL-3, CXCL9/10, and CCL2/4 in the hippocampus of 5xFAD mice. Furthermore, increased microgliosis assessed using Iba-1 and CD68 dual immunostaining was significantly reduced by LD-LDRT and LMD-CDRT in the hippocampus of 5xFAD mice. Moreover, LD-LDRT and LMD-CDRT decreased the amyloid plaque burden in the hippocampus of 5xFAD mice and attenuated their cognitive impairment; these effects persisted for 4 to 5 weeks.
CONCLUSIONS: The present study showed that LD-LDRT alleviates cognitive impairments and prevents the accumulation of amyloid plaques by regulating neuroinflammation in the late stage of AD in 5xFAD mice, with an efficacy equivalent to that of LMD-CDRT. Furthermore, the findings suggest that compared with LMD-CDRT, LD-LDRT may facilitate accessible and convenient treatment in clinical trials.}, }
@article {pmid34140407, year = {2021}, author = {Doyle, JJ and Maios, C and Vrancx, C and Duhaime, S and Chitramuthu, B and Bennett, HPJ and Bateman, A and Parker, JA}, title = {Chemical and genetic rescue of in vivo progranulin-deficient lysosomal and autophagic defects.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {118}, number = {25}, pages = {}, pmid = {34140407}, issn = {1091-6490}, support = {P40 OD010440/OD/NIH HHS/United States ; }, abstract = {In 2006, GRN mutations were first linked to frontotemporal dementia (FTD), the leading cause of non-Alzheimer dementias. While much research has been dedicated to understanding the genetic causes of the disease, our understanding of the mechanistic impacts of GRN deficiency has only recently begun to take shape. With no known cure or treatment available for GRN-related FTD, there is a growing need to rapidly advance genetic and/or small-molecule therapeutics for this disease. This issue is complicated by the fact that, while lysosomal dysfunction seems to be a key driver of pathology, the mechanisms linking a loss of GRN to a pathogenic state remain unclear. In our attempt to address these key issues, we have turned to the nematode, Caenorhabditis elegans, to model, study, and find potential therapies for GRN-deficient FTD. First, we show that the loss of the nematode GRN ortholog, pgrn-1, results in several behavioral and molecular defects, including lysosomal dysfunction and defects in autophagic flux. Our investigations implicate the sphingolipid metabolic pathway in the regulation of many of the in vivo defects associated with pgrn-1 loss. Finally, we utilized these nematodes as an in vivo tool for high-throughput drug screening and identified two small molecules with potential therapeutic applications against GRN/pgrn-1 deficiency. These compounds reverse the biochemical, cellular, and functional phenotypes of GRN deficiency. Together, our results open avenues for mechanistic and therapeutic research into the outcomes of GRN-related neurodegeneration, both genetic and molecular.}, }
@article {pmid34138642, year = {2021}, author = {Alexander, GC and Karlawish, J}, title = {The Problem of Aducanumab for the Treatment of Alzheimer Disease.}, journal = {Annals of internal medicine}, volume = {}, number = {}, pages = {}, doi = {10.7326/M21-2603}, pmid = {34138642}, issn = {1539-3704}, }
@article {pmid34133789, year = {2021}, author = {Pei, X and Hu, F and Luo, F and Huang, X and Li, X and Xing, S and Long, D}, title = {The neuroprotective effects of alpha-lipoic acid on an experimental model of Alzheimer's disease in PC12 cells.}, journal = {Journal of applied toxicology : JAT}, volume = {}, number = {}, pages = {}, doi = {10.1002/jat.4213}, pmid = {34133789}, issn = {1099-1263}, support = {81673227//National Natural Science Foundation of China/ ; 81001246//National Natural Science Foundation of China/ ; }, abstract = {With the growth of the aging population, the prevalence of Alzheimer's disease (AD) has increased and influenced the work and daily life of AD patients, imposing a heavy burden on society and the patients' families. AD is a progressive disease with a long duration, and the pathogenesis is very complicated. Here, we found that alpha-lipoic acid (LA), an endogenous, naturally synthesized compound, could attenuate amyloid beta fragment (Aβ25-35)-induced PC12 cell toxicity. Aβ25-35 treatment largely decreased the viability of PC12 cells, increased reactive oxygen species (ROS) levels, and increased the percentage of apoptotic cells, which were accompanied by changes in the expression of the apoptosis-related genes. Further, the Wnt pathway was inactivated, and the expression of Wnt pathway-related proteins such as Frizzled2, GSK3β, and phosphorylated GSK3β were dysregulated after Aβ25-35 treatment. LA efficiently attenuated Aβ25-35 -induced PC12 cell apoptosis and downregulated the phosphorylation-mediated degradation of β-catenin as well as GSK3β. Our results demonstrate that LA rescues Aβ25-35 -induced neurocytotoxicity through the Wnt-β-catenin pathway.}, }
@article {pmid34133088, year = {2021}, author = {Burke, AD and Apostolova, L}, title = {Treatment Challenges and the Hope of Emerging Therapies in Early-Stage Alzheimer Disease.}, journal = {The Journal of clinical psychiatry}, volume = {82}, number = {4}, pages = {}, doi = {10.4088/JCP.BG20044AH4C}, pmid = {34133088}, issn = {1555-2101}, abstract = {Alzheimer disease (AD), the most common cause of dementia, is a degenerative brain disease with no cure. In the United States alone, an estimated 5.8 million people are living with AD. More than half of individuals living with AD and other dementias are not getting an accurate diagnosis and, when they do receive one, clinicians are not effectively communicating with patients and care partners regarding the illness and next steps. Additionally, prompt treatment initiation does not occur in a substantial number of newly diagnosed patients. This Academic Highlights addresses best practices for identifying patients with early-stage AD, discussing treatment goals and challenges with patients who have AD and their care partners, employing current medications approved by the U.S. Food and Drug Administration to slow symptom progression, and staying informed about emerging therapies that offer new hope for disease modification.}, }
@article {pmid34129637, year = {2021}, author = {Triunfol, M and Gouveia, FC}, title = {What's not in the news headlines or titles of Alzheimer disease articles? #InMice.}, journal = {PLoS biology}, volume = {19}, number = {6}, pages = {e3001260}, pmid = {34129637}, issn = {1545-7885}, abstract = {There is increasing scrutiny around how science is communicated to the public. For instance, a Twitter account @justsaysinmice (with 70.4K followers in January 2021) was created to call attention to news headlines that omit that mice, not humans, are the ones for whom the study findings apply. This is the case of many headlines reporting on Alzheimer disease (AD) research. AD is characterized by a degeneration of the human brain, loss of cognition, and behavioral changes, for which no treatment is available. Around 200 rodent models have been developed to study AD, even though AD is an exclusively human condition that does not occur naturally in other species and appears impervious to reproduction in artificial animal models, an information not always disclosed. It is not known what prompts writers of news stories to either omit or acknowledge, in the story's headlines, that the study was done in mice and not in humans. Here, we raised the hypothesis that how science is reported by scientists plays a role on the news reporting. To test this hypothesis, we investigated whether an association exists between articles' titles and news' headlines regarding the omission, or not, of mice. To this end, we analyzed a sample of 623 open-access scientific papers indexed in PubMed in 2018 and 2019 that used mice either as models or as the biological source for experimental studies in AD research. We found a significant association (p < 0.01) between articles' titles and news stories' headlines, revealing that when authors omit the species in the paper's title, writers of news stories tend to follow suit. We also found that papers not mentioning mice in their titles are more newsworthy and significantly more tweeted than papers that do. Our study shows that science reporting may affect media reporting and asks for changes in the way we report about findings obtained with animal models used to study human diseases.}, }
@article {pmid34119804, year = {2021}, author = {Montazeri, K and Farhadi, M and Fekrazad, R and Akbarnejad, Z and Chaibakhsh, S and Mahmoudian, S}, title = {Transcranial photobiomodulation in the management of brain disorders.}, journal = {Journal of photochemistry and photobiology. B, Biology}, volume = {221}, number = {}, pages = {112207}, doi = {10.1016/j.jphotobiol.2021.112207}, pmid = {34119804}, issn = {1873-2682}, mesh = {Alzheimer Disease/radiotherapy ; Animals ; Brain Diseases/*radiotherapy ; Brain Injuries, Traumatic/radiotherapy ; Disease Models, Animal ; Humans ; *Low-Level Light Therapy ; Parkinson Disease/radiotherapy ; Randomized Controlled Trials as Topic ; }, abstract = {Transcranial photobiomodulation (tPBM) is the process of delivering light photons through the skull to benefit from its modifying effect. Brain disorders are important health problems. The aim of this review was to determine the existing evidence of effectiveness, useful parameters, and safety of tPBM in the management of traumatic brain injury, stroke, Parkinson, and Alzheimer's disease as the common brain disorders. Four online databases, including Cochrane, Pub Med, Embase, and Google scholar were searched according to the Preferred Reporting Items for Systematic Reviews and meta-analyses (PRISMA) guidelines. 4728 articles were obtained in the initial search. Only those articles that were published until September 2020 and designed as randomized clinical trials (RCTs) or animal-controlled studies were included. 6 RCTs, 2 related supplementary articles, and 38 controlled animal studies met the inclusion criteria of this study. No RCTs were performed in the fields of Alzheimer's and Parkinson's diseases. The human RCTs and animal studies reported no adverse events resulted from the use of tPBM. Useful parameters of tPBM were identified according to the controlled animal studies. Since the investigated RCTs had no homogenous results, making an evidence-based decision for definite therapeutic application of tPBM is still unattainable. Altogether, these data support the need for large confirmatory well-designed RCTs for using tPBM as a novel, safe, and easy-to-administer treatment of brain disorders.
EVIDENCE BEFORE THIS STUDY: High prevalence and complications of brain disorders and also side effects of neuropsychiatric medications have encouraged researchers to find alternative therapeutic techniques which tPBM can be one of them. In present review we tried to determine the existing evidence of effectiveness, useful parameters, and safety of tPBM in the management of traumatic brain injury, stroke, Alzheimer, and Parkinson's disease as common brain disorders. Four online databases, including "Cochrane", "Pub Med", "Embase", and "Google scholar" were searched. Only those articles that were published until September 2020 and designed as RCTs or animal-controlled studies were included. Search keywords were the followings: transcranial photobiomodulation" OR "transcranial low-level laser therapy" AND "stroke" OR "traumatic brain injury" OR "Alzheimer" OR "Parkinson". Several studies have confirmed effectiveness of tPBM in treatment of different brain disorders but the level of evidence of its effectiveness remain to be determined.
ADDED VALUE OF THIS STUDY: In this study we systematically reviewed human RCTs to determine the existing evidence of tPBM effectiveness in management of four mentioned brain disorders. Since the outcomes of the reviewed RCTs were not homogeneous, further well-designed RCTs are required to decide more definitively on the evidence of this noninvasive and probably safe therapeutic intervention. We hypothesized that non-homogeneous outcomes could be due to inefficiency of PBM parameters. Controlled animal studies have the advantage of using objective tests to evaluate the results and compare them with the control group. We determined useful tPBM parameters based on these studies.
This research is part of our main project of tinnitus treatment using photobiomodulation (PBM). Evidence of central nervous system involvement in tinnitus led us to believe that treatment protocol of tinnitus should also include transcranial PBM. The determined useful parameters can be helpful in designing more efficient tPBM protocols in the management of brain disorders and tinnitus as a common debilitating symptom that can be associated with these disorders.}, }
@article {pmid34116955, year = {2021}, author = {Kim, JI and Zhu, D and Barry, E and Kovac, E and Aboumohamed, A and Agalliu, I and Sankin, A}, title = {Intravesical Bacillus Calmette-Guérin Treatment Is Inversely Associated With the Risk of Developing Alzheimer Disease or Other Dementia Among Patients With Non-muscle-invasive Bladder Cancer.}, journal = {Clinical genitourinary cancer}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.clgc.2021.05.001}, pmid = {34116955}, issn = {1938-0682}, abstract = {BACKGROUND: The immune system plays an important role in the pathogenesis of Alzheimer disease (AD), but it remains unclear whether bacillus Calmette-Guérin (BCG) may affect the risk of AD or not.
METHODS: Using retrospective chart review, we collected data regarding demographics, comorbidities, cancer diagnosis, BCG treatment, and subsequent diagnosis of AD or other dementia in a racially/ethnically diverse cohort of patients with non-muscle-invasive bladder cancer (NIMBC) receiving treatment between 1984 and 2020 in the Bronx, New York. We used Cox proportional hazard models to examine association between BCG treatment and risk of incident AD or other dementia, adjusting for age, gender, race/ethnicity, and major comorbidities.
RESULTS: In our cohort of 1290 patients with NMIBC, a total of 99 (7.7%) patients developed AD or other dementia during follow-up. Patients who received BCG treatment (25%) had a 60% lowered incidence of AD or other dementia (adjusted hazard ratio [HR], 0.41; 95% confidence interval [CI], 0.21-0.80) in comparison to those who did not receive BCG. There was also suggestive evidence that the reduction in risk of AD or other dementia associated with BCG treatment was stronger in men (adjusted HR, 0.34; 95% CI, 0.15-0.81) but not in women (adjusted HR, 0.75; 95% CI 0.25-2.24). When we stratified the patients who received BCG by type of treatments, patients who received both induction and maintenance rounds of BCG had a further lowered incidence of AD or other dementia (HR, 0.23; 95% CI, 0.06-0.96) than patients who did not receive BCG.
CONCLUSIONS: To our knowledge, our study is one of the first to suggest that BCG treatment is associated with a reduced risk of developing AD or other dementia in a multiethnic population, independent of significant comorbidities. Larger cohort studies are needed to corroborate our findings.}, }
@article {pmid34111056, year = {2021}, author = {Diez-Sepulveda, JC and Uribe-Buritica, FL and Angel-Isaza, AM and Bustamante-Cristancho, LA and Mejia-Herrera, F and Watts-Pajaro, FA and Rojas-Martinez, MF}, title = {An 80-Year-Old Woman with Alzheimer Disease and Accidental Poisoning with Pyrethroid Pesticide Successfully Treated with Intravenous Lipid Emulsion.}, journal = {The American journal of case reports}, volume = {22}, number = {}, pages = {e928420}, pmid = {34111056}, issn = {1941-5923}, mesh = {Aged ; Aged, 80 and over ; *Alzheimer Disease/drug therapy ; *Drug Overdose/drug therapy ; Fat Emulsions, Intravenous/therapeutic use ; Female ; Humans ; *Pesticides ; *Pyrethrins/therapeutic use ; }, abstract = {BACKGROUND Pesticides are commonly used in the agricultural industry. Overdose can be lethal due to its effects generating closure of the voltage-gated sodium channels in the axonal membranes. Most case reports of toxicity refer to skin exposure and there are very few that refer to effects due to its oral intake. CASE REPORT We report the case of an elderly woman with Alzheimer disease who accidentally swallowed 50 g of Lambda Cyhalothrin (GOLPE 5 M E®), a pyrethroid of medium toxicity containing a cyano group. It severely harmed the woman's health, causing severe central nervous system depression and refractory vasodilated shock requiring the use of vasopressors. Its management was challenging, requiring orotracheal intubation, vasopressors, and admission to the Intensive Care Unit (ICU). The emergency care team decided to use intravenous lipid emulsion, which clearly helped with the recovery and successful discharge of the patient. CONCLUSIONS The use of intravenous lipid emulsion for the treatment of pyrethroid poisoning can lead to successful outcomes, as described in this case report.}, }
@article {pmid34106590, year = {2021}, author = {Lee, JY and Kim, JY and Lee, JY and Jung, JH and Jung, IC}, title = {Efficacy of Jihwangeumja (Dihuang Yinzi) on cognitive function and activities of daily living in patients with Alzheimer disease: A protocol for a systematic review and meta-analysis.}, journal = {Medicine}, volume = {100}, number = {19}, pages = {e25592}, pmid = {34106590}, issn = {1536-5964}, support = {HB16C0044//Ministry of Health and Welfare/ ; }, mesh = {Activities of Daily Living ; Alzheimer Disease/*drug therapy/*psychology ; Cognition ; Drugs, Chinese Herbal/*therapeutic use ; Humans ; }, abstract = {BACKGROUND: This systematic review protocol describes the methods proposed to evaluate the efficacy and safety of Jihwangeumja in patients with Alzheimer disease.
METHODS: The following databases, PubMed, EMBASE, CENTRAL, Cumulative Index to Nursing and Allied Health Literature, China National Knowledge Infrastructure, National Digital Science Library, Korean Information Service System, and Korean Medical Database will be searched for relevant publications without language or publication status restrictions. Search terms will be based on "Alzheimer" for participants and "Jihwangeumja" or "Dihuang Yinzi" for interventions. Two researchers will independently extract the study data from the included studies and only randomized controlled trials will be included. The risk of bias will also be assessed independently by 2 researchers using the Cochrane risk of bias tool. We will use RevMan software random-effects and fixed-effect models for the assessment of heterogeneity and data synthesis. Any changes in the plan for documenting significant protocol amendments will require the researchers to have a revision agreement and register the international prospective register of systematic review modification.
RESULTS: The treatment effect and safety will be measured by meta-analysis and the quality of the included studies will be reviewed.
CONCLUSION: This systematic review will provide evidence regarding the efficacy and safety of Jihwangeumja.
ETHICS AND DISSEMINATION: Ethical approval is not required because individual patient data will not be included in this paper. The study findings will be disseminated through conference presentations.
OSF REGISTRATION: DOI: 10.17605/OSF.IO/HXA58.}, }
@article {pmid34103899, year = {2021}, author = {Weng, G and Zhou, B and Liu, T and Huang, Z and Huang, S}, title = {Tetramethylpyrazine Improves Cognitive Function of Alzheimer's Disease Mice by Regulating SSTR4 Ubiquitination.}, journal = {Drug design, development and therapy}, volume = {15}, number = {}, pages = {2385-2399}, pmid = {34103899}, issn = {1177-8881}, abstract = {Purpose: Many researches have investigated the functions of tetramethylpyrazine (TMP) in Alzheimer's disease (AD). This study aimed to discuss the underlying mechanism of TMP in AD mice.
Methods: TMP (200 mg/kg) was administered to 6-month-old APP/PS1 transgenic mice, and behavioral changes and hippocampal nerve injury in AD mice were detected. Apoptosis and autophagy-related protein levels were detected. Changes in gene expression before and after TMP treatment were compared using transcriptome sequencing. The effects of Cullin 4B (CUL4B) overexpression and somatostatin receptor 4 (SSTR4) silencing on AD symptoms and SSTR4 ubiquitination in APP/PS1 mice were observed. SH-SY5Y and PC12 cells were treated with 25 μmol/L Aβ25-35 and TMP to observe cell viability, apoptosis, and autophagy. Cell viability and apoptosis were measured again after treatment with proteasome inhibitor MG132 or lysosomal inhibitor 3-mA.
Results: TMP treatment improved the behavioral cognition of APP/PS1 mice and improved the neuronal apoptosis and damage in brain tissue. CUL4B was significantly upregulated in APP/PS1 mouse brain tissue, and SSRT4 protein was downregulated, and the levels of CUL4B and SSRT4 were negatively correlated. TMP treatment downregulated CUL4B, inhibited SSRT4 ubiquitination and upregulated SSRT4 protein level in APP/PS1 mouse brain tissue, while CUL4B overexpression or SSRT4 silencing reversed the effect of TMP. TMP and MG132 improved the decreased activity, increased apoptosis and increased SSRT4 protein in SH-SY5Y and PC12 cells treated with Aβ25-35, but not 3-mA. CUL4B overexpression promoted the ubiquitination of SSTR4 in cells, which partially reversed the effect of TMP.
Conclusion: TMP could improve the cognitive ability of AD mice by inhibiting CUL4B expression and the ubiquitination degradation of SSTR, and alleviating neuronal apoptosis and injury. This study may offer a new therapeutic option for AD treatment.}, }
@article {pmid34102977, year = {2021}, author = {Kulkarni, NP and Vaidya, B and Narula, A and Sharma, SS}, title = {Neuroprotective Potential of Caffeic Acid Phenethyl Ester (CAPE) in CNS Disorders: Mechanistic and Therapeutic Insights.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/1570159X19666210608165509}, pmid = {34102977}, issn = {1875-6190}, abstract = {Neurological disorders like Alzheimer's disease (AD), Parkinson's disease (PD), stroke, amyotrophic lateral sclerosis, Huntington's disease (HD), epilepsy, traumatic brain injury (TBI), depression and anxiety are responsible for thousands of deaths worldwide every year. With the increase in life expectancy, there has been a rise in the prevalence of these disorders. Age is one of the major risk factors for these neurological disorders and with the aged population is set to rise to 1.25 billion by 2050. There is a growing concern to look for new therapeutic molecules to treat age-related diseases. Caffeic acid phenethyl ester (CAPE) is a molecule obtained from a number of botanical sources such as the bark of conifer trees as well as propolis which is extracted from beehives. Though CAPE remains relatively unexplored in human trials, it possesses antioxidant, anti-inflammatory, antimitogenic and anti-cancer activities as shown by preclinical studies. Apart from this, it also exhibits tremendous potential for the treatment of neurological disorders through modulation of multiple molecular pathways and attenuation of behavioural deficits. In the present article, we have reviewed the therapeutic potential of CAPE and its mechanisms in the treatment of neurological disorders.}, }
@article {pmid34099509, year = {2021}, author = {Kikuchi, K and Tatebe, T and Sudo, Y and Yokoyama, M and Kidana, K and Chiu, YW and Takatori, S and Arita, M and Hori, Y and Tomita, T}, title = {GPR120 signaling controls amyloid-β degrading activity of matrix metalloproteinases.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {}, number = {}, pages = {}, pmid = {34099509}, issn = {1529-2401}, support = {P50 AG016574/AG/NIA NIH HHS/United States ; R01 AG032990/AG/NIA NIH HHS/United States ; R01 NS080820/NS/NINDS NIH HHS/United States ; U01 AG046139/AG/NIA NIH HHS/United States ; P01 AG017216/AG/NIA NIH HHS/United States ; R01 AG018023/AG/NIA NIH HHS/United States ; U01 AG006786/AG/NIA NIH HHS/United States ; P01 AG003949/AG/NIA NIH HHS/United States ; U24 NS072026/NS/NINDS NIH HHS/United States ; P30 AG019610/AG/NIA NIH HHS/United States ; P50 AG025711/AG/NIA NIH HHS/United States ; }, abstract = {Alzheimer disease (AD) is characterized by the extensive deposition of amyloid-β peptide (Aβ) in the brain. Brain Aβ level is regulated by a balance between Aβ production and clearance. The clearance rate of Aβ is decreased in the brains of sporadic AD patients, indicating that the dysregulation of Aβ clearance mechanisms affects the pathological process of AD. Astrocytes are among the most abundant cells in the brain and are implicated in the clearance of brain Aβ via their regulation of the blood-brain barrier, glymphatic system, and proteolytic degradation. The cellular morphology and activity of astrocytes are modulated by several molecules, including ω3 polyunsaturated fatty acids, such as docosahexaenoic acid, which is one of the most abundant lipids in the brain, via the G protein-coupled receptor GPR120/FFAR4. In this study, we analyzed the role of GPR120 signaling in the Aβ-degrading activity of astrocytes. Treatment with the selective antagonist upregulated the matrix metalloproteinase (MMP) inhibitor-sensitive Aβ-degrading activity in primary astrocytes. Moreover, the inhibition of GPR120 signaling increased the levels of Mmp2 and Mmp14 mRNAs, and decreased the expression levels of tissue inhibitor of metalloproteinases 3 (Timp3) and Timp4, suggesting that GPR120 negatively regulates the astrocyte-derived MMP network. Finally, the intracerebral injection of GPR120 specific antagonist substantially decreased the levels of Tris-buffered saline-soluble Aβ in male AD model mice, and this effect was canceled by the coinjection of an MMP inhibitor. These data indicate that astrocytic GPR120 signaling negatively regulates the Aβ degrading activity of MMPs.SIGNIFICANT STATEMENTThe level of amyloid β (Aβ) in the brain is a crucial determinant of the development of Alzheimer disease. Here we found that astrocytes, which are the most abundant cell type in the central nervous system, harbors degrading activity against amyloid β, which is regulated by GPR120 signaling. GPR120 is involved in the inflammatory response and obesity in peripheral organs. However, the pathophysiological role of GPR120 in Alzheimer disease remains unknown. We found that selective inhibition of GPR120 signaling in astrocytes increased the Aβ-degrading activity of matrix metalloproteases. Our results suggest that GPR120 in astrocytes is a novel therapeutic target for the development of anti-Aβ therapeutics.}, }
@article {pmid34093032, year = {2021}, author = {Svob Strac, D and Konjevod, M and Sagud, M and Nikolac Perkovic, M and Nedic Erjavec, G and Vuic, B and Simic, G and Vukic, V and Mimica, N and Pivac, N}, title = {Personalizing the Care and Treatment of Alzheimer's Disease: An Overview.}, journal = {Pharmacogenomics and personalized medicine}, volume = {14}, number = {}, pages = {631-653}, pmid = {34093032}, issn = {1178-7066}, abstract = {Alzheimer's disease (AD) is a progressive, complex, and multifactorial neurodegenerative disorder, still without effective and stable therapeutic strategies. Currently, available medications for AD are based on symptomatic therapy, which include acetylcholinesterase (AChE) inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonist. Additionally, medications such as antipsychotic drugs, antidepressants, sedative, and hypnotic agents, and mood stabilizers are used for the management of behavioral and psychological symptoms of dementia (BPSD). Clinical research has been extensively investigated treatments focusing on the hallmark pathology of AD, including the amyloid deposition, tau hyperphosphorylation, neuroinflammation, and vascular changes; however, so far without success, as all new potential drugs failed to show significant clinical benefit. The underlying heterogeneous etiology and diverse symptoms of AD suggest that a precision medicine strategy is required, which would take into account the complex genetic, epigenetic, and environmental landscape of each AD patient. The article provides a comprehensive overview of the literature on AD, the current and potential therapy of both cognitive symptoms as well as BPSD, with a special focus on gut microbiota and epigenetic modifications as new emerging drug targets. Their specific patterns could represent the basis for novel individually tailored approaches aimed to optimize precision medicine strategies for AD prevention and treatment. However, the successful application of precision medicine to AD demands a further extensive research of underlying pathological processes, as well as clinical and biological complexity of this multifactorial neurodegenerative disorder.}, }
@article {pmid34088777, year = {2021}, author = {Meier, SR and Sehlin, D and Roshanbin, S and Lim Falk, V and Saito, T and Saido, TC and Neumann, U and Rokka, J and Eriksson, J and Syvanen, S}, title = {11C-PIB and 124I-antibody PET provide differing estimates of brain amyloid-beta after therapeutic intervention.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {}, number = {}, pages = {}, doi = {10.2967/jnumed.121.262083}, pmid = {34088777}, issn = {1535-5667}, abstract = {Positron emission tomography (PET) imaging of amyloid-β (Aβ) has become an important component of Alzheimer's disease (AD) diagnosis. 11C-Pittsburgh compound B (11C-PiB) and analogs bind to fibrillar Aβ. However, levels of nonfibrillar, soluble aggregates of Aβ, appear more dynamic during disease progression and more affected by Aβ reducing treatments. The aim of this study was to compare an antibody-based PET ligand, targeting nonfibrillar Aβ, with 11C-PiB after β-secretase (BACE-1) inhibition in two AD mouse models at an advanced stage of Aβ pathology. Methods: Transgenic ArcSwe mice (16 months) were treated with the BACE-1 inhibitor NB-360 for 2 months, while another group was kept as controls. A third group was analyzed at the age of 16 months as baseline. Mice were PET scanned with 11C-PiB to measure Aβ plaque load followed by a scan with the bispecific radioligand 124I-RmAb158-scFv8D3 to investigate nonfibrillar aggregates of Aβ. The same study design was then applied for another mouse model, AppNL-G-F. In this case, NB-360 treatment was initiated at the age of 8 months and animals were scanned with 11C-PiB-PET and 125I-RmAb158-scFv8D3 single-photon emission computer tomography (SPECT). Brain tissue was isolated after scanning and Aβ levels were assessed. Results: 124I-RmAb158-scFv8D3 concentrations measured with PET in hippocampus and thalamus of NB-360 treated ArcSwe mice were similar to those observed in baseline animals and significantly lower than concentrations observed in same-age untreated controls. Reduced 125I-RmAb158-scFv8D3 retention was also observed with SPECT in hippocampus, cortex and cerebellum of NB-360 treated AppNL-G-F mice. Radioligand in vivo concentrations corresponded with postmortem brain tissue analysis of soluble Aβ aggregates. For both models, mice treated with NB-360 did not display a reduced 11C-PiB signal compared to untreated controls, and further, both NB-360 and control mice tended, although not reaching significance, to show higher 11C-PiB signal than the baseline groups. Conclusion: This study demonstrated the ability of an antibody-based radioligand to detect changes in brain Aβ levels after anti-Aβ therapy in ArcSwe and AppNL-G-F mice with pronounced Aβ pathology. In contrast, the decreased Aβ levels could not be quantified with 11C-PiB PET, suggesting that these ligands detect different pools of the Aβ.}, }
@article {pmid34080526, year = {2021}, author = {Manandhar, S and Priya, K and Mehta, CH and Nayak, UY and Kabekkodu, SP and Pai, KSR}, title = {Repositioning of antidiabetic drugs for Alzheimer's disease: possibility of Wnt signaling modulation by targeting LRP6 an in silico based study.}, journal = {Journal of biomolecular structure & dynamics}, volume = {}, number = {}, pages = {1-15}, doi = {10.1080/07391102.2021.1930583}, pmid = {34080526}, issn = {1538-0254}, abstract = {Alzheimer disease (AD) is the most common, irreversible and progressive form of dementia for which the exact pathology and cause are still not clear. At present, we are only confined to symptomatic treatment, and the lack of disease-modifying therapeutics is worrisome. Alteration of Wnt signaling has been linked to metabolic diseases as well as AD. The crosstalk between Canonical Wnt signaling and insulin signaling pathway has been widely studied and accepted from several clinical and preclinical studies that have proven the beneficial effect of antidiabetic medications in the case of memory and cognition loss. This structure-based in silico study was focused on exploring the link between the currently available FDA approved antidiabetic drugs and the Wnt signaling pathway. The library of antidiabetics was obtained from drug bank and was screened for their binding affinity with protein (PDB ID: 3S2K) LRP6, a coreceptor of the Wnt signaling pathway using GLIDE module of Schrodinger. The top molecules, with higher docking score, binding energy and stable interactions, were subjected to energy-based calculation using MMGBSA, followed by a molecular dynamics-based simulation study. Drugs of class α-glucosidase inhibitors and peroxisome proliferator-activated receptors (PPARs) agonists were found to have a strong affinity towards LRP6 proteins, highlighting the possibility of the modulation of Wnt signaling by antidiabetics as one of the possible mechanisms for use in AD. However, further experimental based in vitro and in vivo studies are warranted for verification and support.Communicated by Ramaswamy H. Sarma.}, }
@article {pmid34080437, year = {2021}, author = {Lu, L and Dai, WZ and Zhu, XC and Ma, T}, title = {Analysis of Serum miRNAs in Alzheimer's Disease.}, journal = {American journal of Alzheimer's disease and other dementias}, volume = {36}, number = {}, pages = {15333175211021712}, doi = {10.1177/15333175211021712}, pmid = {34080437}, issn = {1938-2731}, mesh = {*Alzheimer Disease/genetics ; Gene Expression Profiling ; Gene Regulatory Networks ; Humans ; *MicroRNAs/blood ; Signal Transduction ; }, abstract = {This paper was aimed to analyze the microRNA (miRNA) signatures in Alzheimer disease (AD) and find the significant expressions of miRNAs, their target genes, the functional enrichment analysis of the confirmed genes, and potential drug treatment. The miRNA expression information of the gene expression profile data was downloaded from the Gene Expression Omnibus database. The total data sample size is 1309, including 1021 AD samples and 288 normal samples. A total of 21 differentially expressed miRNAs were obtained, of which 16 (hsa-miR-6761-3p, hsa-miR-6747-3p, hsa-miR-6875-3p, hsa-miR-6754-3p, hsa-miR-6736-3p, hsa-miR-6762-3p, hsa-miR-6787-3p, hsa-miR-208a-5p, hsa-miR-6740-3p, hsa-miR-6778-3p, hsa-miR-595, hsa-miR-6753-3p, hsa-miR-4747-3p, hsa-miR-3646, hsa-miR-6716-3p and hsa-miR-4435) were up-regulated and 5 (hsa-miR-125a-3p, hsa-miR-22-3p, hsa-miR-24-3p, hsa-miR-6131 and hsa-miR-125b-1-3p) were down-regulated in AD. A total of 6 miRNAs (hsa-miR-595, hsa-miR-3646, hsa-miR-4435 hsa-miR-125a-3p, hsa-miR-22-3p and hsa-miR-24-3p) and 78 miRNA-disease-related gene sub-networks were predicted, and 116 ceRNA regulatory relationship pairs, and the ceRNA regulatory network were obtained. The results of enrichment analysis suggested that the main target pathways of several miRNAs differentially expressed in AD were mitogen-activated protein kinase signal pathway. According to the prediction results of Drug-Gene Interaction database 2.0, we obtained 53 pairs of drug-gene interaction, including 7 genes (PTGS2, EGFR, CALM1, PDE4D, FGFR2, HMGCR, cdk6) and 53 drugs. We hope our results are helpful to find a viable way to prevent, delay the onset, diagnose, and treat AD.}, }
@article {pmid34079697, year = {2021}, author = {Guo, XY and Chang, Y and Kim, Y and Rhee, HY and Cho, AR and Park, S and Ryu, CW and San Lee, J and Lee, KM and Shin, W and Park, KC and Kim, EJ and Jahng, GH}, title = {Development and evaluation of a T1 standard brain template for Alzheimer disease.}, journal = {Quantitative imaging in medicine and surgery}, volume = {11}, number = {6}, pages = {2224-2244}, pmid = {34079697}, issn = {2223-4292}, abstract = {Background: Patients with Alzheimer disease (AD) and mild cognitive impairment (MCI) have high variability in brain tissue loss, making it difficult to use a disease-specific standard brain template. The objective of this study was to develop an AD-specific three-dimensional (3D) T1 brain tissue template and to evaluate the characteristics of the populations used to form the template.
Methods: We obtained 3D T1-weighted images from 294 individuals, including 101 AD, 96 amnestic MCI, and 97 cognitively normal (CN) elderly individuals, and segmented them into different brain tissues to generate AD-specific brain tissue templates. Demographic data and clinical outcome scores were compared between the three groups. Voxel-based analyses and regions-of-interest-based analyses were performed to compare gray matter volume (GMV) and white matter volume (WMV) between the three participant groups and to evaluate the relationship of GMV and WMV loss with age, years of education, and Mini-Mental State Examination (MMSE) scores.
Results: We created high-resolution AD-specific tissue probability maps (TPMs). In the AD and MCI groups, losses of both GMV and WMV were found with respect to the CN group in the hippocampus (F >44.60, P<0.001). GMV was lower with increasing age in all individuals in the left (r=-0.621, P<0.001) and right (r=-0.632, P<0.001) hippocampi. In the left hippocampus, GMV was positively correlated with years of education in the CN groups (r=0.345, P<0.001) but not in the MCI (r=0.223, P=0.0293) or AD (r=-0.021, P=0.835) groups. WMV of the corpus callosum was not significantly correlated with years of education in any of the three subject groups (r=0.035 and P=0.549 for left, r=0.013 and P=0.821 for right). In all individuals, GMV of the hippocampus was significantly correlated with MMSE scores (left, r=0.710 and P<0.001; right, r=0.680 and P<0.001), while WMV of the corpus callosum showed a weak correlation (left, r=0.142 and P=0.015; right, r=0.123 and P=0.035).
Conclusions: A 3D, T1 brain tissue template was created using imaging data from CN, MCI, and AD participants considering the participants' age, sex, and years of education. Our disease-specific template can help evaluate brains to promote early diagnosis of MCI individuals and aid treatment of MCI and AD individuals.}, }
@article {pmid34057082, year = {2021}, author = {Wei, W and Liu, Y and Dai, CL and Baazaoui, N and Tung, YC and Liu, F and Iqbal, K}, title = {Neurotrophic Treatment Initiated During Early Postnatal Development Prevents the Alzheimer-Like Behavior and Synaptic Dysfunction.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {82}, number = {2}, pages = {631-646}, doi = {10.3233/JAD-201599}, pmid = {34057082}, issn = {1875-8908}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by impairments in synaptic plasticity and cognitive performance. Cognitive dysfunction and loss of neuronal plasticity are known to begin decades before the clinical diagnosis of the disease. The important influence of congenital genetic mutations on the early development of AD provides a novel opportunity to initiate treatment during early development to prevent the Alzheimer-like behavior and synaptic dysfunction.
OBJECTIVE: To explore strategies for early intervention to prevent Alzheimer's disease.
METHODS: In the present study, we investigated the effect of treatment during early development with a ciliary neurotrophic factor (CNTF) derived peptidergic compound, P021 (Ac-DGGLAG-NH2) on cognitive function and synaptic plasticity in 3xTg-AD transgenic mouse model of AD. 3xTg-AD and genetic background-matched wild type female mice were treated from birth to postnatal day 120 with P021 in diet or as a control with vehicle diet, and cognitive function and molecular markers of neuroplasticity were evaluated.
RESULTS: P021 treatment during early development prevented cognitive impairment and increased expressions of pCREB and BDNF that activated downstream various signaling cascades such as PLC/PKC, MEK/ERK and PI3K/Akt, and ameliorated synaptic protein deficit in 4-month-old 3xTg-AD mice.
CONCLUSION: These findings indicate that treatment with the neurotrophic peptide mimetic such as P021 during early development can be an effective therapeutic strategy to rescue synaptic deficit and cognitive impairment in familial AD and related tauopathies.}, }
@article {pmid34052296, year = {2021}, author = {Abd El-Fatah, IM and Abdelrazek, HMA and Ibrahim, SM and Abdallah, DM and El-Abhar, HS}, title = {Dimethyl fumarate abridged tauo-/amyloidopathy in a D-Galactose/ovariectomy-induced Alzheimer's-like disease: Modulation of AMPK/SIRT-1, AKT/CREB/BDNF, AKT/GSK-3β, adiponectin/Adipo1R, and NF-κB/IL-1β/ROS trajectories.}, journal = {Neurochemistry international}, volume = {148}, number = {}, pages = {105082}, doi = {10.1016/j.neuint.2021.105082}, pmid = {34052296}, issn = {1872-9754}, abstract = {Since the role of estrogen in postmenauposal-associated dementia is still debatable, this issue urges the search for other medications. Dimethyl fumarate (DMF) is a drug used for the treatment of multiple sclerosis and has shown a neuroprotective effect against other neurodegenerative diseases. Accordingly, the present study aimed to evaluate the effect of DMF on an experimental model of Alzheimer disease (AD) using D-galactose (D-Gal) administered to ovariectomized (OVX) rats, resembling a postmenopausal dementia paradigm. Adult 18-month old female Wistar rats were allocated into sham-operated and OVX/D-Gal groups that were either left untreated or treated with DMF for 56 days starting three weeks after sham-operation or ovariectomy. DMF succeeded to ameliorate cognitive (learning/short- and long-term memory) deficits and to enhance the dampened overall activity (NOR, Barnes-/Y-maze tests). These behavioral upturns were associated with increased intact neurons (Nissl stain) and a reduction in OVX/D-Gal-mediated hippocampal CA1 neurodegeneration and astrocyte activation assessed as GFAP immunoreactivity. Mechanistically, DMF suppressed the hippocampal contents of AD-surrogate markers; viz., apolipoprotein (APO)-E1, BACE1, Aβ42, and hyperphosphorylated Tau. Additionally, DMF has augmented the neuroprotective parameters p-AKT, its downstream target CREB and BDNF. Besides, it activated AMPK, and enhanced SIRT-1, as well as antioxidant defenses (SOD, GSH). On the other hand, DMF inhibited the transcription factor NF-κB, IL-1β, adiponectin/adiponectin receptor type (AdipoR)1, GSK-3β, and MDA. Accordingly, in this postmenopausal AD model, DMF treatment by pursuing the adiponectin/AdipoR1, AMPK/SIRT-1, AKT/CREB/BDNF, AKT/GSK-3β, and APO-E1 quartet hampered the associated tauo-/amyloidopathy and NF-κB-mediated oxidative/inflammatory responses to advance insights into its anti-amnesic effect.}, }
@article {pmid34044035, year = {2021}, author = {Souders, CL and Rushin, A and Sanchez, CL and Toth, D and Adamovsky, O and Martyniuk, CJ}, title = {Mitochondrial and transcriptome responses in rat dopaminergic neuronal cells following exposure to the insecticide fipronil.}, journal = {Neurotoxicology}, volume = {85}, number = {}, pages = {173-185}, doi = {10.1016/j.neuro.2021.05.011}, pmid = {34044035}, issn = {1872-9711}, abstract = {The phenylpyrazole fipronil is an insecticide that inhibits γ -amino-butyric acid (GABA) ionotropic receptors in the central nervous system. Experimental evidence suggests that fipronil acts as a neurotoxin and it is implicated in neurodegenerative diseases; however, the mechanisms of neurotoxicity are not fully elucidated. The objective of this study was to quantify mechanisms of fipronil-induced neurotoxicity in dopamine cells. Rat primary immortalized mesencephalic dopaminergic cells (N27) were treated with fipronil (0.25 up to 500 μM depending on the assay). We measured endpoints related to mitochondrial bioenergetics, mitophagy, mitochondrial membrane potential, and ATP production in addition to discerning transcriptome responses to the pesticide. Fipronil reduced cell viability at 500 μM after 24 h exposure and caspase 3/7 activity was significant increased after 6 and 12 h by 250 and 500 μM fipronil. Subsequent endpoints were thus assessed at concentrations that were below cytotoxicity. We measured oxidative respiration of N27 cells following a 24 h exposure to one dose of either 0.25, 2.5, 25, or 50 μM fipronil. Oxygen consumption rates (OCR) were not different between vehicle-control and 0.25 or 2.5 μM fipronil treatments, but there was a ∼40-60 % reduction in basal respiration, as well as reduced oligomycin-induced ATP production at 50 μM. The reduction in OCR is hypothesized to be related to lower mitochondrial mass due to mitophagy. Mitochondrial membrane potential was also sensitive to fipronil, and it was compromised at concentrations of 2.5 μM and above. To further elucidate the mechanisms linked to neurotoxicity, we conducted transcriptomics in dopamine cells following treatment with 25 μM fipronil. Fipronil suppressed transcriptional networks associated with mitochondria (damage, depolarization, permeability, and fission), consistent with its effects on mitochondrial membrane potential. Altered gene networks also included those related to Alzheimer disease, inflammatory disease, nerve fiber degeneration, and neurofibrillary tangles. This study clarifies molecular targets of fipronil-induced neurotoxicity and supports, through multiple lines of evidence, that fipronil acts as a mitochondrial toxicant in dopamine cells. This is relevant to neurodegenerative diseases like Parkinson's disease as exposure to fipronil is associated with the progressive loss of nigrostriatal dopaminergic neurons in rodents.}, }
@article {pmid34036518, year = {2021}, author = {Elfouly, A and Awny, M and Ibrahim, MK and Aboelsaad, M and Tian, J and Sayed, M}, title = {Effects of Long-Acting Testosterone Undecanoate on Behavioral Parameters and Na + , K+-ATPase mRNA Expression in Mice with Alzheimer`s Disease.}, journal = {Neurochemical research}, volume = {46}, number = {9}, pages = {2238-2248}, pmid = {34036518}, issn = {1573-6903}, abstract = {Previous studies have shown that testosterone attenuates stress-induced mood dysfunction and memory deterioration. However, the exact mechanism is still unknown. This study was conducted to investigate the role of long-term testosterone undecanoate on the behavioral responses in AD induced by AlCl3 + D-galactose administration and the possible alteration of the gene expression level of the Na/K ATPase pump. Adult male mice received AlCl3 in drinking water (10 mg/kg/day) and (D-gal 200 mg/kg/day), subcutaneously for 90 consecutive days, then received a single intramuscular (I.M) injection of castor oil (vehicle) on day 91, while treated groups received a single I.M injection of either low (100 mg/kg/45 days) or high dose (500 mg/kg/45 days) respectively of long-acting testosterone undecanoate on day 91. The time spent in the interaction zone during the open field test, preference index to novel objects in the novel object recognition test, spontaneous alternation percentage (SAP) in Y-maze test, and escape latency time in the Morris water maze test were used to measure the locomotor activity, long-term memory, and spatial memory in mice, respectively. The results showed that testosterone undecanoate treatment improved locomotor activity, improved preference to novel objects, improved spatial memory, and reversed anxiety and depression induced by AlCl3 + D-galactose administration in male mice, suggesting the enhancement of behavioral and memory functions brought by testosterone treatment. Moreover, testosterone undecanoate treatment did alter gene expression levels of Na/K ATPase isoforms in the brain hippocampus. In most cases, altered gene expression was significant and correlated with the observed behavioral changes. Taken together, our findings provide new insight into the effects of long-acting testosterone undecanoate administration on locomotor activity, long-term memory, anxiety, and spatial memory in male mice with Alzheimer's disease.}, }
@article {pmid34033708, year = {2021}, author = {Burke, AD}, title = {Can Emerging Therapies Resolve Unmet Needs With Current Treatment in Early-Stage Alzheimer Disease?.}, journal = {The Journal of clinical psychiatry}, volume = {82}, number = {3}, pages = {}, doi = {10.4088/JCP.BG20044WC3C}, pmid = {34033708}, issn = {1555-2101}, abstract = {While no current medications for Alzheimer disease (AD) can modify the disease, the agents do slow symptom progression. The earlier the medications are started for patients diagnosed with AD, the greater the potential benefit. Clinical trials are in progress on drugs with a variety of mechanisms that may modulate the disease course: neuronal protection; protein synthesis or aggregation inhibition; immunologic priming with antibodies; vaccines; and secretase inhibition. Early diagnosis, whether in the primary care setting or the specialty setting, continues to be critical to give patients their best chance at managing their illness. Although current treatments cannot give patients back what they have already lost, in the near future, drugs may be able to slow or even halt their cognitive and functional decline if clinicians identify AD early enough in the disease process.}, }
@article {pmid34032549, year = {2021}, author = {Kandil, LS and Farid, RM and ElGamal, SS and Hanafy, AS}, title = {Intranasal galantamine/chitosan complex nanoparticles elicit neuroprotection potentials in rat brains via antioxidant effect.}, journal = {Drug development and industrial pharmacy}, volume = {47}, number = {5}, pages = {735-740}, doi = {10.1080/03639045.2021.1934861}, pmid = {34032549}, issn = {1520-5762}, mesh = {Administration, Intranasal ; Animals ; Antioxidants ; *Chitosan ; Galantamine ; Male ; *Nanoparticles ; Neuroprotection ; Oxidative Stress ; Rats ; Rats, Wistar ; }, abstract = {BACKGROUND: Alzheimer's disease is a common cause of dementia in the elderly. Galantamine hydrobromide (GH) is an anti-Alzheimer cholinesterase inhibitor that has an intrinsic antioxidant effect. In a previous study, GH was complexed with chitosan to prepare intranasal GH/chitosan complex nanoparticles (CX-NP2). The nanoparticles were located in rat brains 1 h after nasal administration and showed pharmacological superiority to GH nasal solution without showing histopathological toxicity.
OBJECTIVE: This study aimed to investigate whether the long-term administration of CX-NP2 leads to biochemical toxicity in rat brains compared to GH nasal solution.
METHODS: CX-NP2 dispersion and GH solution were administrated intranasally to male Wistar rats for 30 days (3 mg/kg/day). Malondialdehyde (MDA), lipid peroxidation marker, glutathione (GSH), superoxide dismutase (SOD) activity and tumor necrosis factor-α (TNF-α) were assessed in the brain extracts in all groups.
RESULTS: There was statistically insignificant difference between the CX-NP2 and GH nasal solution treated groups in all biochemical toxicity parameters assessed. Interestingly, MDA and TNF-α levels in the CX-NP2-treated group significantly decreased compared to the control group. Also, GSH level and SOD activity were significantly enhanced in CX-NP2 treated group compared to the control group.
CONCLUSIONS: CX-NP2 did not induce a statistically significant oxidative stress or neuroinflammation in rat brains after 30-day treatment, they rather elicited neuroprotective potentials.HighlightsIntranasal GH/chitosan complex nanoparticles (CX-NP2) show promising potential as a brain targeting carrier.Compared to GH nasal solution, nasal CX-NP2 formulation did not exert oxidative stress nor neuroinflammation when administered for 30 days.}, }
@article {pmid34025423, year = {2021}, author = {Gáspár, A and Hutka, B and Ernyey, AJ and Tajti, BT and Varga, BT and Zádori, ZS and Gyertyán, I}, title = {Intracerebroventricularly Injected Streptozotocin Exerts Subtle Effects on the Cognitive Performance of Long-Evans Rats.}, journal = {Frontiers in pharmacology}, volume = {12}, number = {}, pages = {662173}, pmid = {34025423}, issn = {1663-9812}, abstract = {Intracerebroventricularly injected streptozotocin (STZ)-induced learning impairment has been an increasingly used rat model of Alzheimer disease. The evoked pathological changes involve many symptoms of the human disease (cognitive decline, increase in β-amyloid and phospho-tau level, amyloid plaque-like deposits). However, the model has predominantly been used with Wistar rats in the literature. The objective of the current study was to transfer it to Long-Evans rats with the ulterior aim to integrate it in a complex cognitive test battery where we use this strain because of its superior cognitive capabilities. We performed two experiments (EXP1, EXP2) with three months old male animals. At EXP1, rats were treated with 2 × 1.5 mg/kg STZ (based on the literature) or citrate buffer vehicle injected bilaterally into the lateral ventricles on days 1 and 3. At EXP2 animals were treated with 3 × 1.5 mg/kg STZ or citrate buffer vehicle injected in the same way as in EXP1 at days 1, 3, and 5. Learning and memory capabilities of the rats were then tested in the following paradigms: five choice serial reaction time test (daily training, started from week 2 or 8 post surgery in Exp1 or Exp2, respectively, and lasting until the end of the experiment); novel object recognition (NOR) test (at week 8 or 14), passive avoidance (at week 11 or 6) and Morris water-maze (at week 14 or 6). 15 or 14 weeks after the STZ treatment animals were sacrificed and brain phospho-tau/tau protein ratio and β -amyloid level were determined by western blot technique. In EXP1 we could not find any significant difference between the treated and the control groups in any of the assays. In EXP2 we found significant impairment in the NOR test and elevated β-amyloid level in the STZ treated group in addition to slower learning of the five-choice paradigm and a trend for increased phospho-tau/tau ratio. Altogether our findings suggest that the Long-Evans strain may be less sensitive to the STZ treatment than the Wistar rats and higher doses may be needed to trigger pathological changes in these animals. The results also highlight the importance of strain diversity in modelling human diseases.}, }
@article {pmid34024838, year = {2021}, author = {Alves, SS and Silva-Junior, RMPD and Servilha-Menezes, G and Homolak, J and Šalković-Petrišić, M and Garcia-Cairasco, N}, title = {Insulin Resistance as a Common Link Between Current Alzheimer's Disease Hypotheses.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {82}, number = {1}, pages = {71-105}, doi = {10.3233/JAD-210234}, pmid = {34024838}, issn = {1875-8908}, abstract = {Almost 115 years ago, Alois Alzheimer described Alzheimer's disease (AD) for the first time. Since then, many hypotheses have been proposed. However, AD remains a severe health public problem. The current medical approaches for AD are limited to symptomatic interventions and the complexity of this disease has led to a failure rate of approximately 99.6%in AD clinical trials. In fact, no new drug has been approved for AD treatment since 2003. These failures indicate that we are failing in mimicking this disease in experimental models. Although most studies have focused on the amyloid cascade hypothesis of AD, the literature has made clear that AD is rather a multifactorial disorder. Therefore, the persistence in a single theory has resulted in lost opportunities. In this review, we aim to present the striking points of the long scientific path followed since the description of the first AD case and the main AD hypotheses discussed over the last decades. We also propose insulin resistance as a common link between many other hypotheses.}, }
@article {pmid34024231, year = {2021}, author = {Bailus, BJ and Scheeler, SM and Simons, J and Sanchez, MA and Tshilenge, KT and Creus-Muncunill, J and Naphade, S and Lopez-Ramirez, A and Zhang, N and Lakshika Madushani, K and Moroz, S and Loureiro, A and Schreiber, KH and Hausch, F and Kennedy, BK and Ehrlich, ME and Ellerby, LM}, title = {Modulating FKBP5/FKBP51 and autophagy lowers HTT (huntingtin) levels.}, journal = {Autophagy}, volume = {}, number = {}, pages = {1-22}, doi = {10.1080/15548627.2021.1904489}, pmid = {34024231}, issn = {1554-8635}, support = {R01 NS094422/NS/NINDS NIH HHS/United States ; R01 NS100529/NS/NINDS NIH HHS/United States ; }, abstract = {Current disease-modifying therapies for Huntington disease (HD) focus on lowering mutant HTT (huntingtin; mHTT) levels, and the immunosuppressant drug rapamycin is an intriguing therapeutic for aging and neurological disorders. Rapamycin interacts with FKBP1A/FKBP12 and FKBP5/FKBP51, inhibiting the MTORC1 complex and increasing cellular clearance mechanisms. Whether the levels of FKBP (FK506 binding protein) family members are altered in HD models and if these proteins are potential therapeutic targets for HD have not been investigated. Here, we found levels of FKBP5 are significantly reduced in HD R6/2 and zQ175 mouse models and human HD isogenic neural stem cells and medium spiny neurons derived from induced pluripotent stem cells. Moreover, FKBP5 interacts and colocalizes with HTT in the striatum and cortex of zQ175 mice and controls. Importantly, when we decreased FKBP5 levels or activity by genetic or pharmacological approaches, we observed reduced levels of mHTT in our isogenic human HD stem cell model. Decreasing FKBP5 levels by siRNA or pharmacological inhibition increased LC3-II levels and macroautophagic/autophagic flux, suggesting autophagic cellular clearance mechanisms are responsible for mHTT lowering. Unlike rapamycin, the effect of pharmacological inhibition with SAFit2, an inhibitor of FKBP5, is MTOR independent. Further, in vivo treatment for 2 weeks with SAFit2, results in reduced HTT levels in both HD R6/2 and zQ175 mouse models. Our studies establish FKBP5 as a protein involved in the pathogenesis of HD and identify FKBP5 as a potential therapeutic target for HD.Abbreviations : ACTB/β-actin: actin beta; AD: Alzheimer disease; BafA1: bafilomycin A1; BCA: bicinchoninic acid; BBB: blood brain barrier; BSA: bovine serum albumin; CoIP: co-immunoprecipitation; DMSO: dimethyl sulfoxide; DTT: dithiothreitol; FKBPs: FK506 binding proteins; HD: Huntington disease; HTT: huntingtin; iPSC: induced pluripotent stem cells; MAP1LC3/LC3:microtubule associated protein 1 light chain 3; MAPT/tau: microtubule associated protein tau; MES: 2-ethanesulfonic acid; MOPS: 3-(N-morphorlino)propanesulfonic acid); MSN: medium spiny neurons; mHTT: mutant huntingtin; MTOR: mechanistic target of rapamycin kinase; NSC: neural stem cells; ON: overnight; PD: Parkinson disease; PPIase: peptidyl-prolyl cis/trans-isomerases; polyQ: polyglutamine; PPP1R1B/DARPP-32: protein phosphatase 1 regulatory inhibitor subunit 1B; PTSD: post-traumatic stress disorder; RT: room temperature; SQSTM1/p62: sequestosome 1; SDS-PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis; TBST:Tris-buffered saline, 0.1% Tween 20; TUBA: tubulin; ULK1: unc-51 like autophagy activating kinase 1; VCL: vinculin; WT: littermate controls.}, }
@article {pmid34023120, year = {2021}, author = {Richards, K and Britt, KC and Cuellar, N and Wang, Y and Morrison, J}, title = {Clinical Decision-Making: Restless Legs Syndrome and Dementia in Older Adults.}, journal = {The Nursing clinics of North America}, volume = {56}, number = {2}, pages = {265-274}, doi = {10.1016/j.cnur.2021.02.005}, pmid = {34023120}, issn = {1558-1357}, mesh = {Aged ; Aged, 80 and over ; *Decision Making ; Dementia/*complications/epidemiology/psychology ; Female ; Humans ; Male ; Restless Legs Syndrome/epidemiology/*etiology/psychology ; Sleep Wake Disorders/epidemiology/etiology/psychology ; Surveys and Questionnaires ; }, abstract = {Restless legs syndrome (RLS), one of the more prevalent sleep disturbances among older adults, impacts quality of life. Patients with dementia are at high risk for developing RLS and may be unable to describe their symptoms. Often underdiagnosed, RLS can contribute to discomfort, pain, nighttime agitation, disturbed sleep, and falls. Clinical assessment is crucial and should include a thorough evaluation with input from the patient and family, deprescribing medication if possible, and consideration of common sleep-disturbing factors. Evidence-based treatment in this population is limited; overall focus should center on relieving discomfort while identifying and treating bothersome sleep symptoms.}, }
@article {pmid34018966, year = {2021}, author = {McMurray, J and Levy, A and Holyoke, P}, title = {Psychometric Evaluation and Workflow Integration Study of a Tablet-Based Tool to Detect Mild Cognitive Impairment in Older Adults: Protocol for a Mixed Methods Study.}, journal = {JMIR research protocols}, volume = {10}, number = {5}, pages = {e25520}, pmid = {34018966}, issn = {1929-0748}, abstract = {BACKGROUND: With the rapid aging of the global population, experts anticipate a surge in the prevalence of mild cognitive impairment (MCI) and dementia worldwide. It is argued that developing more sensitive, easy to administer, and valid MCI screening tools for use in primary care settings may initiate timely clinical and personal care planning and treatment, enabling early access to programs and services. Including functional competence measures in screening tests makes them more ecologically valid and may help to identify cognitive deficits at an earlier stage.
OBJECTIVE: We aim to conduct a preliminary evaluative study comparing the sensitivity, specificity, and reliability of the BrainFx Screen (referred to as SCREEN hereafter), a novel digital tool designed to assess functional competence and detect early signs of cognitive impairment, with the Quick Mild Cognitive Impairment, a validated and highly sensitive tool that detects MCI in the older adult population. We will also investigate the perceived usefulness and integration of the SCREEN into primary care practice to identify demonstrable impacts on clinical workflow and health care providers' (HCP) perceptions of its success as a screening tool. Patients' perceptions of completing the SCREEN and its impact on their quality of life will also be explored.
METHODS: This study has a concurrent, mixed methods, prospective, and quasi-experimental design. Participants will be recruited from 5 primary care family health teams (FHTs; defined by multidisciplinary practice and capitated funding) across southwestern Ontario, Canada. Participants will include HCPs, patients, care partners, and FHT administrative executives. Patients 55 years and older with no history of diagnoses for MCI, dementia, or Alzheimer disease rostered in one of the FHTs participating in the study will be eligible to participate. Their care partners will help triangulate the qualitative data collected from patients. Participating FHTs will identify an occupational therapist from their site to participate in the study; this HCP will both administer the research protocol and participate in semistructured in-depth interviews and questionnaires. Principal component analysis will be conducted on the SCREEN data to understand the test components better. Tests comparing sensitivity, specificity, and test-retest reliability will assess the validity of SCREEN as a screening tool for MCI.
RESULTS: This paper describes the study protocol and its activities to date. Data collection was halted early because of COVID-19 restrictions on research activity, and data analysis is currently in progress.
CONCLUSIONS: At the end of the project, we anticipate having an initial comparative evaluation of the SCREEN as a tool for early detection of MCI in primary care older adult patient populations. Resource constraints on this research study limit our ability to conduct a randomized controlled trial; however, the results will assist developers of the SCREEN in determining whether rigorous controlled testing is warranted.
DERR1-10.2196/25520.}, }
@article {pmid34004093, year = {2021}, author = {Goldfarb, D}, title = {Advances in Diagnosis of Alzheimer Disease and Emerging Treatment Targets.}, journal = {The Journal of clinical psychiatry}, volume = {82}, number = {3}, pages = {}, doi = {10.4088/JCP.LI19012AS1C}, pmid = {34004093}, issn = {1555-2101}, abstract = {Until recently, the diagnosis of Alzheimer disease (AD) could not be truly made until an autopsy was done. Patients' diagnosis relied on clinicians' skills to recognize signs and symptoms of AD, and the diagnosis was often incorrect. The rate of misdiagnosis was higher in earlier disease stages when symptoms are milder. Researchers have made great strides over the past 2 decades in identifying diagnostic biomarkers and treatment targets. Can AD now be diagnosed before patients show symptoms? What do potential treatments look like? This CME presentation highlights exciting developments.}, }
@article {pmid34004089, year = {2021}, author = {Burke, AD and Apostolova, L}, title = {Talking With Patients and Care Partners About Treatment Goals and Challenges in Early-Stage Alzheimer Disease.}, journal = {The Journal of clinical psychiatry}, volume = {82}, number = {3}, pages = {}, doi = {10.4088/JCP.BG20044WC2C}, pmid = {34004089}, issn = {1555-2101}, abstract = {Alzheimer disease (AD) requires timely diagnosis and treatment initiation as early as possible to delay further loss of functioning. Clinicians must attempt to answer patients' and care partners' questions about treatment goals and expected challenges. In this webcast, Drs Burke and Apostolova address topics critical to the care of patients with early-stage AD. They highlight barriers to diagnosis, describe genetic risk factors, and emphasize the role of neuropsychologic testing. Drs Burke and Apostolova agree that, although current medications slow symptom progression associated with AD, emerging therapies offer hope for disease modification. These experts also talk about important conversations to have with patients and their care partners, such as about diet, exercise, driving, and plans for the later stage of illness.}, }
@article {pmid33991495, year = {2021}, author = {Ahmadi, N and Hosseini, MJ and Rostamizadeh, K and Anoush, M}, title = {Investigation of therapeutic effect of curcumin α and β glucoside anomers against Alzheimer's disease by the nose to brain drug delivery.}, journal = {Brain research}, volume = {1766}, number = {}, pages = {147517}, doi = {10.1016/j.brainres.2021.147517}, pmid = {33991495}, issn = {1872-6240}, abstract = {Alzheimer's disease (AD) is one of the greatest geriatric medicinal challenges of our century and is the main disease leading to dementia. Despite extensive scientific research advances, available disease-modifying treatment strategies remained limited; thus, increasing demand for new drugs. In recent years, medicinal plants attracted attention due to their potential role in dementia. In the present study, α and β anomers of curcumin glucosides (CGs) were synthesized and evaluated for Alzheimer's treatment. CGs were synthesized by fusion reaction as a novel and easy method with more advantages (high yield, short reaction time, and low chemicals), and the products were characterized using HNMR. Wistar male rats were used to administer different treatments. They divided into control, sham, Alzheimer, and test groups (Alzheimer + α anomer and Alzheimer + β anomer). Animals received normal saline, Scopolamine (1 mg/kg), high dose anomers, scopolamine, and two doses (12.5 and 25 mg/kg) of anomers, respectively, for 10 days. Then the Morris Water Maze (MWM) test was performed on all animals. Finally, the animals' brains were extracted and homogenized for glutathione, acetylcholine esterase activity, protein carbonyl, and lipid peroxide level detection. The escape latency and the distance towards the hidden platform in Morris water maze in the Alzheimer group were significantly higher than both the control and test groups. Besides, there were no significant differences between sham and control groups in all tests. Both anomers led to a significant increase in glutathione, and acetylcholine levels while they caused a decrease in lipid peroxidation and protein carbonyl levels in brain tissue. It seems that intranasal administration of both anomers positively influenced maze learning in scopolamine receiving subjects. Although both anomers resulted in similar biochemistry tests, a higher dose of β anomer indicated better results than α anomer not only in behavioral tests but also in biochemical tests.}, }
@article {pmid33977953, year = {2021}, author = {Li, J and Wang, T and Liu, P and Yang, F and Wang, X and Zheng, W and Sun, W}, title = {Hesperetin ameliorates hepatic oxidative stress and inflammation via the PI3K/AKT-Nrf2-ARE pathway in oleic acid-induced HepG2 cells and a rat model of high-fat diet-induced NAFLD.}, journal = {Food & function}, volume = {12}, number = {9}, pages = {3898-3918}, doi = {10.1039/d0fo02736g}, pmid = {33977953}, issn = {2042-650X}, mesh = {Animals ; Antioxidant Response Elements ; Diet, High-Fat/*adverse effects ; Hep G2 Cells ; Hepatocytes/*drug effects/metabolism ; Hesperidin/*pharmacology ; Humans ; Interleukin-6/metabolism ; Lipid Metabolism/drug effects ; Liver/drug effects/*metabolism/pathology ; Liver Cirrhosis/pathology ; Male ; NF-E2-Related Factor 2/metabolism ; Non-alcoholic Fatty Liver Disease/etiology/*metabolism/pathology ; Oleic Acid/pharmacology ; Oxidative Stress/*drug effects ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Transcription Factor RelA/metabolism ; Transcriptional Activation ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {Non-alcoholic fatty liver disease (NAFLD) is considered the most common liver disease. Dietary supplementation has become a promising strategy for managing NAFLD. Hesperetin, a citrus flavonoid, is mainly found in citrus fruits (oranges, grapefruit, and lemons) and possesses multiple pharmacological properties, including anti-cancer, anti-Alzheimer and anti-diabetic effects. However, the anti-NAFLD effect and mechanisms of hesperetin remain unclear. In this study, we investigated the therapeutic effect of hesperetin against NAFLD and the underlying mechanism in vitro and in vivo. In oleic acid (OA)-induced HepG2 cells, hesperetin upregulated antioxidant levels (SOD/GPx/GR/GCLC/HO-1) by triggering the PI3 K/AKT-Nrf2 pathway, alleviating OA-induced reactive oxygen species (ROS) overproduction and hepatotoxicity. Furthermore, hesperetin suppressed NF-κB activation and reduced inflammatory cytokine secretion (TNF-α and IL-6). More importantly, we revealed that this anti-inflammatory effect is attributed to reduced ROS overproduction by the Nrf2 pathway, as pre-treatment with Nrf2 siRNA or an inhibitor of superoxide dismutase (SOD) or/and glutathione peroxidase (GPx) abolished hesperetin-induced NF-κB inactivation and reductions in inflammatory cytokine secretion. In a rat model of high-fat diet (HFD)-induced NAFLD, we confirmed that hesperetin relieved hepatic steatosis, oxidative stress, inflammatory cell infiltration and fibrosis. Moreover, hesperetin activated the PI3 K/AKT-Nrf2 pathway in the liver, increasing antioxidant expression and inhibiting NF-κB activation and inflammatory cytokine secretion. In summary, our results demonstrate that hesperetin ameliorates hepatic oxidative stress through the PI3 K/AKT-Nrf2 pathway and that this antioxidative effect further suppresses NF-κB-mediated inflammation during NAFLD progression. Thus, our study suggests that hesperetin may be an effective dietary supplement for improving NAFLD by suppressing hepatic oxidative stress and inflammation.}, }
@article {pmid33977683, year = {2021}, author = {Samandari-Bahraseman, MR and Elyasi, L}, title = {Apelin-13 protects human neuroblastoma SH-SY5Y cells against amyloid-beta induced neurotoxicity: Involvement of anti oxidant and anti apoptotic properties.}, journal = {Journal of basic and clinical physiology and pharmacology}, volume = {}, number = {}, pages = {}, doi = {10.1515/jbcpp-2020-0294}, pmid = {33977683}, issn = {2191-0286}, abstract = {OBJECTIVES: We investigated the effect of apelin-13 on the cellular model of AD, amyloid-β (Aβ) treated SH-SY5Y cells in rats.
METHODS: The SH-SY5Y cells were pretreated with different doses of apelin-13 (1, 2.5, 5, and 10 μg/mL), half an hour before adding 50% Aβ treatment. After 24 h, cells were evaluated for survival, oxidative stress, mitochondrial calcium release, caspase-3, and cytochrome c levels, compared to control group (beta-actin). Statistical analysis was performed by SPSS 16.
RESULTS: Apelin-13 at the dose of 2.5 μg/mL protected against IC50 Aβ (p<0.001). Apelin-13 at doses of 1, 2.5, and 5 μg/mL showed protective effects against the reactive oxygen species (ROS) produced by Aβ (p<0.001). Apelin-13 at doses of 2.5 and 5 μg/mL reduced calcium release, caspase-3, and cytochrome c (all p<0.001).
CONCLUSIONS: Apelin-13 prevented apoptosis, oxidative stress, and mitochondrial toxicity and can be a suitable option for treatment of AD. The appropriate treatment strategy for humans has to be investigated in future studies.}, }
@article {pmid33970919, year = {2021}, author = {Stojanovic, F and Taktek, M and Khieu, NH and Huang, J and Jiang, S and Rennie, K and Chakravarthy, B and Costain, WJ and Cuperlovic-Culf, M}, title = {NMR analysis of the correlation of metabolic changes in blood and cerebrospinal fluid in Alzheimer model male and female mice.}, journal = {PloS one}, volume = {16}, number = {5}, pages = {e0250568}, pmid = {33970919}, issn = {1932-6203}, abstract = {The development of effective therapies as well as early, molecular diagnosis of Alzheimer's disease is impeded by the lack of understanding of the underlying pathological mechanisms. Metabolomics studies of body fluids as well as brain tissues have shown major changes in metabolic profiles of Alzheimer's patients. However, with analysis performed at the late stages of the disease it is not possible to distinguish causes and consequence. The mouse model APP/PS1 expresses a mutant amyloid precursor protein resulting in early Amyloid β (Aβ) accumulation as well as many resulting physiological changes including changes in metabolic profile and metabolism. Analysis of metabolic profile of cerebrospinal fluid (CSF) and blood of APP/PS1 mouse model can provide information about metabolic changes in these body fluids caused by Aβ accumulation. Using our novel method for analysis of correlation and mathematical ranking of significant correlations between metabolites in CSF and blood, we have explored changes in metabolite correlation and connectedness in APP/PS1 and wild type mice. Metabolites concentration and correlation changes in CSF, blood and across the blood brain barrier determined in this work are affected by the production of amyloid plaque. Metabolite changes observed in the APP/PS1 mouse model are the response to the mutation causing plaque formation, not the cause for the plaque suggesting that they are less relevant in the context of early treatment and prevention then the metabolic changes observed only in humans.}, }
@article {pmid33968600, year = {2021}, author = {Gürdere, MB and Budak, Y and Kocyigit, UM and Taslimi, P and Tüzün, B and Ceylan, M}, title = {ADME properties, bioactivity and molecular docking studies of 4-amino-chalcone derivatives: new analogues for the treatment of Alzheimer, glaucoma and epileptic diseases.}, journal = {In silico pharmacology}, volume = {9}, number = {1}, pages = {34}, pmid = {33968600}, issn = {2193-9616}, abstract = {In this study, in vitro inhibition effects of (E)-1-(4-aminophenyl)-3-(aryl) prop-2-en-1-one (4-amino-chalcones) derivatives (3a-o) on acetylcholinesterase (AChE) enzyme and human erythrocyte carbonic anhydrase I and II isoenzymes (hCA I- II) were investigated. And also, the biological activities of 4-amino-chalcone derivatives against enzymes which names are acetylcholinesterase (PDB ID: 1OCE), human Carbonic Anhydrase I (PDB ID: 2CAB), human carbonic anhydrase II (PDB ID: 3DC3), were compared. After the results obtained, ADME/T analysis was performed in order to use 4-amino-chalcone derivatives as a drug in the future. Effective inhibitors of carbonic anhydrase I and II isozymes (hCAI and II) and acetylcholinesterase (AChE) enzymes with Ki values in the range of 2.55 ± 0.35-11.75 ± 3.57 nM for hCA I, 4.31 ± 0.78-17.55 ± 5.86 nM for hCA II and 96.01 ± 25.34-1411.41 ± 32.88 nM for AChE, respectively, were the 4-amino-chalcone derivatives (3a-o) molecules.
Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-021-00094-x.}, }
@article {pmid33964436, year = {2021}, author = {Huang, Y and Huang, W and Yang, G and Wang, R and Ma, L}, title = {Design and synthesis of novel diosgenin-triazole hybrids targeting inflammation as potential neuroprotective agents.}, journal = {Bioorganic & medicinal chemistry letters}, volume = {43}, number = {}, pages = {128092}, doi = {10.1016/j.bmcl.2021.128092}, pmid = {33964436}, issn = {1464-3405}, abstract = {Alzheimer's disease is a progressive neurodegenerative disease, and its incidence is expected to increase as the global population ages. Recent studies provide increasing evidence that inflammation plays a key role in the pathogenesis and progression of AD. Diosgenin, an active ingredient in Dioscorea nipponica Makino, is a promising bioactive lead compound in the treatment of Alzheimer's disease, which exhibited anti-inflammatory activity. To search for more efficient anti-Alzheimer agents, a series of novel diosgenin-triazolyl hybrids were designed, synthesized, and their neuroprotective effects against oxygen-glucose deprivation-induced neurotoxicity and LPS-induced NO production were evaluated. Most of these new hybrids displayed better activities than DIO. In particular, the promising compound L6 not only demonstrated an excellent neuroprotective effect but also showed the best anti-inflammatory activity. The structure-activity relationship study illustrated that the introduction of benzyl or phenyl triazole did improve the activity, and the introduction of benzyl triazole was better than that of phenyl triazole. The results we obtained showed that the diosgenin skeleton could be a promising structural template for the development of new anti-Alzheimer drug candidates, and compound L6 has the potential to be an important lead compound for further research.}, }
@article {pmid33962665, year = {2021}, author = {Berres, M and Monsch, AU and Spiegel, R}, title = {Using historical data to facilitate clinical prevention trials in Alzheimer disease? An analysis of longitudinal MCI (mild cognitive impairment) data sets.}, journal = {Alzheimer's research & therapy}, volume = {13}, number = {1}, pages = {97}, pmid = {33962665}, issn = {1758-9193}, mesh = {*Alzheimer Disease/drug therapy ; *Cognitive Dysfunction ; Cohort Studies ; Disease Progression ; Germany ; Humans ; Neuropsychological Tests ; Placebos ; Randomized Controlled Trials as Topic ; Switzerland ; }, abstract = {BACKGROUND: The Placebo Group Simulation Approach (PGSA) aims at partially replacing randomized placebo-controlled trials (RPCTs), making use of data from historical control groups in order to decrease the needed number of study participants exposed to lengthy placebo treatment. PGSA algorithms to create virtual control groups were originally derived from mild cognitive impairment (MCI) data of the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. To produce more generalizable algorithms, we aimed to compile five different MCI databases in a heuristic manner to create a "standard control algorithm" for use in future clinical trials.
METHODS: We compared data from two North American cohort studies (n=395 and 4328, respectively), one company-sponsored international clinical drug trial (n=831) and two convenience patient samples, one from Germany (n=726), and one from Switzerland (n=1558).
RESULTS: Despite differences between the five MCI samples regarding inclusion and exclusion criteria, their baseline demographic and cognitive performance data varied less than expected. However, the five samples differed markedly with regard to their subsequent cognitive performance and clinical development: (1) MCI patients from the drug trial did not deteriorate on verbal fluency over 3 years, whereas patients in the other samples did; (2) relatively few patients from the drug trial progressed from MCI to dementia (about 10% after 4 years), in contrast to the other four samples with progression rates over 30%.
CONCLUSION: Conventional MCI criteria were insufficient to allow for the creation of well-defined and internationally comparable samples of MCI patients. More recently published criteria for MCI or "MCI due to AD" are unlikely to remedy this situation. The Alzheimer scientific community needs to agree on a standard set of neuropsychological tests including appropriate selection criteria to make MCI a scientifically more useful concept. Patient data from different sources would then be comparable, and the scientific merits of algorithm-based study designs such as the PGSA could be properly assessed.}, }
@article {pmid33957376, year = {2021}, author = {Şeker, M and Özbek, Y and Yener, G and Özerdem, MS}, title = {Complexity of EEG Dynamics for Early Diagnosis of Alzheimer's Disease Using Permutation Entropy Neuromarker.}, journal = {Computer methods and programs in biomedicine}, volume = {206}, number = {}, pages = {106116}, doi = {10.1016/j.cmpb.2021.106116}, pmid = {33957376}, issn = {1872-7565}, mesh = {*Alzheimer Disease/diagnosis ; *Cognitive Dysfunction/diagnosis ; Early Diagnosis ; Electroencephalography ; Entropy ; Humans ; }, abstract = {BACKGROUND AND OBJECTIVE: Electroencephalogram (EEG) is one of the most demanded screening tools that investigates the effects of Alzheimer's Disease (AD) on human brain. Identification of AD in early stage gives rise to efficient treatment in dementia. Mild Cognitive Impairment (MCI) is considered as a conversion stage. Reducing EEG complexity can be used as a marker to detect AD. The aim of this study is to develop a 3-way diagnostic classification using EEG complexity in the detection of MCI/AD in clinical practice. This study also investigates the effects of different eyes states, i.e. eyes-open, eyes-closed on classification performance.
METHODS: EEG recordings from 85 AD, 85 MCI subjects, and 85 Healthy Controls with eyes-open and eyes- closed are analyzed. Permutation Entropy (PE) values are computed from frontal, central, parietal, temporal, and occipital regions for each EEG epoch. Distribution of PE values are visualized to observe discrimination of MCI/AD with HC. Visual investigations are combined with statistical analysis using ANOVA to determine whether groups are significant or not. Multinomial Logistic Regression model is applied to feature sets in order to classify participants individually.
RESULTS: Distribution of measured PE shows that EEG complexity is lower in AD and higher in HC group. MCI group is observed as an intermediate form due to heterogeneous values. Results from 3-way classification indicate that F1-scores and rates of sensitivity and specificity achieve the highest overall discrimination rates reaching up to 100% for at TP8 for eyes-closed condition; and C3, C4, T8, O2 electrodes for eyes-open condition. Classification of HC from both patient groups is achieved best. Eyes-open state increases discrimination of MCI and AD.
CONCLUSIONS: This nonlinear EEG methodology study contributes to literature with high discrimination rates for identification of AD. PE is recommended as a practical diagnostic neuro-marker for AD studies. Resting state EEG at eyes-open condition can be more advantageous over eyes-closed EEG recordings for diagnosis of AD.}, }
@article {pmid33953832, year = {2021}, author = {Ikram, M and Jo, MG and Park, TJ and Kim, MW and Khan, I and Jo, MH and Kim, MO}, title = {Oral Administration of Gintonin Protects the Brains of Mice against Aβ-Induced Alzheimer Disease Pathology: Antioxidant and Anti-Inflammatory Effects.}, journal = {Oxidative medicine and cellular longevity}, volume = {2021}, number = {}, pages = {6635552}, pmid = {33953832}, issn = {1942-0994}, mesh = {Administration, Oral ; Alzheimer Disease/*drug therapy/*prevention & control ; Animals ; Anti-Inflammatory Agents/pharmacology/*therapeutic use ; Antioxidants/pharmacology/*therapeutic use ; Disease Models, Animal ; Glycoproteins/*therapeutic use ; Male ; Mice ; Oxidative Stress/*drug effects ; Plant Extracts/pharmacology/*therapeutic use ; }, abstract = {The study was aimed at analyzing the protective effects of gintonin in an amyloid beta- (Aβ-) induced Alzheimer's disease (AD) mouse model. For the development of the Aβ-induced AD mouse model, the amyloid-β (Aβ 1-42) peptide was stereotaxically injected into the brains of mice. Subsequently, gintonin was administered at a dose of 100 mg/kg/day/per oral (p.o) for four weeks daily, and its effects were evaluated by using western blotting, fluorescence analysis of brain sections, biochemical tests, and memory-related behavioral evaluations. To elucidate the effects of gintonin at the mechanistic level, the activation of endogenous antioxidant mechanisms, as well as the activation of astrocytes, microglia, and proinflammatory mediators such as nuclear factor erythroid 2-related factor 2 (NRF-2) and heme oxygenase-1 (HO-1), was evaluated. In addition, microglial cells (BV-2 cells) were used to analyze the effects of gintonin on microglial activation and signaling mechanisms. Collectively, the results suggested that gintonin reduced elevated oxidative stress by improving the expression of NRF-2 and HO-1 and thereby reducing the generation of reactive oxygen species (ROS) and lipid peroxidation (LPO). Moreover, gintonin significantly suppressed activated microglial cells and inflammatory mediators in the brains of Aβ-injected mice. Our findings also indicated improved synaptic and memory functions in the brains of Aβ-injected mice after treatment with gintonin. These results suggest that gintonin may be effective for relieving AD symptoms by regulating oxidative stress and inflammatory processes in a mouse model of AD. Collectively, the findings of this preclinical study highlight and endorse the potential, multitargeted protective effects of gintonin against AD-associated oxidative damage, neuroinflammation, cognitive impairment, and neurodegeneration.}, }
@article {pmid33952652, year = {2021}, author = {Ballarini, T and Melo van Lent, D and Brunner, J and Schröder, A and Wolfsgruber, S and Altenstein, S and Brosseron, F and Buerger, K and Dechent, P and Dobisch, L and Duzel, E and Ertl-Wagner, B and Fliessbach, K and Freiesleben, SD and Frommann, I and Glanz, W and Hauser, D and Haynes, JD and Heneka, MT and Janowitz, D and Kilimann, I and Laske, C and Maier, F and Metzger, CD and Munk, M and Perneczky, R and Peters, O and Priller, J and Ramirez, A and Rauchmann, B and Roy, N and Scheffler, K and Schneider, A and Spottke, A and Spruth, EJ and Teipel, SJ and Vukovich, R and Wiltfang, J and Jessen, F and Wagner, M and , }, title = {Mediterranean Diet, Alzheimer Disease Biomarkers and Brain Atrophy in Old Age.}, journal = {Neurology}, volume = {}, number = {}, pages = {}, pmid = {33952652}, issn = {1526-632X}, abstract = {OBJECTIVE: To determine if following a Mediterranean-like diet (MeDi) relates to cognitive functions and in vivo biomarkers for Alzheimer's disease (AD), we analyzed cross-sectional data from the German Longitudinal Cognitive Impairment and Dementia Study METHOD: The sample (n=512, mean age: 69.5±5.9 years) included 169 cognitively normal participants and subjects at higher AD risk (53 AD relatives, 209 SCD and 81 MCI). We defined MeDi adherence based on the Food Frequency Questionnaire. Brain volume outcomes were generated via voxel-based morphometry on T1-MRI and cognitive performance with an extensive neuropsychological battery. AD-related biomarkers (Aβ42/40 ratio, pTau181) in cerebrospinal fluid were assessed in n=226 individuals. We analyzed the associations between MeDi and the outcomes with linear regression models controlling for several covariates. Additionally, we applied hypothesis-driven mediation and moderation analysis.
RESULTS: Higher MeDi adherence related to larger mediotemporal gray matter volume (p<0.05 FWE corrected), better memory (β±SE = 0.03 ± 0.02; p=0.038), and less amyloid (Aβ42/40 ratio, β±SE = 0.003 ± 0.001; p=0.008) and pTau181 pathology (β±SE = -1.96±0.68; p=0.004). Mediotemporal volume mediated the association between MeDi and memory (40% indirect mediation). Finally, MeDi favorably moderated the associations between Aβ42/40 ratio, pTau181 and mediotemporal atrophy. Results were consistent correcting for ApoE-ε4 status.
CONCLUSION: Our findings corroborate the view of MeDi as a protective factor against memory decline and mediotemporal atrophy. Importantly, they suggest that these associations might be explained by a decrease of amyloidosis and tau-pathology. Longitudinal and dietary intervention studies should further examine this conjecture and its treatment implications.}, }
@article {pmid33946559, year = {2021}, author = {Ahmad, SS and Khan, MB and Ahmad, K and Lim, JH and Shaikh, S and Lee, EJ and Choi, I}, title = {Biocomputational Screening of Natural Compounds against Acetylcholinesterase.}, journal = {Molecules (Basel, Switzerland)}, volume = {26}, number = {9}, pages = {}, pmid = {33946559}, issn = {1420-3049}, support = {2020R1A6A1A03044512//National Research Foundation of Korea/ ; NRF-2021R1A2C2004177//National Research Foundation of Korea/ ; NRF-2019R1C1C1006542//National Research Foundation of Korea/ ; }, mesh = {Acetylcholinesterase/*chemistry ; Alzheimer Disease/drug therapy ; Binding Sites ; Biological Products/*chemistry/pharmacology ; Cholinesterase Inhibitors/*chemistry/pharmacology ; Computational Biology/*methods ; Databases, Pharmaceutical ; Humans ; *Molecular Docking Simulation ; *Molecular Dynamics Simulation ; Molecular Structure ; Protein Binding ; Protein Conformation ; Structure-Activity Relationship ; }, abstract = {Alzheimer's disease (AD) is the most common form of dementia and is characterized by irreversible and progressive neurodegeneration. Cholinergic dysfunction has been reported in AD, and several cholinesterase inhibitors, including natural compounds and synthetic analogs, have been developed to treat the disease. However, there is currently no treatment for AD, as most drug-like compounds have failed in clinical trials. Acetylcholinesterase (AChE) is the target of most drugs used commercially to treat AD. This work focused on screening natural compounds obtained from the ZINC database (224, 205 compounds) against AChE to identify those possibly capable of enabling the management of AD. Indirubin and dehydroevodiamine were the best potential AChE inhibitors with free binding energies of -10.03 and -9.00 kcal/mol, respectively. The key residue (His447) of the active site of AChE was found to participate in complex interactions with these two molecules. Six H-bonds were involved in the 'indirubin-AChE' interaction and three H-bonds in the 'dehydroevodiamine-AChE' interaction. These compounds were predicted to cross the blood-brain barrier (BBB) and to exhibit high levels of intestinal absorption. Furthermore, 'indirubin-AChE' and 'dehydroevodiamine-AChE' complexes were found to be stable, as determined by root mean square deviation (RMSD) during a 50 ns molecular dynamics simulation study. Based on the free binding energies and stabilities obtained by simulation studies, we recommend that experimental studies be undertaken on indirubin and dehydroevodiamine with a view towards their potential use as treatments for AD.}, }
@article {pmid33935095, year = {2021}, author = {Somaa, F}, title = {A Review of the Application of Hyperbaric Oxygen Therapy in Alzheimer's Disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {81}, number = {4}, pages = {1361-1367}, doi = {10.3233/JAD-210157}, pmid = {33935095}, issn = {1875-8908}, abstract = {Alzheimer's disease (AD) is considered as the most common cause of dementia in elderly population. While the exact mechanism of AD has not been discovered, hyperbolic oxygen therapy (HBOT) has been proven to be effective in the treatment of this degenerative disease. The objectives of this article are to review the literature available on molecular and physiological mechanisms underlying HBOT and its efficacy in treating AD and to review the effectiveness of HBOT as an alternate treatment intervention in both human and animal models. 391 full text articles were included in the review after literature search between 1980-2021 from two online data base (ScienceDirect and PubMed). The following key words were used: 'hyperbaric oxygen therapy' and 'Alzheimer disease.' Based on the outcomes of clinical and experimental studies, this review advocates the use of HBOT for the treatment of AD. This review explores future directions and recommends further research into a treatment protocol that will maintain long-term cognitive health of AD patients.}, }
@article {pmid33933071, year = {2021}, author = {Balmik, AA and Sonawane, SK and Chinnathambi, S}, title = {The extracellular HDAC6 ZnF UBP domain modulates the actin network and post-translational modifications of Tau.}, journal = {Cell communication and signaling : CCS}, volume = {19}, number = {1}, pages = {49}, pmid = {33933071}, issn = {1478-811X}, support = {CSIR NCL MLP029526//Council of Scientific and Industrial Research, India/ ; }, abstract = {BACKGROUND: Microtubule-associated protein Tau undergoes aggregation in Alzheimer`s disease (AD) and a group of other related diseases collectively known as Tauopathies. In AD, Tau forms aggregates, which are deposited intracellularly as neurofibrillary tangles. Histone deacetylase-6 (HDAC6) plays an important role in aggresome formation, where it recruits polyubiquitinated aggregates to the motor protein dynein.
METHODS: Here, we have studied the effects of HDAC6 ZnF UBP on Tau phosphorylation, ApoE localization, GSK-3β regulation and cytoskeletal organization in neuronal cells by immunocytochemical analysis. This analysis reveals that the cell exposure to the UBP-type zinc finger domain of HDAC6 (HDAC6 ZnF UBP) can modulate Tau phosphorylation and actin cytoskeleton organization.
RESULTS: HDAC6 ZnF UBP treatment to cells did not affect their viability and resulted in enhanced neurite extension and formation of structures similar to podosomes, lamellipodia and podonuts suggesting the role of this domain in actin re-organization. Also, HDAC6 ZnF UBP treatment caused increase in nuclear localization of ApoE and tubulin localization in microtubule organizing centre (MTOC). Therefore, our studies suggest the regulatory role of this domain in different aspects of neurodegenerative diseases. Upon HDAC6 ZnF UBP treatment, inactive phosphorylated form of GSK-3β increases without any change in total GSK-3β level.
CONCLUSIONS: HDAC6 ZnF UBP was found to be involved in cytoskeletal re-organization by modulating actin dynamics and tubulin localization. Overall, our study suggests that ZnF domain of HDAC6 performs various regulatory functions apart from its classical function in aggresome formation in protein misfolding diseases. Video abstract.}, }
@article {pmid33920326, year = {2021}, author = {Cruz-Vicente, P and Passarinha, LA and Silvestre, S and Gallardo, E}, title = {Recent Developments in New Therapeutic Agents against Alzheimer and Parkinson Diseases: In-Silico Approaches.}, journal = {Molecules (Basel, Switzerland)}, volume = {26}, number = {8}, pages = {}, pmid = {33920326}, issn = {1420-3049}, support = {Centro-01-0145-FEDER-000019-C4-Centro de Competências em Cloud Computing//European Regional Development Fund through the "Programa Operacional Regional do Centro (Centro 2020)-Sistema de Apoio à Investigação Científica e Tecnológica-Programas Integrados de IC&DT (Covilhã)/ ; UIDB/00709/2020//Fundação para a Ciência e a Tecnologia/ ; UIDP/04378/2020//Fundação para a Ciência e a Tecnologia/ ; UIDB/04378/2020//Fundação para a Ciência e a Tecnologia/ ; SFRH/BSAB/150376/2019//Fundação para a Ciência e a Tecnologia/ ; }, mesh = {Acetylcholinesterase/genetics/metabolism ; Alzheimer Disease/*drug therapy/genetics/metabolism/pathology ; Amyloid Precursor Protein Secretases/antagonists & inhibitors/genetics/metabolism ; Antiparkinson Agents/chemical synthesis/*therapeutic use ; Aspartic Acid Endopeptidases/antagonists & inhibitors/genetics/metabolism ; Catechol O-Methyltransferase/genetics/metabolism ; Cholinesterase Inhibitors/chemical synthesis/*therapeutic use ; Clinical Trials as Topic ; Computer Simulation ; Dopamine Agents/chemical synthesis/*therapeutic use ; Drug Design ; Excitatory Amino Acid Antagonists/chemical synthesis/*therapeutic use ; GPI-Linked Proteins/antagonists & inhibitors/genetics/metabolism ; Gene Expression Regulation ; Humans ; Neuroprotective Agents/chemical synthesis/*therapeutic use ; Parkinson Disease/*drug therapy/genetics/metabolism/pathology ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors/genetics/metabolism ; Sirtuins/antagonists & inhibitors/genetics/metabolism ; }, abstract = {Neurodegenerative diseases (ND), including Alzheimer's (AD) and Parkinson's Disease (PD), are becoming increasingly more common and are recognized as a social problem in modern societies. These disorders are characterized by a progressive neurodegeneration and are considered one of the main causes of disability and mortality worldwide. Currently, there is no existing cure for AD nor PD and the clinically used drugs aim only at symptomatic relief, and are not capable of stopping neurodegeneration. Over the last years, several drug candidates reached clinical trials phases, but they were suspended, mainly because of the unsatisfactory pharmacological benefits. Recently, the number of compounds developed using in silico approaches has been increasing at a promising rate, mainly evaluating the affinity for several macromolecular targets and applying filters to exclude compounds with potentially unfavorable pharmacokinetics. Thus, in this review, an overview of the current therapeutics in use for these two ND, the main targets in drug development, and the primary studies published in the last five years that used in silico approaches to design novel drug candidates for AD and PD treatment will be presented. In addition, future perspectives for the treatment of these ND will also be briefly discussed.}, }
@article {pmid33920113, year = {2021}, author = {Whitmore, CA and Boules, MI and Behof, WJ and Haynes, JR and Koktysh, D and Rosenberg, AJ and Tantawy, MN and Pham, W}, title = {Design, Synthesis, and Validation of a Novel [11C]Promethazine PET Probe for Imaging Abeta Using Autoradiography.}, journal = {Molecules (Basel, Switzerland)}, volume = {26}, number = {8}, pages = {}, pmid = {33920113}, issn = {1420-3049}, support = {AG061138/NH/NIH HHS/United States ; }, mesh = {Alzheimer Disease/*diagnosis/diagnostic imaging/pathology ; Animals ; Autoradiography ; Brain/*diagnostic imaging/drug effects ; Humans ; Mice ; Plaque, Amyloid/diagnosis/diagnostic imaging/pathology ; Positron-Emission Tomography ; Promethazine/chemical synthesis/chemistry/*pharmacology ; Radiochemistry ; Radiopharmaceuticals/chemical synthesis/chemistry/*pharmacology ; }, abstract = {Promethazine, an antihistamine drug used in the clinical treatment of nausea, has been demonstrated the ability to bind Abeta in a transgenic mouse model of Alzheimer's disease. However, so far, all of the studies were performed in vitro using extracted tissues. In this work, we report the design and synthesis of a novel [11C]promethazine PET radioligand for future in vivo studies. The [11C]promethazine was isolated by RP-HPLC with radiochemical purity >95% and molar activity of 48 TBq/mmol. The specificity of the probe was demonstrated using human hippocampal tissues via autoradiography.}, }
@article {pmid33916300, year = {2021}, author = {Senol Deniz, FS and Eren, G and Orhan, IE and Sener, B and Ozgen, U and Aldaba, R and Calis, I}, title = {Outlining In Vitro and In Silico Cholinesterase Inhibitory Activity of Twenty-Four Natural Products of Various Chemical Classes: Smilagenin, Kokusaginine, and Methyl Rosmarinate as Emboldening Inhibitors.}, journal = {Molecules (Basel, Switzerland)}, volume = {26}, number = {7}, pages = {}, pmid = {33916300}, issn = {1420-3049}, support = {2021//Türkiye Bilimler Akademisi/ ; }, mesh = {Binding Sites ; Biological Products/*chemistry/isolation & purification/*pharmacology ; Cholinesterase Inhibitors/*chemistry/isolation & purification/*pharmacology ; Furans/chemistry/pharmacology ; Inhibitory Concentration 50 ; Molecular Conformation ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Molecular Structure ; Protein Binding ; Quinolines/chemistry/pharmacology ; Spirostans/chemistry/pharmacology ; Structure-Activity Relationship ; }, abstract = {Cholinesterase (ChE) inhibition is an important treatment strategy for Alzheimer's disease (AD) as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are involved in the pathology of AD. In the current work, ChE inhibitory potential of twenty-four natural products from different chemical classes (i.e., diosgenin, hecogenin, rockogenin, smilagenin, tigogenin, astrasieversianins II and X, astragalosides I, IV, and VI, cyclocanthosides E and G, macrophyllosaponins A-D, kokusaginin, lamiide, forsythoside B, verbascoside, alyssonoside, ipolamide, methyl rosmarinate, and luteolin-7-O-glucuronide) was examined using ELISA microtiter assay. Among them, only smilagenin and kokusaginine displayed inhibitory action against AChE (IC50 = 43.29 ± 1.38 and 70.24 ± 2.87 µg/mL, respectively). BChE was inhibited by only methyl rosmarinate and kokusaginine (IC50 = 41.46 ± 2.83 and 61.40 ± 3.67 µg/mL, respectively). IC50 values for galantamine as the reference drug were 1.33 ± 0.11 µg/mL for AChE and 52.31 ± 3.04 µg/mL for BChE. Molecular docking experiments showed that the orientation of smilagenin and kokusaginine was mainly driven by the interactions with the peripheral anionic site (PAS) comprising residues of hAChE, while kokusaginine and methyl rosmarinate were able to access deeper into the active gorge in hBChE. Our data indicate that similagenin, kokusaginine, and methyl rosmarinate could be hit compounds for designing novel anti-Alzheimer agents.}, }
@article {pmid33911901, year = {2021}, author = {Pisa, F and Reinold, J and Lavikainen, P and Koponen, M and Taipale, H and Tanskanen, A and Tiihonen, J and Hartikainen, S and Tolppanen, AM}, title = {Hip Fracture Risk in Antiepileptic Drug Initiators and Non-Initiators with Alzheimer's Disease.}, journal = {Clinical epidemiology}, volume = {13}, number = {}, pages = {295-307}, pmid = {33911901}, issn = {1179-1349}, abstract = {Objective: To determine the risk of hip fracture in persons with Alzheimer´s disease (AD) who initiated antiepileptic drugs (AEDs).
Methods: In the Medication use and AD (MEDALZ) cohort of 70,719 Finnish community dwellers with clinically verified incident AD diagnosis in 2005-2011, we identified all incident users of AEDs using national Prescription register. AEDs were classified as older (valproate, carbamazepine, clonazepam, phenytoin, levetiracetam, primidone) or newer (pregabalin, gabapentin, oxcarbazepine, lamotrigine, topiramate). We matched each user to 2 non-users. Incident hip fractures until 2015 were identified from the Care register for health care. We calculated inverse probability of treatment weighted hazard ratios (HR), with 95% confidence intervals, using Cox regression.
Results: Altogether 5522 incident users were identified and matched to 11,044 non-users (in both groups, women: 65%; median age: 81 years). Altogether 53.3% of users initiated with newer AEDs (pregabalin 79.8%, gabapentin 10.2%) while 46.7% initiated with older AEDs (valproate 67.6%, carbamazepine 13.0%). Age- and sex-adjusted IR of hip fracture per 100 person-years was 1.8 (95% CI 1.6-1.9) in non-users and 2.0 (95% CI 1.8-2.2) in users. Increased risk of hip fracture was observed in users (HR 1.17, 95% CI 1.05-1.30) compared with non-users. The risk was higher for short duration of use (<14 weeks, HR 3.64, 95% CI 2.90-4.58) than for medium duration (14 to <64 weeks, HR 1.74, 95% CI 1.48-2.05) or ≥64 weeks' use (HR 1.23, 95% CI 1.08-1.40), compared to non-users with same follow-up time. Older AEDs had HR of 1.46 (1.03-2.08) compared with newer AEDs.
Conclusion: Our results imply that AED use is associated with an increased risk of hip fracture in people with AD. These findings prompt careful consideration before prescribing AEDs to persons with AD. Persons with AD treated with antiepileptics should be carefully monitored due to their increased risk of falling and fractures.}, }
@article {pmid33884656, year = {2021}, author = {Zou, H and Zhou, N and Huang, Y and Luo, A and Sun, J}, title = {Phenotypes, roles, and modulation of regulatory lymphocytes in periodontitis and its associated systemic diseases.}, journal = {Journal of leukocyte biology}, volume = {}, number = {}, pages = {}, doi = {10.1002/JLB.3VMR0321-027RRR}, pmid = {33884656}, issn = {1938-3673}, abstract = {Periodontitis is a common chronic inflammatory disease that can result in tooth loss and poses a risk to systemic health. Lymphocytes play important roles in periodontitis through multiple mechanisms. Regulatory lymphocytes including regulatory B cells (Bregs) and T cells (Tregs) are the main immunosuppressive cells that maintain immune homeostasis, and are critical to our understanding of the pathogenesis of periodontitis and the development of effective treatments. In this review, we discuss the phenotypes, roles, and modulating strategies of regulatory lymphocytes including Bregs and Tregs in periodontitis and frequently cooccurring inflammatory diseases such as rheumatoid arthritis, Alzheimer disease, diabetes mellitus, and stroke. The current evidence suggests that restoring immune balance through therapeutic targeting of regulatory lymphocytes is a promising strategy for the treatment of periodontitis and other systemic inflammatory diseases.}, }
@article {pmid33883015, year = {2021}, author = {Marchi, LZ and Ferreira, RGD and de Lima, GNS and da Silva, JAS and da Cruz, DMC and Fernandez-Calvo, B and Andrade, SMMDS}, title = {Multisite transcranial direct current stimulation associated with cognitive training in episodic memory and executive functions in individuals with Alzheimer's disease: a case report.}, journal = {Journal of medical case reports}, volume = {15}, number = {1}, pages = {185}, pmid = {33883015}, issn = {1752-1947}, mesh = {Aged, 80 and over ; Alzheimer Disease/*therapy ; Brazil ; Cognition/*physiology ; Executive Function ; Female ; Humans ; Memory/*physiology ; *Memory, Episodic ; *Transcranial Direct Current Stimulation ; Treatment Outcome ; }, abstract = {BACKGROUND: Dementia is among the most common chronic noncommunicable neurodegenerative diseases. In the long term, it causes disability and loss of autonomy and independence. It is estimated that there are 35.6 million people with Alzheimer's disease worldwide. Several clinical aspects of this disease have been widely studied, but the main focus of study has been memory loss, which is one of the first symptoms. The present study proposes an innovative intervention that combines cognitive training and multisite transcranial direct current stimulation, which interferes with other clinical aspects of the subject.
CASE PRESENTATION: In this study, we present two subjects diagnosed with mild Alzheimer's disease. Subject 1 is an 82-year-old Brazilian Latin American woman with a high school education who was diagnosed with Alzheimer's disease 8 years ago and uses an Exelon patch. Subject 2 is an 88-year-old Brazilian Latin American woman with an incomplete primary education who was diagnosed with Alzheimer's disease 1 year ago and received medical orientation to temporarily discontinue medications for Alzheimer's disease. Both participants were subjected to intermittent cognitive training sessions and concomitant transcranial stimulation in three weekly 30-minute sessions in which a brain area was stimulated every 10 minutes for a total of 24 sessions, with a 2-month follow-up. Transcranial stimulation was applied to six different regions of the cortex: the dorsolateral prefrontal cortex bilaterally, the somatosensory association cortex bilaterally and Broca's and Wernicke's areas. Comparing the results of tests performed before and after the treatment period, a 1-point improvement was observed for both subjects on the Word Recall task of the Alzheimer Disease Assessment Scale, which evaluates symptoms related to the decline of episodic memory. Improvement in the executive functions domain was also observed through the results of the Stroop test, Victoria version.
CONCLUSIONS: The results from the two presented cases show that multisite transcranial stimulation associated with cognitive training is an effective adjuvant method for the treatment of patients diagnosed with mild Alzheimer's disease. Its effects can benefit patients' daily routines by reducing cognitive deficits by keeping intact areas active and/or compensating for lost functions. Trial registration NCT02772185. Registered 13 May 2016, http://www.clinicaltrials.gov/ct2/show/NCT02772185 . Retrospectively registered.}, }
@article {pmid33881530, year = {2021}, author = {Lin, CH and Chen, PK and Wang, SH and Lane, HY}, title = {Effect of Sodium Benzoate on Cognitive Function Among Patients With Behavioral and Psychological Symptoms of Dementia: Secondary Analysis of a Randomized Clinical Trial.}, journal = {JAMA network open}, volume = {4}, number = {4}, pages = {e216156}, pmid = {33881530}, issn = {2574-3805}, mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/*drug therapy ; Cognition/*drug effects ; Double-Blind Method ; Drug Administration Schedule ; Female ; Humans ; Male ; Sex Factors ; Sodium Benzoate/*administration & dosage ; }, abstract = {Importance: Female gender is a major risk factor for dementia; however, gender has not yet been adequately addressed by clinical trials. A recent study demonstrated that sodium benzoate, a D-amino acid oxidase inhibitor, improved cognitive function in early-phase Alzheimer disease.
Objective: To examine the potential gender difference in the effects of benzoate treatment on the behavioral and psychological symptoms of dementia (BPSD).
This post hoc secondary analysis used data from a randomized, double-masked, placebo-controlled trial conducted in 3 major medical centers in Taiwan and enrolled 97 patients with BPSD. Data were analyzed between February 2014 and November 2017.
Interventions: Six weeks of treatment of 250 to 1500 mg/d of sodium benzoate or placebo.
Main Outcomes and Measures: The primary outcome measures were Alzheimer disease assessment scale-cognitive subscale (ADAS-cog) and Behavioral Pathology in Alzheimer Disease Rating Scale (BEHAVE-AD) scores.
Results: Among 97 total participants (62 [64%] women; mean [SD] age, 75.4 [7.7] years), 49 patients (30 women and 19 men) were randomized to sodium benzoate, and 48 (32 women and 16 men) were randomized to placebo. Among 62 women, 6-week benzoate treatment significantly surpassed placebo in the effects on ADAS-cog performance (mean [SD] difference in score between baseline and end point, -3.1 [6.4] points vs 0 [4.5] points; Cohen d = 0.56; P = .04) but not BEHAVE-AD performance. In contrast, among 35 men, the 2 treatment groups did not differ significantly in both ADAS-cog and BEHAVE-AD scores. Compared with placebo, benzoate treatment also increased estradiol to follicle-stimulating hormone ratios among women (mean [SD] difference between baseline and end point, 0 [0.2] vs -0.1 [0.3]; P = .03).
Conclusions and Relevance: These findings suggest that benzoate treatment may improve cognitive function in women with later-phase dementia. In the future, longer dose-finding trials are warranted to further clarify the efficacy of benzoate for later-phase dementia and investigate the role of sex hormones and other factors in the pathogenesis of dementia.
Trial Registration: ClinicalTrials.gov Identifier: NCT02103673.}, }
@article {pmid33872681, year = {2021}, author = {El Gaamouch, F and Liu, K and Lin, HY and Wu, C and Wang, J}, title = {Development of grape polyphenols as multi-targeting strategies for Alzheimer's disease.}, journal = {Neurochemistry international}, volume = {147}, number = {}, pages = {105046}, pmid = {33872681}, issn = {1872-9754}, support = {P50 AT008661/AT/NCCIH NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD) is by far the most prevalent neurodegenerative disease of aging and is a major burden for patients, caregivers, and the overall health care system. The complexity of AD pathophysiology and the lack of deep understanding of disease mechanisms impeded the development of AD therapy. Currently approved treatments for AD only modestly improve cognitive function but do not modify disease course. The lack of pharmacological approaches has led to the consideration of alternative strategies to prevent or to slow down the progression of AD. There has been a growing interest in the scientific community regarding the impact of diet and nutrition on AD. Grape derived nutraceuticals and phytochemical compounds have demonstrated anti-amyloidogenic, antioxidative, anti-inflammatory and neurotrophic properties and present as potential novel strategies for AD treatment. In this review, we summarize promising grape derived polyphenols that have been shown to modulate AD pathophysiology including amyloid plaques and neurofibrillary tangles formation, AD-induced oxidative stress, neuroinflammation and synaptic dysfunction.}, }
@article {pmid33860663, year = {2021}, author = {K C, S and Kakoty, V and Krishna, KV and Dubey, SK and Chitkara, D and Taliyan, R}, title = {Neuroprotective Efficacy of Co-Encapsulated Rosiglitazone and Vorinostat Nanoparticle on Streptozotocin Induced Mice Model of Alzheimer Disease.}, journal = {ACS chemical neuroscience}, volume = {12}, number = {9}, pages = {1528-1541}, doi = {10.1021/acschemneuro.1c00022}, pmid = {33860663}, issn = {1948-7193}, mesh = {*Alzheimer Disease/drug therapy ; Animals ; Mice ; *Nanoparticles ; PPAR gamma ; Rosiglitazone/pharmacology ; Streptozocin ; *Thiazolidinediones/pharmacology ; Vorinostat/pharmacology ; }, abstract = {Anomalies in brain insulin signaling have been demonstrated to be involved in the pathology of Alzheimer disease (AD). In this context, the neuroprotective efficacy of an insulin sensitizer, rosiglitazone, has been confirmed in our previous study. In the present study, we hypothesize that a combination of an epigenetic modulator, vorinostat, along with rosiglitazone can impart improved gene expression of neurotrophic factors and attenuate biochemical and cellular alteration associated with AD mainly by loading these drugs in a surface modified nanocarrier system for enhanced bioavailability and enhanced therapeutic efficacy. Hence, in this study, rosiglitazone and vorinostat were loaded onto a poloxamer stabilized polymeric nanocarrier system and administered to mice in the intracerebroventricular streptozotocin (3 mg/kg) induced model of AD. Treatment with the free drug combination (rosiglitazone 5 mg/kg, vorinostat 25 mg/kg) for 3 weeks attenuated the behavioral, biochemical, and cellular alterations as compared to either treatment alone (rosiglitazone 10 mg/kg, vorinostat 50 mg/kg). Further, the coencapsulated nanoformulation (rosiglitazone 5 mg/kg, vorinostat 25 mg/kg) exerted better neuroprotective efficacy than the free drug combination as evidenced by improved behavioral outcome, reduced oxidative stress, and elevated levels of neurotrophic factors. In conclusion, the synergistic neuroprotective efficacy of rosiglitazone and vorinostat has been increased through the poloxamer stabilized polymeric nanocarrier system.}, }
@article {pmid33850616, year = {2020}, author = {Zeinivand, M and Nahavandi, A and Baluchnejadmojarad, T and Roghani, M and Golab, F}, title = {Dalteparin as a Novel Therapeutic Agent to Prevent Diabetic Encephalopathy by Targeting Oxidative Stress and Inflammation.}, journal = {Basic and clinical neuroscience}, volume = {11}, number = {6}, pages = {795-804}, pmid = {33850616}, issn = {2008-126X}, abstract = {Introduction: Hepcidin is the main modulator of systemic iron metabolism, and its role in the brain has been clarified recently. Studies have shown that hepcidin plays an important role in neuronal iron load and inflammation. This issue is of significance because neuronal iron load and inflammation are pathophysiological processes that are highly linked to neurodegeneration. Moreover, the activity of hepcidin has recently been manipulated to recover the neuronal impairment caused by brain inflammation in animal models.
Methods: Streptozotocin (STZ) was used to induce type 1 diabetes. Male Wistar rats (n = 40) with a weight range of 200-250 g were divided into control, diabetic, diabetic + insulin, and diabetic + dalteparin groups. Dalteparin (100 mg/kg IP) and insulin (100 mg/kg SC) were administered for 8 weeks. At the end of the experiment, Y-maze and passive avoidance tasks were carried out. The animals were perfused randomly and their hippocampal tissue was isolated for the analysis of markers such as lipid peroxidation like Malondialdehyde (MDA), hepcidin expression, iron, and ferritin. Blood samples were taken for the measurement of serum inflammatory cytokine Interleukin (IL)-6.
Results: The findings indicated that treatment with dalteparin reduced IL-6, MDA, ferritin, and hepcidin expression in diabetic rats compared to treatment with insulin (P<0.05). Moreover, treatment with dalteparin did not decrease the iron level or prevented its decline.
Conclusion: Treatment with dalteparin improved the cognitive dysfunctions and symptoms of Alzheimer disease in STZ-induced diabetic rats by appropriately modulating and reducing oxidative stress and neuroinflammation. This may enhance the existing knowledge of therapeutics to reduce cognitive impairment in diabetes and is suggested to be a potential therapeutic agent in diabetes.}, }
@article {pmid33847926, year = {2021}, author = {Grunenwald, A and Roumenina, LT}, title = {The Benefits of Complement Measurements for the Clinical Practice.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {2227}, number = {}, pages = {1-20}, pmid = {33847926}, issn = {1940-6029}, mesh = {Alzheimer Disease/diagnosis/immunology/metabolism ; Atypical Hemolytic Uremic Syndrome/diagnosis/immunology/metabolism ; Autoimmune Diseases/diagnosis/immunology/metabolism ; Complement Activation/physiology ; Complement System Proteins/*analysis/metabolism ; Diagnostic Tests, Routine/*methods ; Drug Development ; Graft Rejection/diagnosis/immunology/metabolism ; Humans ; Kidney Diseases/diagnosis/immunology/metabolism ; Macular Degeneration/diagnosis/immunology/metabolism ; Neoplasms/diagnosis/immunology/metabolism ; *Practice Patterns, Physicians' ; }, abstract = {The complement cascade is an evolutionary ancient innate immune defense system, playing a major role in the defense against infections. Its function in maintaining host homeostasis on activated cells has been emphasized by the crucial role of its overactivation in ever growing number of diseases, such as atypical hemolytic uremic syndrome (aHUS), autoimmune diseases as systemic lupus erythematosus (SLE), C3 glomerulopathies (C3GN), age-related macular degeneration (AMD), graft rejection, Alzheimer disease, and cancer, to name just a few. The last decade of research on complement has extended its implication in many pathological processes, offering new insights to potential therapeutic targets and asserting the necessity of reliable, sensitive, specific, accurate, and reproducible biomarkers to decipher complement role in pathology. We need to evaluate accurately which pathway or role should be targeted pharmacologically, and optimize treatment efficacy versus toxicity. This chapter is an introduction to the role of complement in human diseases and the use of complement-related biomarkers in the clinical practice. It is a part of a book intending to give reliable and standardized methods to evaluate complement according to nowadays needs and knowledge.}, }
@article {pmid33845375, year = {2021}, author = {Saviano, A and Casillo, GM and Raucci, F and Pernice, A and Santarcangelo, C and Piccolo, M and Ferraro, MG and Ciccone, M and Sgherbini, A and Pedretti, N and Bonvicini, D and Irace, C and Daglia, M and Mascolo, N and Maione, F}, title = {Supplementation with ribonucleotide-based ingredient (Ribodiet®) lessens oxidative stress, brain inflammation, and amyloid pathology in a murine model of Alzheimer.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {139}, number = {}, pages = {111579}, doi = {10.1016/j.biopha.2021.111579}, pmid = {33845375}, issn = {1950-6007}, mesh = {Alzheimer Disease/*prevention & control/psychology ; Amyloid beta-Peptides ; Animals ; Behavior, Animal/drug effects ; Biomarkers ; Cerebral Amyloid Angiopathy/*prevention & control/psychology ; Diet ; *Dietary Supplements ; Encephalitis/*prevention & control/psychology ; Gliosis/prevention & control ; Injections, Intraventricular ; Male ; Mice ; Nonheme Iron Proteins/metabolism ; Oxidative Stress/*drug effects ; Peptide Fragments ; Psychomotor Performance/drug effects ; Ribonucleotides/pharmacology/*therapeutic use ; }, abstract = {Alzheimer's disease (AD) is the most common type of dementia worldwide, characterized by the deposition of neurofibrillary tangles and amyloid-β (Aβ) peptides in the brain. Additionally, increasing evidence demonstrates that a neuroinflammatory state and oxidative stress, iron-dependent, play a crucial role in the onset and disease progression. Besides conventional therapies, the use of natural-based products represents a future medical option for AD treatment and/or prevention. We, therefore, evaluated the effects of a ribonucleotides-based ingredient (Ribodiet®) in a non-genetic mouse model of AD. To this aim, mice were injected intracerebroventricularly (i.c.v.) with Aβ1-42 peptide (3 µg/3 μl) and after with Ribodiet® (0.1-10 mg/mouse) orally (p.o.) 3 times weekly for 21 days following the induction of experimental AD. The mnemonic and cognitive decline was then evaluated, and, successively, we have assessed ex vivo the modulation of different cyto-chemokines on mice brain homogenates. Finally, the level of GFAP, S100β, and iron-related metabolic proteins were monitored as markers of reactive gliosis, neuro-inflammation, and oxidative stress. Results indicate that Ribodiet® lessens oxidative stress, brain inflammation, and amyloid pathology via modulation of iron-related metabolic proteins paving the way for its rationale use for the treatment of AD and other age-related diseases.}, }
@article {pmid33842683, year = {2021}, author = {Müller, P and Vellage, AK and Schmicker, M and Menze, I and Grothe, MJ and Teipel, SJ and Müller, NG}, title = {Structural MRI of the basal forebrain as predictor of cognitive response to galantamine in healthy older adults-A randomized controlled double-blinded crossover study.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {7}, number = {1}, pages = {e12153}, pmid = {33842683}, issn = {2352-8737}, abstract = {Introduction: Cholinesterase inhibitors can enhance cognitive functions in healthy elderly and delay cognitive decline in patients with Alzheimer`s disease (AD). However, not everyone benefits from this treatment (non-responders). Current studies show clinical meaningful improvements only in one third of AD patients treated with cholinesterase inhibitors.
Methods: Here we investigate structural magnetic resonance imaging of the basal forebrain cholinergic system volume (BFvol) as a potential predictor of cognitive response to a single dose of galantamine in healthy adults (n = 18; 59 to 75 years).
Results: We observed that the cognitive response to galantamine, more specifically the attention-dependent filtering performance in a delayed match-to-sample working memory task, correlated with BFvol: Only participants with high BFvol showed a significant positive effect of galantamine on the ability to filter out distracting information during the working memory encoding process.
Discussion: Future studies need to assess whether BFvol may serve as a predictor of the galantamine response in AD patients, too.}, }
@article {pmid33841127, year = {2021}, author = {Duong, MT and Nasrallah, IM and Wolk, DA and Chang, CCY and Chang, TY}, title = {Cholesterol, Atherosclerosis, and APOE in Vascular Contributions to Cognitive Impairment and Dementia (VCID): Potential Mechanisms and Therapy.}, journal = {Frontiers in aging neuroscience}, volume = {13}, number = {}, pages = {647990}, pmid = {33841127}, issn = {1663-4365}, support = {P30 AG010124/AG/NIA NIH HHS/United States ; R01 AG037609/AG/NIA NIH HHS/United States ; R01 AG063544/AG/NIA NIH HHS/United States ; R21 AG056281/AG/NIA NIH HHS/United States ; }, abstract = {Vascular contributions to cognitive impairment and dementia (VCID) are a common cause of cognitive decline, yet limited therapies exist. This cerebrovascular disease results in neurodegeneration via acute, chronic, local, and systemic mechanisms. The etiology of VCID is complex, with a significant impact from atherosclerosis. Risk factors including hypercholesterolemia and hypertension promote intracranial atherosclerotic disease and carotid artery stenosis (CAS), which disrupt cerebral blood flow and trigger ischemic strokes and VCID. Apolipoprotein E (APOE) is a cholesterol and phospholipid carrier present in plasma and various tissues. APOE is implicated in dyslipidemia and Alzheimer disease (AD); however, its connection with VCID is less understood. Few experimental models for VCID exist, so much of the present information has been drawn from clinical studies. Here, we review the literature with a focus on the clinical aspects of atherosclerotic cerebrovascular disease and build a working model for the pathogenesis of VCID. We describe potential intermediate steps in this model, linking cholesterol, atherosclerosis, and APOE with VCID. APOE4 is a minor isoform of APOE that promotes lipid dyshomeostasis in astrocytes and microglia, leading to chronic neuroinflammation. APOE4 disturbs lipid homeostasis in macrophages and smooth muscle cells, thus exacerbating systemic inflammation and promoting atherosclerotic plaque formation. Additionally, APOE4 may contribute to stromal activation of endothelial cells and pericytes that disturb the blood-brain barrier (BBB). These and other risk factors together lead to chronic inflammation, atherosclerosis, VCID, and neurodegeneration. Finally, we discuss potential cholesterol metabolism based approaches for future VCID treatment.}, }
@article {pmid33841007, year = {2021}, author = {Choi, SH and Lee, NE and Cho, HJ and Lee, RM and Rhim, H and Kim, HC and Han, M and Lee, EH and Park, J and Nah, SY}, title = {Gintonin facilitates brain delivery of donepezil, a therapeutic drug for Alzheimer disease, through lysophosphatidic acid 1/3 and vascular endothelial growth factor receptors.}, journal = {Journal of ginseng research}, volume = {45}, number = {2}, pages = {264-272}, pmid = {33841007}, issn = {1226-8453}, abstract = {Background: Gintonin is a ginseng-derived exogenous G-protein-coupled lysophosphatidic acid (LPA) receptor ligand, which exhibits in vitro and in vivo functions against Alzheimer disease (AD) through lysophosphatidic acid 1/3 receptors. A recent study demonstrated that systemic treatment with gintonin enhances paracellular permeability of the blood-brain barrier (BBB) through the LPA1/3 receptor. However, little is known about whether gintonin can enhance brain delivery of donepezil (DPZ) (Aricept), which is a representative cognition-improving drug used in AD clinics. In the present study, we examined whether systemic administration of gintonin can stimulate brain delivery of DPZ.
Methods: We administered gintonin and DPZ alone or coadministered gintonin with DPZ intravenously or orally to rats. Then we collected the cerebral spinal fluid (CSF) and serum and determined the DPZ concentration through liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis.
Results: Intravenous, but not oral, coadministration of gintonin with DPZ increased the CSF concentration of DPZ in a concentration- and time-dependent manner. Gintonin-mediated enhancement of brain delivery of DPZ was blocked by Ki16425, a LPA1/3 receptor antagonist. Coadministration of vascular endothelial growth factor (VEGF) + gintonin with DPZ similarly increased CSF DPZ concentration. However, gintonin-mediated enhancement of brain delivery of DPZ was blocked by axitinip, a VEGF receptor antagonist. Mannitol, a BBB disrupting agent that increases the BBB permeability, enhanced gintonin-mediated enhancement of brain delivery of DPZ.
Conclusions: We found that intravenous, but not oral, coadministration of gintonin facilitates brain delivery of DPZ from plasma via LPA1/3 and VEGF receptors. Gintonin is a potential candidate as a ginseng-derived novel agent for the brain delivery of DPZ for treatment of patients with AD.}, }
@article {pmid33838585, year = {2021}, author = {Pasieka, A and Panek, D and Jończyk, J and Godyń, J and Szałaj, N and Latacz, G and Tabor, J and Mezeiova, E and Chantegreil, F and Dias, J and Knez, D and Lu, J and Pi, R and Korabecny, J and Brazzolotto, X and Gobec, S and Höfner, G and Wanner, K and Więckowska, A and Malawska, B}, title = {Discovery of multifunctional anti-Alzheimer's agents with a unique mechanism of action including inhibition of the enzyme butyrylcholinesterase and γ-aminobutyric acid transporters.}, journal = {European journal of medicinal chemistry}, volume = {218}, number = {}, pages = {113397}, doi = {10.1016/j.ejmech.2021.113397}, pmid = {33838585}, issn = {1768-3254}, mesh = {Alzheimer Disease/*drug therapy/metabolism ; Butyrylcholinesterase/*metabolism ; Cholinesterase Inhibitors/chemical synthesis/chemistry/*pharmacology ; Dose-Response Relationship, Drug ; *Drug Discovery ; GABA Plasma Membrane Transport Proteins/*metabolism ; Humans ; Molecular Structure ; Neuroprotective Agents/chemical synthesis/chemistry/*pharmacology ; Structure-Activity Relationship ; }, abstract = {Looking for an effective anti-Alzheimer's agent is very challenging; however, a multifunctional ligand strategy may be a promising solution for the treatment of this complex disease. We herein present the design, synthesis and biological evaluation of novel hydroxyethylamine derivatives displaying unique, multiple properties that have not been previously reported. The original mechanism of action combines inhibitory activity against disease-modifying targets: β-secretase enzyme (BACE1) and amyloid β (Aβ) aggregation, along with an effect on targets associated with symptom relief - inhibition of butyrylcholinesterase (BuChE) and γ-aminobutyric acid transporters (GATs). Among the obtained molecules, compound 36 exhibited the most balanced and broad activity profile (eeAChE IC50 = 2.86 μM; eqBuChE IC50 = 60 nM; hBuChE IC50 = 20 nM; hBACE1 IC50 = 5.9 μM; inhibition of Aβ aggregation = 57.9% at 10 μM; mGAT1 IC50 = 10.96 μM; and mGAT2 IC50 = 19.05 μM). Moreover, we also identified 31 as the most potent mGAT4 and hGAT3 inhibitor (IC50 = 5.01 μM and IC50 = 2.95 μM, respectively), with high selectivity over other subtypes. Compounds 36 and 31 represent new anti-Alzheimer agents that can ameliorate cognitive decline and modify the progress of disease.}, }
@article {pmid33836798, year = {2021}, author = {Leinenga, G and Koh, WK and Götz, J}, title = {A comparative study of the effects of Aducanumab and scanning ultrasound on amyloid plaques and behavior in the APP23 mouse model of Alzheimer disease.}, journal = {Alzheimer's research & therapy}, volume = {13}, number = {1}, pages = {76}, pmid = {33836798}, issn = {1758-9193}, mesh = {*Alzheimer Disease/drug therapy ; Amyloid beta-Peptides/metabolism ; Animals ; Antibodies, Monoclonal, Humanized ; Brain/diagnostic imaging/metabolism ; Disease Models, Animal ; Mice ; Mice, Transgenic ; *Plaque, Amyloid/drug therapy ; }, abstract = {BACKGROUND: Aducanumab is an anti-amyloid-β (Aβ) antibody that achieved reduced amyloid pathology in Alzheimer's disease (AD) trials; however, it is controversial whether it also improved cognition, which has been suggested would require a sufficiently high cumulative dose of the antibody in the brain. Therapeutic ultrasound, in contrast, has only begun to be investigated in human AD clinical trials. We have previously shown that scanning ultrasound in combination with intravenously injected microbubbles (SUS), which temporarily and safely opens the blood-brain barrier (BBB), removes amyloid and restores cognition in APP23 mice. However, there has been no direct testing of how the effects of SUS compare to immunotherapy or whether a combination therapy is more effective.
METHODS: In a study comprising four treatment arms, we tested the efficacy of an Aducanumab analog, Adu, both in comparison to SUS, and as a combination therapy, in APP23 mice (aged 13-22 months), using sham as a control. The active place avoidance (APA) test was used to test spatial memory, and histology and ELISA were used to measure amyloid. Brain antibody levels were also determined.
RESULTS: We found that both Adu and SUS reduced the total plaque area in the hippocampus with no additive effect observed with the combination treatment (SUS + Adu). Whereas in the cortex where there was a trend towards reducing the total plaque area from either Adu or SUS, only the combination treatment yielded a statistically significant decrease in total plaque area compared to sham. Only the SUS and SUS + Adu groups included animals that had their plaque load reduced to below 1% from above 10%. There was a robust improvement in spatial memory for the SUS + Adu group only, and in this group the level of Adu, when measured 3 days post-treatment, was 5-fold higher compared to those mice that received Adu on its own. Together, these findings suggest that SUS should be considered as a treatment option for AD. Alternatively, a combination trial using Aducanumab together with ultrasound to increase brain levels of the antibody may be warranted.}, }
@article {pmid33818056, year = {2021}, author = {Pan, Y and Zhang, Y and Liu, N and Lu, W and Yang, J and Li, Y and Liu, Z and Wei, Y and Lou, Y and Kong, J}, title = {Vitamin D Attenuates Alzheimer-like Pathology Induced by Okadaic Acid.}, journal = {ACS chemical neuroscience}, volume = {12}, number = {8}, pages = {1343-1350}, doi = {10.1021/acschemneuro.0c00812}, pmid = {33818056}, issn = {1948-7193}, mesh = {Aged ; *Alzheimer Disease/chemically induced/drug therapy ; *Cognitive Dysfunction/chemically induced/drug therapy ; Humans ; Okadaic Acid/toxicity ; Phosphorylation ; Vitamin D ; tau Proteins/metabolism ; }, abstract = {Many elderly individuals suffer from Alzheimer's disease (AD), which causes a growing concern. We investigated the mechanism underlying the effects of vitamin D (VD) as a prophylactic treatment. A mouse model of okadaic-acid-induced AD-like pathology was used in vivo and in vitro. Morris water maze and field trials were used to assess cognitive function. The expression levels of VDR, MTHFR, LCMT-1, PP2A, p-TAU (Thr396), and T-TAU and the methylation level of PP2A were measured by Western blotting, and a reversal of the increase in the levels of these proteins in an AD cell model was observed. We used MTHFR-knockdown SH-SY5Y cells to further test the effects of VD, treated these cells with cycloheximide and MG132, and used RT-PCR to explore the mechanism underlying MTHFR targeting. We found that the effects of VD on AD were impaired by MTHFR knockdown through a pretranscriptional mechanism. In addition, VD attenuated AD-induced cognitive impairment and significantly suppressed the expression of TAU. Our findings indicated that VD treatment alleviated TAU accumulation and rescued methylated PP2A by increasing the expression of LCMT-1 and MTHFR.}, }
@article {pmid33816762, year = {2021}, author = {Forcano, L and Fauria, K and Soldevila-Domenech, N and Minguillón, C and Lorenzo, T and Cuenca-Royo, A and Menezes-Cabral, S and Pizarro, N and Boronat, A and Molinuevo, JL and de la Torre, R and , }, title = {Prevention of cognitive decline in subjective cognitive decline APOE ε4 carriers after EGCG and a multimodal intervention (PENSA): Study design.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {7}, number = {1}, pages = {e12155}, pmid = {33816762}, issn = {2352-8737}, abstract = {Introduction: Subjects exhibiting subjective cognitive decline (SCD) are at an increased risk for mild cognitive impairment and dementia. Given the delay between risk exposure and disease onset, SCD individuals are increasingly considered a good target population for cost-effective lifestyle-based Alzheimer's disease prevention trials.
Methods: The PENSA study is a randomized, double-blind, controlled clinical trial that aims to evaluate the efficacy of a personalized multimodal intervention in lifestyle (diet counseling, physical activity, cognitive training, and social engagement) combined with the use of epigallocatechin gallate (EGCG) over 12 months, in slowing down cognitive decline and improving brain connectivity. The study population includes 200 individuals meeting SCD criteria and carrying the apolipoprotein E ε4 allele, who will be randomized into four treatment arms (multimodal intervention + EGCG/placebo, or lifestyle recommendations + EGCG/placebo). The primary efficacy outcome is change in the composite score for cognitive performance measured with the Alzheimer's Disease Cooperative Study Preclinical Alzheimer Cognitive Composite (ADCS-PACC-like) adding to the original version the Interference score from the Stroop Color and Word Test and the Five Digit Test. Secondary efficacy outcomes are (1) change in functional magnetic resonance imaging (fMRI) and structural neuronal connectivity (structural MRI) and (2) the safety assessment of the EGCG compound. This study is framed within the WW-FINGERS consortium.
Discussion: The use of new technologies (i.e., mobile ecological momentary assessments [EMAs], activity tracker) in the PENSA study allows the collection of continuous data on lifestyle behaviors (diet and physical activity) and mood, enabling a personalized design as well as an intensive follow-up of participants. These data will be used to give feedback to participants about their own performance along the intervention, promoting their involvement and adherence. The results of the study may aid researchers on the design of future clinical trials involving preventive lifestyle multicomponent interventions.}, }
@article {pmid33809771, year = {2021}, author = {Queda, F and Calò, S and Gwizdala, K and Magalhães, JD and Cardoso, SM and Chaves, S and Piemontese, L and Santos, MA}, title = {Novel Donepezil-Arylsulfonamide Hybrids as Multitarget-Directed Ligands for Potential Treatment of Alzheimer's Disease.}, journal = {Molecules (Basel, Switzerland)}, volume = {26}, number = {6}, pages = {}, pmid = {33809771}, issn = {1420-3049}, mesh = {Acetylcholinesterase/metabolism ; Alzheimer Disease/*drug therapy/metabolism ; Amyloid beta-Peptides/metabolism ; Cell Line, Tumor ; Cholinesterase Inhibitors/pharmacology ; Donepezil/*pharmacology ; Humans ; Ligands ; Piperazines/pharmacology ; Piperidines/pharmacology ; Structure-Activity Relationship ; Sulfonamides/*pharmacology ; }, abstract = {Alzheimer's disease (AD) is one of the most devastating neurodegenerative disorders, characterized by multiple pathological features. Therefore, multi-target drug discovery has been one of the most active fields searching for new effective anti-AD therapies. Herein, a series of hybrid compounds are reported which were designed and developed by combining an aryl-sulfonamide function with a benzyl-piperidine moiety, the pharmacophore of donepezil (a current anti-AD acetylcholinesterase AChE inhibitor drug) or its benzyl-piperazine analogue. The in vitro results indicate that some of these hybrids achieve optimized activity towards two main AD targets, by displaying excellent AChE inhibitory potencies, as well as the capability to prevent amyloid-β (Aβ) aggregation. Some of these hybrids also prevented Aβ-induced cell toxicity. Significantly, drug-like properties were predicted, including for blood-brain permeability. Compound 9 emerged as a promising multi-target lead compound (AChE inhibition (IC50 1.6 μM); Aβ aggregation inhibition 60.7%). Overall, this family of hybrids is worthy of further exploration, due to the wide biological activity of sulfonamides.}, }
@article {pmid33801961, year = {2021}, author = {Jain, AP and Sathe, G}, title = {Proteomics Landscape of Alzheimer's Disease.}, journal = {Proteomes}, volume = {9}, number = {1}, pages = {}, pmid = {33801961}, issn = {2227-7382}, abstract = {Alzheimer's disease (AD) is the most prevalent form of dementia, and the numbers of AD patients are expected to increase as human life expectancy improves. Deposition of β-amyloid protein (Aβ) in the extracellular matrix and intracellular neurofibrillary tangles are molecular hallmarks of the disease. Since the precise pathophysiology of AD has not been elucidated yet, effective treatment is not available. Thus, understanding the disease pathology, as well as identification and development of valid biomarkers, is imperative for early diagnosis as well as for monitoring disease progression and therapeutic responses. Keeping this goal in mind several studies using quantitative proteomics platform have been carried out on both clinical specimens including the brain, cerebrospinal fluid (CSF), plasma and on animal models of AD. In this review, we summarize the mass spectrometry (MS)-based proteomics studies on AD and discuss the discovery as well as validation stages in brief to identify candidate biomarkers.}, }
@article {pmid33800891, year = {2021}, author = {Bivona, G and Lo Sasso, B and Gambino, CM and Giglio, RV and Scazzone, C and Agnello, L and Ciaccio, M}, title = {The Role of Vitamin D as a Biomarker in Alzheimer's Disease.}, journal = {Brain sciences}, volume = {11}, number = {3}, pages = {}, pmid = {33800891}, issn = {2076-3425}, abstract = {Vitamin D and cognition is a popular association, which led to a remarkable body of literature data in the past 50 years. The brain can synthesize, catabolize, and receive Vitamin D, which has been proved to regulate many cellular processes in neurons and microglia. Vitamin D helps synaptic plasticity and neurotransmission in dopaminergic neural circuits and exerts anti-inflammatory and neuroprotective activities within the brain by reducing the synthesis of pro-inflammatory cytokines and the oxidative stress load. Further, Vitamin D action in the brain has been related to the clearance of amyloid plaques, which represent a feature of Alzheimer Disease (AD), by the immune cell. Based on these considerations, many studies have investigated the role of circulating Vitamin D levels in patients affected by a cognitive decline to assess Vitamin D's eventual role as a biomarker or a risk factor in AD. An association between low Vitamin D levels and the onset and progression of AD has been reported, and some interventional studies to evaluate the role of Vitamin D in preventing AD onset have been performed. However, many pitfalls affected the studies available, including substantial discrepancies in the methods used and the lack of standardized data. Despite many studies, it remains unclear whether Vitamin D can have a role in cognitive decline and AD. This narrative review aims to answer two key questions: whether Vitamin D can be used as a reliable tool for diagnosing, predicting prognosis and response to treatment in AD patients, and whether it is a modifiable risk factor for preventing AD onset.}, }
@article {pmid33798905, year = {2021}, author = {de Souza, IFF and Dos Santos, TQ and Placido, RV and Mangerona, BA and Carvalho, FC and Boralli, VB and Ruela, ALM and Pereira, GR}, title = {The liquid crystalline phase behaviour of a nasal formulation modifies the brain disposition of donepezil in rats in the treatment of Alzheimer's disease.}, journal = {Colloids and surfaces. B, Biointerfaces}, volume = {203}, number = {}, pages = {111721}, doi = {10.1016/j.colsurfb.2021.111721}, pmid = {33798905}, issn = {1873-4367}, mesh = {*Alzheimer Disease/drug therapy ; Animals ; Brain ; Donepezil ; Liposomes ; Rats ; Rats, Wistar ; }, abstract = {Although nanoparticles, polymeric micelles, liposomes, nanoemulsions, and microemulsions were extensively evaluated as formulations for nasal administration of drugs, lyotropic liquid crystal (LLC) mesophases have been few studied. The phase transition from a low-viscosity microemulsion to a more viscous LLC may improve the mucoadhesion of the formulation. Donepezil is a drug administered orally in the treatment of Alzheimer's disease, and with gastrointestinal side effects that are typical of acetylcholinesterase inhibitors. Based on this, donepezil administration by nasal pathway using a mucoadhesive LLC may be a feasible alternative. A colloidal formulation was selected from a ternary diagram, combining CETETH-10, oleic acid, and water (40:45:15, w/w). Donepezil was incorporated into the formulation, and the characterisation included in vitro studies, such as mucoadhesion and drug release. Pharmacokinetics in Wistar rats included evaluations by the nasal pathway with donepezil incorporated into microemulsion. A phase transition from an isotropic to an anisotropic system was observed after the swelling of the microemulsion with artificial nasal fluid (12-20 %). The release of donepezil in vitro occurred in a sustained manner. Significant levels of donepezil were achieved in the brain after nasal administration of the microemulsion, as a promising strategy for the treatment of Alzheimer's disease.}, }
@article {pmid33796018, year = {2021}, author = {Südkamp, N and Shchyglo, O and Manahan-Vaughan, D}, title = {Absence of Pannexin 1 Stabilizes Hippocampal Excitability After Intracerebral Treatment With Aβ (1-42) and Prevents LTP Deficits in Middle-Aged Mice.}, journal = {Frontiers in aging neuroscience}, volume = {13}, number = {}, pages = {591735}, pmid = {33796018}, issn = {1663-4365}, abstract = {Beta-amyloid protein [Aβ(1-42)] plays an important role in the disease progress and pathophysiology of Alzheimer's disease (AD). Membrane properties and neuronal excitability are altered in the hippocampus of transgenic AD mouse models that overexpress amyloid precursor protein. Although gap junction hemichannels have been implicated in the early pathogenesis of AD, to what extent Pannexin channels contribute to Aβ(1-42)-mediated brain changes is not yet known. In this study we, therefore, investigated the involvement of Pannexin1 (Panx1) channels in Aβ-mediated changes of neuronal membrane properties and long-term potentiation (LTP) in an animal model of AD. We conducted whole-cell patch-clamp recordings in CA1 pyramidal neurons 1 week after intracerebroventricular treatments of adult wildtype (wt) and Panx1 knockout (Panx1-ko) mice with either oligomeric Aβ(1-42), or control peptide. Panx1-ko hippocampi treated with control peptide exhibited increased neuronal excitability compared to wt. In addition, action potential (AP) firing frequency was higher in control Panx1-ko slices compared to wt. Aβ-treatment reduced AP firing frequency in both cohorts. But in Aβ-treated wt mice, spike frequency adaptation was significantly enhanced, when compared to control wt and to Aβ-treated Panx1-ko mice. Assessment of hippocampal LTP revealed deficits in Aβ-treated wt compared to control wt. By contrast, Panx1-ko exhibited LTP that was equivalent to LTP in control ko hippocampi. Taken together, our data show that in the absence of Pannexin1, hippocampi are more resistant to the debilitating effects of oligomeric Aβ. Both Aβ-mediated impairments in spike frequency adaptation and in LTP that occur in wt animals, are ameliorated in Panx1-ko mice. These results suggest that Panx1 contributes to early changes in hippocampal neuronal and synaptic function that are triggered by oligomeric Aβ.}, }
@article {pmid33790404, year = {2021}, author = {Nakamura, Y and Yamamoto, T and Xu, X and Kobayashi, S and Tanaka, S and Tamitani, M and Saito, T and Saido, TC and Yano, M}, title = {Enhancing calmodulin binding to ryanodine receptor is crucial to limit neuronal cell loss in Alzheimer disease.}, journal = {Scientific reports}, volume = {11}, number = {1}, pages = {7289}, pmid = {33790404}, issn = {2045-2322}, support = {26293189 to MY//The Ministry of Education in Japan/ ; 15K09085 to TY//The Ministry of Education in Japan/ ; 15K09142 to SK//The Ministry of Education in Japan/ ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive neuronal cell loss. Recently, dysregulation of intracellular Ca2+ homeostasis has been suggested as a common proximal cause of neural dysfunction in AD. Here, we investigated (1) the pathogenic role of destabilization of ryanodine receptor (RyR2) in endoplasmic reticulum (ER) upon development of AD phenotypes in AppNL-G-F mice, which harbor three familial AD mutations (Swedish, Beyreuther/Iberian, and Arctic), and (2) the therapeutic effect of enhanced calmodulin (CaM) binding to RyR2. In the neuronal cells from AppNL-G-F mice, CaM dissociation from RyR2 was associated with AD-related phenotypes, i.e. Aβ accumulation, TAU phosphorylation, ER stress, neuronal cell loss, and cognitive dysfunction. Surprisingly, either genetic (by V3599K substitution in RyR2) or pharmacological (by dantrolene) enhancement of CaM binding to RyR2 reversed almost completely the aforementioned AD-related phenotypes, except for Aβ accumulation. Thus, destabilization of RyR2 due to CaM dissociation is most likely an early and fundamental pathogenic mechanism involved in the development of AD. The discovery that neuronal cell loss can be fully prevented simply by stabilizing RyR2 sheds new light on the treatment of AD.}, }
@article {pmid33771384, year = {2021}, author = {Zhao, J and Li, T and Wang, J}, title = {Association between psoriasis and dementia: A systematic review.}, journal = {Neurologia (Barcelona, Spain)}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.nrl.2020.12.007}, pmid = {33771384}, issn = {2173-5808}, abstract = {INTRODUCTION: Risk factors for dementia include genetic factors, aging, environmental factors, certain diseases, and unhealthy lifestyle; most types of dementia share a common chronic systemic inflammatory phenotype. Psoriasis is also considered to be a chronic systemic inflammatory disease. It has been suggested that psoriasis may also contribute to the risk of dementia. The aim of this study was to systematically review the literature on the association between psoriasis and dementia.
DEVELOPMENT: Articles were selected according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched the PubMed and Web of Science databases to identify articles published in peer-reviewed journals and studying the association between psoriasis and dementia. Studies meeting the inclusion criteria were reviewed. We used the Newcastle-Ottawa Scale to assess the quality of each study. After applying the inclusion and exclusion criteria, we included 8 studies for review, 3 of which were found to present a higher risk of bias. Six of the 8 studies supported the hypothesis that prior diagnosis of psoriasis increases the risk of dementia; one study including only a few cases reported that psoriasis decreased the risk of dementia, and one study including relatively young patients found no significant association between psoriasis and the risk of dementia.
CONCLUSION: Most studies included in this review supported the hypothesis that psoriasis constitutes a risk factor for dementia. However, well-designed stratified cohort studies assessing both psoriasis severity and treatment status are still required to determine the real effect of psoriasis on the risk of dementia and its subtypes.}, }
@article {pmid33762220, year = {2021}, author = {Benussi, A and Cantoni, V and Cotelli, MS and Cotelli, M and Brattini, C and Datta, A and Thomas, C and Santarnecchi, E and Pascual-Leone, A and Borroni, B}, title = {Exposure to gamma tACS in Alzheimer's disease: A randomized, double-blind, sham-controlled, crossover, pilot study.}, journal = {Brain stimulation}, volume = {14}, number = {3}, pages = {531-540}, doi = {10.1016/j.brs.2021.03.007}, pmid = {33762220}, issn = {1876-4754}, abstract = {OBJECTIVE: To assess whether exposure to non-invasive brain stimulation with transcranial alternating current stimulation at γ frequency (γ-tACS) applied over Pz (an area overlying the medial parietal cortex and the precuneus) can improve memory and modulate cholinergic transmission in mild cognitive impairment due to Alzheimer's disease (MCI-AD).
METHODS: In this randomized, double-blind, sham controlled, crossover pilot study, participants were assigned to a single 60 min treatment with exposure to γ-tACS over Pz or sham tACS. Each subject underwent a clinical evaluation including assessment of episodic memory pre- and post-γ-tACS or sham stimulation. Indirect measures of cholinergic transmission evaluated using transcranial magnetic stimulation (TMS) pre- and post-γ-tACS or sham tACS were evaluated.
RESULTS: Twenty MCI-AD participants completed the study. No tACS-related side effects were observed, and the intervention was well tolerated in all participants. We observed a significant improvement at the Rey auditory verbal learning (RAVL) test total recall (5.7 [95% CI, 4.0 to 7.4], p < 0.001) and long delayed recall scores (1.3 [95% CI, 0.4 to 2.1], p = 0.007) after γ-tACS but not after sham tACS. Face-name associations scores improved during γ-tACS (4.3 [95% CI, 2.8 to 5.8], p < 0.001) but not after sham tACS. Short latency afferent inhibition, an indirect measure of cholinergic transmission evaluated with TMS, increased only after γ-tACS (0.31 [95% CI, 0.24 to 0.38], p < 0.001) but not after sham tACS.
CONCLUSIONS: exposure to γ-tACS over Pz showed a significant improvement of memory performances, along with restoration of intracortical connectivity measures of cholinergic neurotransmission, compared to sham tACS.}, }
@article {pmid33754647, year = {2021}, author = {Köylü, A and Altunkaynak, BZ and Delibaş, B}, title = {Effects of tacrolimus on c-fos in hippocampus and memory performances in streptozotocin model of Alzheimer’s disease of rats.}, journal = {Turkish journal of medical sciences}, volume = {51}, number = {4}, pages = {2159-2166}, doi = {10.3906/sag-2008-291}, pmid = {33754647}, issn = {1303-6165}, abstract = {Background/aim: Calcineurin, an inhibitor of calcium dependent phosphatase is highly presented in a brain of an Alzheimer’s disease. Aging brain gets more sensitive to hyperactivation of calcineurin, and this event causes tau neurofibrillary plaque accumulation, which is one of the outcomes of this disease. The regions of hippocampus are much effected from the results of this process. Our hypothesis is that a calcineurin inhibitor, tacrolimus, could prevent the accumulation and the decrease of the neuronal cells. Therefore, this immunosuppressive drug could be a candidate for an early treatment of Alzheimer disease.
Materials and methods: Fifteen male Wistar albino rats were divided to three groups; control, Alzheimer, and Alzheimer+Tacrolimus. The Alzheimer group received an injection of streptozotocin intracerebroventricularly for the purpose of modelling the disease via generating free radicals leading a cognitive impairment. Alzheimer+Tacrolimus group first received an oral drug, a calcineurin inhibitor for 10 days afterwards prepared for the model as same as the Alzheimer group received. Finally, all groups performed the Morris water maze test for four days then sacrificed. For the aim of counting neurons in the hippocampus stereological methods, as well as for an evaluation of cellular response to stress in dentate gyrus, a c-Fos immunohistochemistry was performed.
Results: According to the probe trial of Morris water maze test, the latency time was dramatically higher at both Alzheimer and Alzheimer+Tacrolimus group (p < 0.01). We confirmed these results with our stereology data. The results from stereology technique indicate that there was a neuronal decrease at the hippocampus regions in Alzheimer and Alzheimer+Tacrolimus group. Our outcomes from immunohistochemical data showed a significant increase in the number of c-Fos-positive cells in Alzheimer group when comparing with Alzheimer+Tacrolimus group (p < 0.001).
Conclusion: There was none preventive effect for neuronal loss in the hippocampus under the effect of tacrolimus drug according to stereological results. However, tacrolimus administration may have reduced cellular stress and cell damage.}, }
@article {pmid33749645, year = {2021}, author = {Miranda, A and Montiel, E and Ulrich, H and Paz, C}, title = {Selective Secretase Targeting for Alzheimer's Disease Therapy.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {81}, number = {1}, pages = {1-17}, doi = {10.3233/JAD-201027}, pmid = {33749645}, issn = {1875-8908}, abstract = {Alzheimer's disease (AD) is associated with marked atrophy of the cerebral cortex and accumulation of amyloid plaques and neurofibrillary tangles. Amyloid plaques are formed by oligomers of amyloid-β (Aβ) in the brain, with a length of 42 and 40 amino acids. α-secretase cleaves amyloid-β protein precursor (AβPP) producing the membrane-bound fragment CTFα and the soluble fragment sAβPPα with neuroprotective activity; β-secretase produces membrane-bound fragment CTFβ and a soluble fragment sAβPPβ. After α-secretase cleavage of AβPP, γ-secretase cleaves CTFα to produce the cytoplasmic fragment AICD and P3 in the non-amyloidogenic pathway. CTFβ is cleaved by γ-secretase producing AICD as well as Aβ in amyloidogenic pathways. In the last years, the study of natural products and synthetic compounds, such as α-secretase activity enhancers, β-secretase inhibitors (BACE-1), and γ-secretase activity modulators, have been the focus of pharmaceuticals and researchers. Drugs were improved regarding solubility, blood-brain barrier penetration, selectivity, and potency decreasing Aβ42. In this regard, BACE-1 inhibitors, such as Atabecestat, NB-360, Umibecestat, PF-06751979 Verubecestat, LY2886721, Lanabecestat, LY2811376 and Elenbecestat, were submitted to phase I-III clinical trials. However, inhibition of Aβ production did not recover cognitive functions or reverse disease progress. Novel strategies are being developed, aiming at a partial reduction of Aβ production, such as the development of γ-secretase modulators or α-secretase activity enhancers. Such therapeutic tools shall focus on slowing down or minimizing the progression of neuronal damage. Here, we summarize structures and activities of the latest compounds designed for AD treatment, with remarkable in vitro, in vivo, and clinical phase activities.}, }
@article {pmid33748669, year = {2021}, author = {Van Dyk, K and Zhou, X and Small, BJ and Ahn, J and Zhai, W and Ahles, T and Graham, D and Jacobsen, PB and Jim, H and McDonald, BC and Nudelman Holohan, K and Patel, SK and Rebeck, GW and Root, JC and Saykin, AJ and Cohen, HJ and Mandelblatt, JS and Carroll, JE}, title = {Protective Effects of APOE ε2 Genotype on Cognition in Older Breast Cancer Survivors: The Thinking and Living With Cancer Study.}, journal = {JNCI cancer spectrum}, volume = {5}, number = {2}, pages = {pkab013}, pmid = {33748669}, issn = {2515-5091}, support = {K08 CA241337/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; R35 CA197289/CA/NCI NIH HHS/United States ; }, abstract = {Background: Cancer-related cognitive decline (CRCD) has been linked to apolipoprotein E (APOE) gene ε4 polymorphisms. APOE ε4 polymorphisms are also the strongest genetic risk for late-onset Alzheimer disease (AD), whereas ε2 polymorphisms protect against AD. However, the effects of ε2 polymorphisms on CRCD have not been evaluated.
Methods: We evaluated nonmetastatic breast cancer survivors (n = 427) and matched noncancer controls (n = 407) ages 60-98 years assessed presystemic therapy from August 2010 to December 2017 with annual follow-up to 24 months. Neuropsychological assessment measured attention, processing speed, executive function, and learning and memory. Linear mixed-effects models tested the effects of having an ε2 allele (vs none) on longitudinal cognitive domain z scores by treatment group (chemotherapy with or without hormonal therapy, hormonal therapy, and control) controlling for covariates; participants with ε2/ε4 genotype were excluded. Sensitivity analyses examined effects of other covariates and any ε4 positivity.
Results: There was an interaction with genotype for attention, processing speed, and executive functioning domain scores (Beta = 0.32, 95% confidence interval = 0.00 to 0.65); the chemotherapy group with an ε2 allele had higher scores at baseline and maintained higher scores over time compared with those without an ε2 allele, and this protective effect was not seen for other groups. There was no effect of ε2 on learning and memory domain scores.
Conclusions: APOE ε2 polymorphisms may protect against CRCD in older breast cancer survivors receiving chemotherapy. With replication, this information could be useful for survivorship care and informing future studies of possible links to AD and defining mechanisms of protection.}, }
@article {pmid33734170, year = {2021}, author = {Haeckert, J and Brendel, M and Beyer, L and Barthel, H and Sabri, O and Hasan, A and Perneczky, R}, title = {Effective Valproic Acid Treatment in a Patient With Delusional Parasitosis Due to Corticobasal Syndrome and Alzheimer Disease.}, journal = {Journal of clinical psychopharmacology}, volume = {41}, number = {3}, pages = {335-337}, doi = {10.1097/JCP.0000000000001378}, pmid = {33734170}, issn = {1533-712X}, }
@article {pmid33716981, year = {2021}, author = {Duez, H and Pourcet, B}, title = {Nuclear Receptors in the Control of the NLRP3 Inflammasome Pathway.}, journal = {Frontiers in endocrinology}, volume = {12}, number = {}, pages = {630536}, pmid = {33716981}, issn = {1664-2392}, abstract = {The innate immune system is the first line of defense specialized in the clearing of invaders whether foreign elements like microbes or self-elements that accumulate abnormally including cellular debris. Inflammasomes are master regulators of the innate immune system, especially in macrophages, and are key sensors involved in maintaining cellular health in response to cytolytic pathogens or stress signals. Inflammasomes are cytoplasmic complexes typically composed of a sensor molecule such as NOD-Like Receptors (NLRs), an adaptor protein including ASC and an effector protein such as caspase 1. Upon stimulation, inflammasome complex components associate to promote the cleavage of the pro-caspase 1 into active caspase-1 and the subsequent activation of pro-inflammatory cytokines including IL-18 and IL-1β. Deficiency or overactivation of such important sensors leads to critical diseases including Alzheimer diseases, chronic inflammatory diseases, cancers, acute liver diseases, and cardiometabolic diseases. Inflammasomes are tightly controlled by a two-step activation regulatory process consisting in a priming step, which activates the transcription of inflammasome components, and an activation step which leads to the inflammasome complex formation and the subsequent cleavage of pro-IL1 cytokines. Apart from the NF-κB pathway, nuclear receptors have recently been proposed as additional regulators of this pathway. This review will discuss the role of nuclear receptors in the control of the NLRP3 inflammasome and the putative beneficial effect of new modulators of inflammasomes in the treatment of inflammatory diseases including colitis, fulminant hepatitis, cardiac ischemia-reperfusion and brain diseases.}, }
@article {pmid33715884, year = {2021}, author = {Zhan-Qiang, H and Hai-Hua, Q and Chi, Z and Miao, W and Cui, Z and Zi-Yin, L and Jing, H and Yi-Wei, W}, title = {miR-146a aggravates cognitive impairment and Alzheimer disease-like pathology by triggering oxidative stress through MAPK signaling.}, journal = {Neurologia (Barcelona, Spain)}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.nrl.2020.12.006}, pmid = {33715884}, issn = {2173-5808}, abstract = {INTRODUCTION: Mir-146a-5p has been widely recognized as a critical regulatory element in the immune response. However, recent studies have shown that miR-146a-5p may also be involved in the development of Alzheimer disease (AD). Regrettably, the related mechanisms are poorly understood. Here, we investigated the effects of miR-146a in mice models and SH-SY5Y cells treated with amyloid β (Aβ)1-42.
METHODS: To create a model of AD, SH-SY5Y cells were treated with Aβ1-42 and mice received intracerebroventricular injections of Aβ1-42. Then, the transcriptional levels of miR-146a were estimated by real-time PCR. We transiently transfected the miR-146a-5p mimic/inhibitor into cells and mice to study the role of miR-146a. The role of signaling pathways including p38 and reactive oxygen species (ROS) was studied by using specific inhibitors. Aβ and amyloid-beta precursor protein (APP)levels were measured by immunoblotting. Furthermore, Aβ expression was analyzed by immunofluorescence and histochemical examinations.
RESULTS: Aβ1-42-stimulated SH-SY5Y cells displayed increased transcriptional levels of miR-146a and APP. Moreover, the p38 MAPK signaling pathway and ROS production were activated upon stimulation with a miR-146a-5p mimic. However, treatment with a miR-146a-5p inhibitor decreased the levels of APP, ROS, and p-p38 MAPK. A similar phenomenon was also observed in the animals treated with Aβ1-42, in which miR-146a upregulation increased the expression of Aβ, p-p38, and ROS, while the inhibition of miR-146a had the opposite effect. This suggests that miR-146a increases Aβ deposition and ROS accumulation via the p-p38 signaling pathway.
CONCLUSIONS: Our research demonstrates that miR-146a-5pa increases Aβ deposition by triggering oxidative stress through activation of MAPK signaling.}, }
@article {pmid33715084, year = {2021}, author = {Shamsipour, S and Sharifi, G and Taghian, F}, title = {An 8-Week Administration of Bifidobacterium bifidum and Lactobacillus plantarum Combined with Exercise Training Alleviates Neurotoxicity of Aβ and Spatial Learning via Acetylcholine in Alzheimer Rat Model.}, journal = {Journal of molecular neuroscience : MN}, volume = {71}, number = {7}, pages = {1495-1505}, pmid = {33715084}, issn = {1559-1166}, abstract = {This study aimed to determine the effects of 8 weeks of an administration of Bifidobacterium bifidum and Lactobacillus plantarum combined with exercise training on neurotoxicity of Aβ, spatial learning, acetylcholine (ACH), and vascular endothelial growth factor (VEGF) in Alzheimer rats. Twenty-five Wistar rats were randomly divided into 5 groups (n = 5 in each): (1) healthy control (control), (2) Alzheimer disease (AD), (3) AD with treadmill exercise (AD + Exe), (4) AD with probiotic (combined administration of Bifidobacterium bifidum and Lactobacillus plantarum) treatment (AD + Pro), and (5) AD with treadmill exercise and probiotic treatment (AD + Exe + Pro). AD was induced by intra-cerebroventricular injection of Aβ1-42 peptide. Then, the training groups exercised on treadmill for 8 weeks, 5 days per weeks. The rats were treated daily with probiotic supplements via gavage for 8 weeks. The Morris water maze (MWM) test was administered to measure spatial learning. Then, the animals were sacrificed and Vegf and ACH were analyzed using the qPCR and immunohistochemistry (IHC) methods, respectively. Results showed that the β-amyloid plaques were significantly increased in the brains of the AD group compared with the control group (p < 0.001). The combined use of probiotics and exercise training significantly increased the time spent in the target quadrant after removing the platform, compared with the AD group in the Morris water maze test (p < 0.001). Crystal violet analysis showed that sole (p < 0.01) and combined exercise training and probiotic supplementation (p < 0.001) significantly reduced the number of dead cells in the brains of rats compared with the AD group. AD significantly decreased Vegf mRNA and ACH in the CA1 area of the hippocampus (p < 0.001). However, mono and combined therapy (exercise and probiotics) significantly increased ACH in the rats' brain compared with the AD group. Overall, 8 weeks of an administration of Bifidobacterium bifidum and Lactobacillus plantarum combined with exercise training can improve spatial learning impairment in the AD rats. Exercise and probiotics seem to offer potential benefits to AD patients by upregulating ACH.}, }
@article {pmid33708071, year = {2021}, author = {Sharma, S and Tiarks, G and Haight, J and Bassuk, AG}, title = {Neuropathophysiological Mechanisms and Treatment Strategies for Post-traumatic Epilepsy.}, journal = {Frontiers in molecular neuroscience}, volume = {14}, number = {}, pages = {612073}, pmid = {33708071}, issn = {1662-5099}, abstract = {Traumatic brain injury (TBI) is a leading cause of death in young adults and a risk factor for acquired epilepsy. Severe TBI, after a period of time, causes numerous neuropsychiatric and neurodegenerative problems with varying comorbidities; and brain homeostasis may never be restored. As a consequence of disrupted equilibrium, neuropathological changes such as circuit remodeling, reorganization of neural networks, changes in structural and functional plasticity, predisposition to synchronized activity, and post-translational modification of synaptic proteins may begin to dominate the brain. These pathological changes, over the course of time, contribute to conditions like Alzheimer disease, dementia, anxiety disorders, and post-traumatic epilepsy (PTE). PTE is one of the most common, devastating complications of TBI; and of those affected by a severe TBI, more than 50% develop PTE. The etiopathology and mechanisms of PTE are either unknown or poorly understood, which makes treatment challenging. Although anti-epileptic drugs (AEDs) are used as preventive strategies to manage TBI, control acute seizures and prevent development of PTE, their efficacy in PTE remains controversial. In this review, we discuss novel mechanisms and risk factors underlying PTE. We also discuss dysfunctions of neurovascular unit, cell-specific neuroinflammatory mediators and immune response factors that are vital for epileptogenesis after TBI. Finally, we describe current and novel treatments and management strategies for preventing PTE.}, }
@article {pmid33704916, year = {2021}, author = {Bigarré, IM and Trombetta, BA and Guo, YJ and Arnold, SE and Carlyle, BC}, title = {IGF2R circular RNA hsa_circ_0131235 expression in the middle temporal cortex is associated with AD pathology.}, journal = {Brain and behavior}, volume = {11}, number = {4}, pages = {e02048}, pmid = {33704916}, issn = {2162-3279}, mesh = {*Alzheimer Disease/genetics ; Cohort Studies ; Humans ; *RNA, Circular ; Real-Time Polymerase Chain Reaction ; Temporal Lobe ; }, abstract = {OBJECTIVE: To identify circular RNAs as candidates for differential expression in the middle temporal (MT) cortex in a well-characterized cohort with contrasting Alzheimer disease (AD) pathology and cognition. Top screen candidates were assessed for proof of circularity and then quantified by qPCR in a larger number of samples.
METHODS: An initial RNA sequencing screen was performed on n = 20 frozen human tissue samples. Filters were applied to select candidate circular RNAs for further investigation. Frozen human tissue samples were selected for global AD pathology burden and global cognition scores (n = 100). Linear and divergent primers were used to assess circularity using RNaseR digestion. RT-qPCR was performed to quantify relative hsa_circ_0131235 abundance.
RESULTS: Eleven circular RNAs were selected for further investigation. Four candidates produced circular RNA primers with appropriate efficiencies for qPCR. RNaseR treatment and analysis by both basic PCR and qPCR confirmed hsa_circ_0131235 circularity. There was a significant main effect of AD pathology on hsa_circ_0131235 expression.
CONCLUSIONS: Elevated hsa_circ_0131235 expression in the MT cortex was significantly associated with AD pathology.}, }
@article {pmid33693397, year = {2020}, author = {Raket, LL}, title = {Statistical Disease Progression Modeling in Alzheimer Disease.}, journal = {Frontiers in big data}, volume = {3}, number = {}, pages = {24}, pmid = {33693397}, issn = {2624-909X}, support = {U01 AG024904/AG/NIA NIH HHS/United States ; }, abstract = {Background: The characterizing symptom of Alzheimer disease (AD) is cognitive deterioration. While much recent work has focused on defining AD as a biological construct, most patients are still diagnosed, staged, and treated based on their cognitive symptoms. But the cognitive capability of a patient at any time throughout this deterioration reflects not only the disease state, but also the effect of the cognitive decline on the patient's pre-disease cognitive capability. Patients with high pre-disease cognitive capabilities tend to score better on cognitive tests that are sensitive early in disease relative to patients with low pre-disease cognitive capabilities at a similar disease stage. Thus, a single assessment with a cognitive test is often not adequate for determining the stage of an AD patient. Repeated evaluation of patients' cognition over time may improve the ability to stage AD patients, and such longitudinal assessments in combinations with biomarker assessments can help elucidate the time dynamics of biomarkers. In turn, this can potentially lead to identification of markers that are predictive of disease stage and future cognitive decline, possibly before any cognitive deficit is measurable. Methods and Findings: This article presents a class of statistical disease progression models and applies them to longitudinal cognitive scores. These non-linear mixed-effects disease progression models explicitly model disease stage, baseline cognition, and the patients' individual changes in cognitive ability as latent variables. Maximum-likelihood estimation in these models induces a data-driven criterion for separating disease progression and baseline cognition. Applied to data from the Alzheimer's Disease Neuroimaging Initiative, the model estimated a timeline of cognitive decline that spans ~15 years from the earliest subjective cognitive deficits to severe AD dementia. Subsequent analyses demonstrated how direct modeling of latent factors that modify the observed data patterns provides a scaffold for understanding disease progression, biomarkers, and treatment effects along the continuous time progression of disease. Conclusions: The presented framework enables direct interpretations of factors that modify cognitive decline. The results give new insights to the value of biomarkers for staging patients and suggest alternative explanations for previous findings related to accelerated cognitive decline among highly educated patients and patients on symptomatic treatments.}, }
@article {pmid33691319, year = {2021}, author = {Piao, Z and Song, L and Yao, L and Zhang, L and Lu, Y}, title = {Schisandrin Restores the Amyloid β-Induced Impairments on Mitochondrial Function, Energy Metabolism, Biogenesis, and Dynamics in Rat Primary Hippocampal Neurons.}, journal = {Pharmacology}, volume = {106}, number = {5-6}, pages = {254-264}, doi = {10.1159/000507818}, pmid = {33691319}, issn = {1423-0313}, mesh = {Alzheimer Disease/drug therapy ; Amyloid beta-Peptides/toxicity ; Animals ; Animals, Newborn ; Cyclooctanes/*pharmacology ; Cytochromes c/antagonists & inhibitors ; Energy Metabolism/*drug effects ; Hippocampus/*cytology/*drug effects ; Lignans/*pharmacology ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*drug effects ; Mitochondrial Dynamics/drug effects ; Models, Biological ; Neurons/*drug effects ; Neuroprotective Agents/*pharmacology ; Organelle Biogenesis ; Peptide Fragments/toxicity ; Polycyclic Compounds/*pharmacology ; Primary Cell Culture ; Rats, Sprague-Dawley ; }, abstract = {INTRODUCTION: Schisandrin which is derived from Schisandra chinensis has shown multiple pharmacological effects on various diseases including Alzheimer's disease (AD). It is demonstrated that mitochondrial dysfunction plays an essential role in the pathogenesis of neurodegenerative disorders.
OBJECTIVE: Our study aims to investigate the effects of schisandrin on mitochondrial functions and metabolisms in primary hippocampal neurons.
METHODS: In our study, rat primary hippocampal neurons were isolated and treated with indicated dose of amyloid β1-42 (Aβ1-42) oligomer to establish a cell model of AD in vitro. Schisandrin (2 μg/mL) was further subjected to test its effects on mitochondrial function, energy metabolism, mitochondrial biogenesis, and dynamics in the Aβ1-42 oligomer-treated neurons.
RESULTS AND CONCLUSIONS: Our findings indicated that schisandrin significantly alleviated the Aβ1-42 oligomer-induced loss of mitochondrial membrane potential and impaired cytochrome c oxidase activity. Additionally, the opening of mitochondrial permeability transition pore and release of cytochrome c were highly restricted with schisandrin treatment. Alterations in cell viability, ATP production, citrate synthase activity, and the expressions of glycolysis-related enzymes demonstrated the relief of defective energy metabolism in Aβ-treated neurons after the treatment of schisandrin. For mitochondrial biogenesis, elevated expression of peroxisome proliferator-activated receptor γ coactivator along with promoted mitochondrial mass was found in schisandrin-treated cells. The imbalance in the cycle of fusion and fission was also remarkably restored by schisandrin. In summary, this study provides novel mechanisms for the protective effect of schisandrin on mitochondria-related functions.}, }
@article {pmid33688938, year = {2021}, author = {Stroup, TS and Olfson, M and Huang, C and Wall, MM and Goldberg, T and Devanand, DP and Gerhard, T}, title = {Age-Specific Prevalence and Incidence of Dementia Diagnoses Among Older US Adults With Schizophrenia.}, journal = {JAMA psychiatry}, volume = {78}, number = {6}, pages = {632-641}, doi = {10.1001/jamapsychiatry.2021.0042}, pmid = {33688938}, issn = {2168-6238}, support = {P50 MH115843/MH/NIMH NIH HHS/United States ; }, abstract = {Importance: People with schizophrenia are at high risk of receiving a diagnosis of dementia. Understanding the magnitude and timing of this increased risk has important implications for practice and policy.
Objective: To estimate the age-specific incidence and prevalence of dementia diagnoses among older US adults with schizophrenia and in a comparison group without serious mental illness (SMI).
This retrospective cohort study used a 50% random national sample of Medicare beneficiaries 66 years or older with fee-for-service plans and Part D prescription drug coverage from January 1, 2007, to December 31, 2017. The cohort with schizophrenia included adults with at least 12 months of continuous enrollment in fee-for-service Medicare and Part D and at least 2 outpatient claims or at least 1 inpatient claim for schizophrenia during the qualifying years. The comparison group included adults with at least 12 months of continuous enrollment in fee-for-service Medicare and Part D and without a diagnosis of schizophrenia, bipolar disorder, or recurrent major depressive disorder during the qualifying year. Data were analyzed from January 1 to July 31, 2020.
Main Outcomes and Measures: Dementia was defined using the Centers for Medicare & Medicaid Services Chronic Conditions Warehouse diagnosis codes for Alzheimer disease and related disorders or senile dementia. Incident diagnoses were defined by at least 12 consecutive eligible months without a qualifying code before meeting dementia criteria.
Results: The study population of 8 011 773 adults 66 years or older (63.4% women; mean [SD] age, 74.0 [8.2] years) included 74 170 individuals with a diagnosis of schizophrenia (56.6% women) and 7 937 603 without an SMI diagnosis (63.5% women) who contributed 336 814 and 55 499 543 person-years of follow-up, respectively. At 66 years of age, the prevalence of diagnosed dementia was 27.9% (17 640 of 63 287) among individuals with schizophrenia compared with 1.3% (31 295 of 2 389 512) in the group without SMI. By 80 years of age, the prevalence of dementia diagnoses was 70.2% (2011 of 2866) in the group with schizophrenia and 11.3% (242 094 of 2 134 602) in the group without SMI. The annual incidence of dementia diagnoses per 1000 person-years at 66 years of age was 52.5 (95% CI, 50.1-54.9) among individuals with schizophrenia and 4.5 (95% CI, 4.4-4.6) among individuals without SMI and increased to 216.2 (95% CI, 179.9-252.6) and 32.3 (95% CI, 32.0-32.6), respectively, by 80 years of age.
Conclusions and Relevance: In this cohort study, compared with older adults without SMI, those with schizophrenia had increased risk of receiving a diagnosis of dementia across a wide age range, possibly because of cognitive and functional deterioration related to schizophrenia or factors contributing to other types of dementia. High rates of dementia among adults with schizophrenia have implications for the course of illness, treatment, and service use.}, }
@article {pmid33687445, year = {2021}, author = {Shaw, C and Hayes-Larson, E and Glymour, MM and Dufouil, C and Hohman, TJ and Whitmer, RA and Kobayashi, LC and Brookmeyer, R and Mayeda, ER}, title = {Evaluation of Selective Survival and Sex/Gender Differences in Dementia Incidence Using a Simulation Model.}, journal = {JAMA network open}, volume = {4}, number = {3}, pages = {e211001}, pmid = {33687445}, issn = {2574-3805}, support = {R21 AG059941/AG/NIA NIH HHS/United States ; R00 AG053410/AG/NIA NIH HHS/United States ; R21 AG055361/AG/NIA NIH HHS/United States ; RF1 AG050782/AG/NIA NIH HHS/United States ; R01 AG069128/AG/NIA NIH HHS/United States ; P2C HD041022/HD/NICHD NIH HHS/United States ; K01 AG049164/AG/NIA NIH HHS/United States ; R01 AG059716/AG/NIA NIH HHS/United States ; R13 AG064971/AG/NIA NIH HHS/United States ; }, mesh = {Age Distribution ; Aged ; Aged, 80 and over ; Dementia/*epidemiology ; Female ; Humans ; Incidence ; Male ; Middle Aged ; *Models, Theoretical ; Risk Factors ; Sex Distribution ; Survival Rate ; }, abstract = {Importance: Dementia research is susceptible to bias arising from selective survival, a process that results in individuals with certain characteristics disproportionately surviving to old age. Spurious associations between risk factors and dementia may be induced when factors associated with longer survival also influence dementia incidence.
Objective: To assess the role of selective survival in explaining reported sex/gender differences in dementia incidence.
This decision analytical model used a simulated cohort of US participants aged 50 years and without dementia at baseline followed up for incident dementia through age 95 years. Selective survival was induced by a selection characteristic (eg, childhood social disadvantage or Alzheimer genetic risk) that influenced both mortality and dementia incidence at varying magnitudes. Data analysis was performed from April 2018 to May 2020.
Exposure: Sex/gender, conceptualized as the combination of biological sex and social consequences of gender.
Main Outcomes and Measures: Dementia incidence rate ratios (IRRs) for women compared with men. In all simulations, it was assumed that there would be no true effect of sex/gender on dementia incidence; all observed sex/gender differences were due to selective survival.
Results: At baseline, the simulation included 100 000 participants aged 50 years (51 000 [51%] women, mirroring the 1919-1921 US birth cohort of non-Latino White individuals at age 50 years); distributions of the selection characteristic were standard normal (mean [SD], 0.0 [1.0]). Observed sex/gender differences in dementia incidence in individuals aged 85 years or older ranged from insignificant (IRR, 1.00; 95% CI, 0.91-1.11) to consistent with sex/gender differences (20% higher risk for women [IRR, 1.20; 95% CI, 1.08-1.32]) reported in an extant study. Simulations in which bias was large enough to explain prior findings required moderate to large differential effects of selective survival (eg, hazard ratio for selection characteristic on mortality at least 2.0 among men, no effect among women).
Conclusions and Relevance: These results suggest that selective survival may contribute to observed sex/gender differences in dementia incidence but do not preclude potential contributions of sex/gender-specific mechanisms. Further research on plausibility of selection characteristics with outcomes of the magnitude required for selective survival to explain sex/gender differences in dementia incidence and sex/gender-specific mechanisms represent an opportunity to understand prevention and treatment of dementia.}, }
@article {pmid33685483, year = {2021}, author = {Roca-Agujetas, V and Barbero-Camps, E and de Dios, C and Podlesniy, P and Abadin, X and Morales, A and Marí, M and Trullàs, R and Colell, A}, title = {Cholesterol alters mitophagy by impairing optineurin recruitment and lysosomal clearance in Alzheimer's disease.}, journal = {Molecular neurodegeneration}, volume = {16}, number = {1}, pages = {15}, pmid = {33685483}, issn = {1750-1326}, abstract = {BACKGROUND: Emerging evidence indicates that impaired mitophagy-mediated clearance of defective mitochondria is a critical event in Alzheimer's disease (AD) pathogenesis. Amyloid-beta (Aβ) metabolism and the microtubule-associated protein tau have been reported to regulate key components of the mitophagy machinery. However, the mechanisms that lead to mitophagy dysfunction in AD are not fully deciphered. We have previously shown that intraneuronal cholesterol accumulation can disrupt the autophagy flux, resulting in low Aβ clearance. In this study, we examine the impact of neuronal cholesterol changes on mitochondrial removal by autophagy.
METHODS: Regulation of PINK1-parkin-mediated mitophagy was investigated in conditions of acute (in vitro) and chronic (in vivo) high cholesterol loading using cholesterol-enriched SH-SY5Y cells, cultured primary neurons from transgenic mice overexpressing active SREBF2 (sterol regulatory element binding factor 2), and mice of increasing age that express the amyloid precursor protein with the familial Alzheimer Swedish mutation (Mo/HuAPP695swe) and mutant presenilin 1 (PS1-dE9) together with active SREBF2.
RESULTS: In cholesterol-enriched SH-SY5Y cells and cultured primary neurons, high intracellular cholesterol levels stimulated mitochondrial PINK1 accumulation and mitophagosomes formation triggered by Aβ while impairing lysosomal-mediated clearance. Antioxidant recovery of cholesterol-induced mitochondrial glutathione (GSH) depletion prevented mitophagosomes formation indicating mitochondrial ROS involvement. Interestingly, when brain cholesterol accumulated chronically in aged APP-PSEN1-SREBF2 mice the mitophagy flux was affected at the early steps of the pathway, with defective recruitment of the key autophagy receptor optineurin (OPTN). Sustained cholesterol-induced alterations in APP-PSEN1-SREBF2 mice promoted an age-dependent accumulation of OPTN into HDAC6-positive aggresomes, which disappeared after in vivo treatment with GSH ethyl ester (GSHee). The analyses in post-mortem brain tissues from individuals with AD confirmed these findings, showing OPTN in aggresome-like structures that correlated with high mitochondrial cholesterol levels in late AD stages.
CONCLUSIONS: Our data demonstrate that accumulation of intracellular cholesterol reduces the clearance of defective mitochondria and suggest recovery of the cholesterol homeostasis and the mitochondrial scavenging of ROS as potential therapeutic targets for AD.}, }
@article {pmid33683313, year = {2021}, author = {Nasrallah, IM and Gaussoin, SA and Pomponio, R and Dolui, S and Erus, G and Wright, CB and Launer, LJ and Detre, JA and Wolk, DA and Davatzikos, C and Williamson, JD and Pajewski, NM and Bryan, RN and , }, title = {Association of Intensive vs Standard Blood Pressure Control With Magnetic Resonance Imaging Biomarkers of Alzheimer Disease: Secondary Analysis of the SPRINT MIND Randomized Trial.}, journal = {JAMA neurology}, volume = {78}, number = {5}, pages = {568-577}, doi = {10.1001/jamaneurol.2021.0178}, pmid = {33683313}, issn = {2168-6157}, support = {HHSN271201300284P/DA/NIDA NIH HHS/United States ; RF1 AG054409/AG/NIA NIH HHS/United States ; UL1 TR001420/TR/NCATS NIH HHS/United States ; R01 HL141846/HL/NHLBI NIH HHS/United States ; S10 OD023495/OD/NIH HHS/United States ; }, abstract = {Importance: Meta-analyses of randomized clinical trials have indicated that improved hypertension control reduces the risk for cognitive impairment and dementia. However, it is unclear to what extent pathways reflective of Alzheimer disease (AD) pathology are affected by hypertension control.
Objective: To evaluate the association of intensive blood pressure control on AD-related brain biomarkers.
This is a substudy of the Systolic Blood Pressure Intervention Trial (SPRINT MIND), a multicenter randomized clinical trial that compared the efficacy of 2 different blood pressure-lowering strategies. Potential participants (n = 1267) 50 years or older with hypertension and without a history of diabetes or stroke were approached for a brain magnetic resonance imaging (MRI) study. Of these, 205 participants were deemed ineligible and 269 did not agree to participate; 673 and 454 participants completed brain MRI at baseline and at 4-year follow-up, respectively; the final follow-up date was July 1, 2016. Analysis began September 2019 and ended November 2020.
Interventions: Participants were randomized to either a systolic blood pressure goal of less than 120 mm Hg (intensive treatment: n = 356) or less than 140 mm Hg (standard treatment: n = 317).
Main Outcomes and Measures: Changes in hippocampal volume, measures of AD regional atrophy, posterior cingulate cerebral blood flow, and mean fractional anisotropy in the cingulum bundle.
Results: Among 673 recruited patients who had baseline MRI (mean [SD] age, 67.3 [8.2] years; 271 women [40.3%]), 454 completed the follow-up MRI at a median (interquartile range) of 3.98 (3.7-4.1) years after randomization. In the intensive treatment group, mean hippocampal volume decreased from 7.45 cm3 to 7.39 cm3 (difference, -0.06 cm3; 95% CI, -0.08 to -0.04) vs a decrease from 7.48 cm3 to 7.46 cm3 (difference, -0.02 cm3; 95% CI, -0.05 to -0.003) in the standard treatment group (between-group difference in change, -0.033 cm3; 95% CI, -0.062 to -0.003; P = .03). There were no significant treatment group differences for measures of AD regional atrophy, cerebral blood flow, or mean fractional anisotropy.
Conclusions and Relevance: Intensive treatment was associated with a small but statistically significant greater decrease in hippocampal volume compared with standard treatment, consistent with the observation that intensive treatment is associated with greater decreases in total brain volume. However, intensive treatment was not associated with changes in any of the other MRI biomarkers of AD compared with standard treatment.
Trial Registration: ClinicalTrials.gov Identifier: NCT01206062.}, }
@article {pmid33674360, year = {2021}, author = {Friedman, LG and McKeehan, N and Hara, Y and Cummings, JL and Matthews, DC and Zhu, J and Mohs, RC and Wang, D and Hendrix, SB and Quintana, M and Schneider, LS and Grundman, M and Dickson, SP and Feldman, HH and Jaeger, J and Finger, EC and Ryan, JM and Niehoff, D and Dickinson, SL and Markowitz, JT and Owen, M and Travaglia, A and Fillit, HM}, title = {Value-Generating Exploratory Trials in Neurodegenerative Dementias.}, journal = {Neurology}, volume = {96}, number = {20}, pages = {944-954}, pmid = {33674360}, issn = {1526-632X}, mesh = {Alzheimer Disease/*drug therapy ; Clinical Trials as Topic/*methods ; Clinical Trials, Phase I as Topic ; Clinical Trials, Phase II as Topic ; Dementia/drug therapy ; Drug Development/*methods ; Frontotemporal Dementia/*drug therapy ; Humans ; Neurodegenerative Diseases/drug therapy ; Outcome Assessment, Health Care ; Proof of Concept Study ; Research Design ; Treatment Failure ; Treatment Outcome ; }, abstract = {Drug development for Alzheimer disease and other neurodegenerative dementias, including frontotemporal dementia, has experienced a long history of phase 2 and phase 3 clinical trials that failed to show efficacy of investigational drugs. Despite differences in clinical and behavioral characteristics, these disorders have shared pathologies and face common challenges in designing early-phase trials that are predictive of late-stage success. Here, we discuss exploratory clinical trials in neurodegenerative dementias. These are generally phase 1b or phase 2a trials that are designed to assess pharmacologic effects and rely on biomarker outcomes, with shorter treatment durations and fewer patients than traditional phase 2 studies. Exploratory trials can establish go/no-go decision points, support proof of concept and dose selection, and terminate drugs that fail to show target engagement with suitable exposure and acceptable safety profiles. Early failure saves valuable resources including opportunity costs. This is especially important for programs in academia and small biotechnology companies but may be applied to high-risk projects in large pharmaceutical companies to achieve proof of concept more rapidly at lower costs than traditional approaches. Exploratory studies in a staged clinical development program may provide promising data to warrant the substantial resources needed to advance compounds through late-stage development. To optimize the design and application of exploratory trials, the Alzheimer's Drug Discovery Foundation and the Association for Frontotemporal Degeneration convened an advisory panel to provide recommendations on outcome measures and statistical considerations for these types of studies and study designs that can improve efficiency in clinical development.}, }
@article {pmid33665436, year = {2021}, author = {Elmorsy, E and Elsharkawy, E and Alhumaydhi, FA and Salama, M}, title = {The protective effect of Indian Catechu methanolic extract against aluminum chloride-induced neurotoxicity, A rodent model of Alzheimer's disease.}, journal = {Heliyon}, volume = {7}, number = {2}, pages = {e06269}, pmid = {33665436}, issn = {2405-8440}, abstract = {Alzheimer's disease (AD) is the commonest neurodegenerative disorder with a wide array of manifestations, courses, and contributing causes. Despite being clinically characterized a long time ago; no treatment has been developed that could improve the pathology or slow down the disease manifestation- so far. Indian Catechu methanolic extract (ICME) has proved to have multiple beneficial effects that support its use in several disorders- especially those with complex etiology. In the present study, we evaluated the neuroprotective effect of ICME in a rat model of AD using Aluminum Chloride (AlCl3). The results showed that ICME could have a positive impact on the course of AD through its anticholinesterase effect and significant antioxidant effect which was reflected on the animals both on behavioral tests as well as hallmark pathological findings.}, }
@article {pmid33657269, year = {2021}, author = {Schnier, C and Janbek, J and Williams, L and Wilkinson, T and Laursen, TM and Waldemar, G and Richter, H and Kostev, K and Lathe, R and G Haas, J}, title = {Antiherpetic medication and incident dementia: Observational cohort studies in four countries.}, journal = {European journal of neurology}, volume = {28}, number = {6}, pages = {1840-1848}, doi = {10.1111/ene.14795}, pmid = {33657269}, issn = {1468-1331}, support = {MR/P011349/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Cohort Studies ; *Dementia/epidemiology ; *Herpesviridae Infections ; Humans ; Incidence ; Registries ; Risk Factors ; }, abstract = {BACKGROUND AND PURPOSE: Several epidemiological studies from Taiwan, all using the same data resource, found significant associations between herpes virus infection, antiherpetic medication, and subsequent dementia. We conducted a multicenter observational cohort study using health registry data from Wales, Germany, Scotland, and Denmark to investigate potential associations between antiherpetic medication and incident dementia, and also to comprehensively investigate such associations broken down according to medication type and dose, type of herpes virus, and dementia subtype.
METHODS: A total of 2.5 million individuals aged 65 years or more were followed up using linked electronic health records in four national observational cohort studies. Exposure and outcome were classified using coded data from primary and secondary care. Data were analyzed using survival analysis with time-dependent covariates.
RESULTS: Results were heterogeneous, with a tendency toward decreased dementia risk in individuals exposed to antiherpetic medication. Associations were not affected by treatment number, herpes subtype, dementia subtype, or specific medication. In one cohort, individuals diagnosed with herpes but not exposed to antiherpetic medication were at higher dementia risk.
CONCLUSIONS: Short-term antiherpetic medication is not markedly associated with incident dementia. Because neither dementia subtype nor herpes subtype modified the association, the small but significant decrease in dementia incidence with antiherpetic administration may reflect confounding and misclassification.}, }
@article {pmid33653273, year = {2021}, author = {Guzmán-Ruiz, MA and Herrera-González, A and Jiménez, A and Candelas-Juárez, A and Quiroga-Lozano, C and Castillo-Díaz, C and Orta-Salazar, E and Organista-Juárez, D and Díaz-Cintra, S and Guevara-Guzmán, R}, title = {Protective effects of intracerebroventricular adiponectin against olfactory impairments in an amyloid β1-42 rat model.}, journal = {BMC neuroscience}, volume = {22}, number = {1}, pages = {14}, pmid = {33653273}, issn = {1471-2202}, abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by cognitive impairment that eventually develops into dementia. Amyloid-beta (Aβ) accumulation is a widely described hallmark in AD, and has been reported to cause olfactory dysfunction, a condition considered an early marker of the disease associated with injuries in the olfactory bulb (OB), the hippocampus (HIPP) and other odor-related cortexes. Adiponectin (APN) is an adipokine with neuroprotective effects. Studies have demonstrated that APN administration decreases Aβ neurotoxicity and Tau hyperphosphorylation in the HIPP, reducing cognitive impairment. However, there are no studies regarding the neuroprotective effects of APN in the olfactory dysfunction observed in the Aβ rat model. The aim of the present study is to determine whether the intracerebroventricular (i.c.v) administration of APN prevents the early olfactory dysfunction in an i.c.v Amyloid-beta1-42 (Aβ1-42) rat model. Hence, we evaluated olfactory function by using a battery of olfactory tests aimed to assess olfactory memory, discrimination and detection in the Aβ rat model treated with APN. In addition, we determined the number of cells expressing the neuronal nuclei (NeuN), as well as the number of microglial cells by using the ionized calcium-binding adapter molecule 1 (Iba-1) marker in the OB and, CA1, CA3, hilus and dentate gyrus (DG) in the HIPP. Finally, we determined Arginase-1 expression in both nuclei through Western blot.
RESULTS: We observed that the i.c.v injection of Aβ decreased olfactory function, which was prevented by the i.c.v administration of APN. In accordance with the olfactory impairment observed in i.c.v Aβ-treated rats, we observed a decrease in NeuN expressing cells in the glomerular layer of the OB, which was also prevented with the i.c.v APN. Furthermore, we observed an increase of Iba-1 cells in CA1, and DG in the HIPP of the Aβ rats, which was prevented by the APN treatment.
CONCLUSION: The present study describes the olfactory impairment of Aβ treated rats and evidences the protective role that APN plays in the brain, by preventing the olfactory impairment induced by Aβ1-42. These results may lead to APN-based pharmacological therapies aimed to ameliorate AD neurotoxic effects.}, }
@article {pmid33652938, year = {2021}, author = {Librizzi, D and Cabanel, N and Zavorotnyy, M and Riehl, E and Kircher, T and Luster, M and Hooshyar Yousefi, B}, title = {Clinical Relevance of [18F]Florbetaben and [18F]FDG PET/CT Imaging on the Management of Patients with Dementia.}, journal = {Molecules (Basel, Switzerland)}, volume = {26}, number = {5}, pages = {}, pmid = {33652938}, issn = {1420-3049}, mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/*diagnostic imaging/genetics/physiopathology ; Amyloid beta-Peptides/genetics/isolation & purification ; Brain/diagnostic imaging/physiopathology ; Cognitive Dysfunction/diagnosis/*diagnostic imaging/physiopathology ; Dementia/diagnosis/*diagnostic imaging/physiopathology ; Female ; Fluorodeoxyglucose F18/*administration & dosage ; Humans ; Male ; Middle Aged ; Positron Emission Tomography Computed Tomography/methods ; tau Proteins/genetics/isolation & purification ; }, abstract = {PET of β-Amyloid plaques (Aβ) using [18F]florbetaben ([18F]FBB) and [18F]fluorodeoxyglucose ([18F]FDG) increasingly aid clinicians in early diagnosis of dementia, including Alzheimer's disease (AD), frontotemporal disease, dementia with Lewy bodies, and vascular dementia. The aim of this retrospective analysis was to evaluate clinical relevance of [18F]FBB, [18F]FDG PET and complimentary CSF measurements in patients with suspected dementia. In this study, 40 patients with clinically suspected or history of dementia underwent (1) measurement of Aβ peptides, total tau, and p-tau protein levels in the cerebrospinal fluid (CSF) compared with healthy controls (HC); (2) clinical and neuropsychological assessment, which included Consortium to Establish a Registry for Alzheimer's Disease neuropsychological assessment battery (CERAD-NAB); (3) [18F]FBB and [18F]FDG PET imaging within an average of 3 weeks. The subjects were within 15 days stratified using PET, CSF measurements as HC, mild cognitive impaired (MCI) and dementia including Alzheimer´s disease. The predictive dementia-related cognitive decline values were supporting the measurements. PET images were evaluated visually and quantitatively using standard uptake value ratios (SUVR). Twenty-one (52.5%) subjects were amyloid-positive (Aβ+), with a median neocortical SUVR of 1.80 for AD versus 1.20 relative to the respective 19 (47.5 %) amyloid-negative (Aβ-) subjects. Moreover, the [18F]FDG and [18F]FBB confirmed within a sub-group of 10 patients a good complimentary role by correlation between amyloid pathology and brain glucose metabolism in 8 out of 10 subjects. The results suggest the clinical relevance for [18F]FBB combined with [18F]FDG PET retention and CFS measurements serving the management of our patients with dementia. Therefore, [18F]FBB combined with [18F]FDG PET is a helpful tool for differential diagnosis, and supports the patients' management as well as treatment.}, }
@article {pmid33646990, year = {2021}, author = {Reiss, AB and Montufar, N and DeLeon, J and Pinkhasov, A and Gomolin, IH and Glass, AD and Arain, HA and Stecker, MM}, title = {Alzheimer Disease Clinical Trials Targeting Amyloid: Lessons Learned From Success in Mice and Failure in Humans.}, journal = {The neurologist}, volume = {26}, number = {2}, pages = {52-61}, doi = {10.1097/NRL.0000000000000320}, pmid = {33646990}, issn = {2331-2637}, abstract = {BACKGROUND: The goal of slowing or halting the development of Alzheimer disease (AD) has resulted in the huge allocation of resources by academic institutions and pharmaceutical companies to the development of new treatments. The etiology of AD is elusive, but the aggregation of amyloid-β and tau peptide and oxidative processes are considered critical pathologic mechanisms. The failure of drugs with multiple mechanisms to meet efficacy outcomes has caused several companies to decide not to pursue further AD studies and has left the field essentially where it has been for the past 15 years. Efforts are underway to develop biomarkers for detection and monitoring of AD using genetic, imaging, and biochemical technology, but this is of minimal use if no intervention can be offered.
REVIEW SUMMARY: In this review, we consider the natural progression of AD and how it continues despite present attempts to modify the amyloid-related machinery to alter the disease trajectory. We describe the mechanisms and approaches to AD treatment targeting amyloid, including both passive and active immunotherapy as well as inhibitors of enzymes in the amyloidogenic pathway.
CONCLUSION: Lessons learned from clinical trials of amyloid reduction strategies may prove crucial for the leap forward toward novel therapeutic targets to treat AD.}, }
@article {pmid33637039, year = {2021}, author = {Watt, JA and Veroniki, AA and Tricco, AC and Straus, SE}, title = {Using a distribution-based approach and systematic review methods to derive minimum clinically important differences.}, journal = {BMC medical research methodology}, volume = {21}, number = {1}, pages = {41}, pmid = {33637039}, issn = {1471-2288}, mesh = {*Alzheimer Disease/diagnosis/drug therapy ; Humans ; *Minimal Clinically Important Difference ; Outcome Assessment, Health Care ; Research Design ; Surveys and Questionnaires ; Systematic Reviews as Topic ; }, abstract = {BACKGROUND: Clinical interpretation of changes measured on a scale is dependent on knowing the minimum clinically important difference (MCID) for that scale: the threshold above which clinicians, patients, and researchers perceive an outcome difference. Until now, approaches to determining MCIDs were based upon individual studies or surveys of experts. However, the comparison of meta-analytic treatment effects to a MCID derived from a distribution of standard deviations (SDs) associated with all trial-specific outcomes in a meta-analysis could improve our clinical understanding of meta-analytic treatment effects.
METHODS: We approximated MCIDs using a distribution-based approach that pooled SDs associated with baseline mean or mean change values for two scales (i.e. Mini-Mental State Exam [MMSE] and Alzheimer Disease Assessment Scale - Cognitive Subscale [ADAS-Cog]), as reported in parallel randomized trials (RCTs) that were included in a systematic review of cognitive enhancing medications for dementia (i.e. cholinesterase inhibitors and memantine). We excluded RCTs that did not report baseline or mean change SD values. We derived MCIDs at 0.4 and 0.5 SDs of the pooled SD and compared our derived MCIDs to previously published MCIDs for the MMSE and ADAS-Cog.
RESULTS: We showed that MCIDs derived from a distribution-based approach approximated published MCIDs for the MMSE and ADAS-Cog. For the MMSE (51 RCTs, 12,449 patients), we derived a MCID of 1.6 at 0.4 SDs and 2 at 0.5 SDs using baseline SDs and we derived a MCID of 1.4 at 0.4 SDs and 1.8 at 0.5 SDs using mean change SDs. For the ADAS-Cog (37 RCTs, 10,006 patients), we derived a MCID of 4 at 0.4 SDs and 5 at 0.5 SDs using baseline SDs and we derived a MCID of 2.6 at 0.4 SDs and 3.2 at 0.5 SDs using mean change SDs.
CONCLUSION: A distribution-based approach using data included in a systematic review approximated known MCIDs. Our approach performed better when we derived MCIDs from baseline as opposed to mean change SDs. This approach could facilitate clinical interpretation of outcome measures reported in RCTs and systematic reviews of interventions. Future research should focus on the generalizability of this method to other clinical scenarios.}, }
@article {pmid33634105, year = {2020}, author = {Chen, C and Liu, P and Wang, J and Yu, H and Zhang, Z and Liu, J and Chen, X and Zhu, F and Yang, X}, title = {Dauricine Attenuates Spatial Memory Impairment and Alzheimer-Like Pathologies by Enhancing Mitochondrial Function in a Mouse Model of Alzheimer's Disease.}, journal = {Frontiers in cell and developmental biology}, volume = {8}, number = {}, pages = {624339}, pmid = {33634105}, issn = {2296-634X}, abstract = {Alzheimer's disease (AD) is characterized by extracellular amyloid plaques composed of β-amyloid (Aβ) and intracellular neurofibrillary tangles containing hyperphosphorylated tau protein. No effective therapy is available for this disease. In this study, we investigated the potential therapeutic effects of dauricine (DAU), a benzyl tetrahydroisoquinoline alkaloid, on AD, and found that DAU administration significantly improved cognitive impairments in 3xTg-AD mice by decreasing Aβ plaques and hyperphosphorylated tau and increasing the hippocampal ATP level. Proteomic and western blot analyses revealed that DAU treatment mainly modified the expression of proteins involved in mitochondrial energy metabolism, such as Aco2, Ndufs1, Cox5a, and SDHB, and that of synapse-related proteins such as Syn1 and Syn2. Pathway analysis revealed that DAU modulated the tricarboxylic acid cycle, synaptic vesicle cycle, glycolysis, and gluconeogenesis in 3xTg-AD mice. Our study suggests that DAU may be a potential drug for the treatment of AD.}, }
@article {pmid33629902, year = {2021}, author = {Yamazaki, K and Yoshimura, A and Miyahara, S and Sugi, S and Itono, M and Kondo, M and Tsuji, N and Shimizu, M and Fukushima, R and Kishimoto, M}, title = {Evaluation of cerebral blood flow in the hippocampus, thalamus, and basal ganglia and the volume of the hippocampus in dogs before and during treatment with prednisolone.}, journal = {American journal of veterinary research}, volume = {82}, number = {3}, pages = {230-236}, doi = {10.2460/ajvr.82.3.230}, pmid = {33629902}, issn = {1943-5681}, mesh = {Animals ; Basal Ganglia/diagnostic imaging ; Brain ; *Cerebrovascular Circulation ; Dogs ; Hippocampus/diagnostic imaging ; *Prednisolone ; Thalamus/diagnostic imaging ; }, abstract = {OBJECTIVE: To examine whether glucocorticoid (GC) administration alters hippocampal cerebral blood flow (CBF) or volume in dogs.
ANIMALS: 6 clinically normal adult Beagles.
PROCEDURES: Each dog underwent CT and MRI to measure the CBF in the hippocampus, basal ganglia, thalamus, and cerebral cortex and the volume of the hippocampus in each hemisphere of the brain before (day 0) and during (days 7 and 21) a 21-day treatment with prednisolone (1.0 mg/kg, PO, q 24 h) and famotidine (0.5 mg/kg, PO, q 12 h). Results for hippocampal volume, anesthesia-related variables, and semiquantitative measurements of CBF (hemisphere-specific ratios of the CBF in the hippocampus, basal ganglia, and thalamus relative to the CBF in the ipsilateral cerebral cortex and the left cerebral cortex CBF-to-right cerebral cortex CBF ratio) were compared across assessment time points (days 0, 7, and 21).
RESULTS: The ratios of CBF in the right hippocampus and right thalamus to that in the right cerebral cortex on day 21 were significantly lower than those on day 0. No meaningful differences were detected in results for the hippocampal volume in either hemisphere or for the anesthesia-related variables across the 3 time points.
Results indicated that GC administration reduced CBF in the hippocampus and thalamus in dogs of the present study, similar to that which occurs in humans. Research on GC-related brain alteration in dogs could potentially contribute to advancements in understanding Alzheimer disease in humans and neurodegenerative conditions in dogs.}, }
@article {pmid33627920, year = {2020}, author = {Feng, X and Li, T and Song, X and Zhu, H}, title = {Bayesian Scalar on Image Regression With Nonignorable Nonresponse.}, journal = {Journal of the American Statistical Association}, volume = {115}, number = {532}, pages = {1574-1597}, pmid = {33627920}, issn = {0162-1459}, support = {R01 MH086633/MH/NIMH NIH HHS/United States ; R01 MH116527/MH/NIMH NIH HHS/United States ; }, abstract = {Medical imaging has become an increasingly important tool in screening, diagnosis, prognosis, and treatment of various diseases given its information visualization and quantitative assessment. The aim of this article is to develop a Bayesian scalar-on-image regression model to integrate high-dimensional imaging data and clinical data to predict cognitive, behavioral, or emotional outcomes, while allowing for nonignorable missing outcomes. Such a nonignorable nonresponse consideration is motivated by examining the association between baseline characteristics and cognitive abilities for 802 Alzheimer patients enrolled in the Alzheimer's Disease Neuroimaging Initiative 1 (ADNI1), for which data are partially missing. Ignoring such missing data may distort the accuracy of statistical inference and provoke misleading results. To address this issue, we propose an imaging exponential tilting model to delineate the data missing mechanism and incorporate an instrumental variable to facilitate model identifiability followed by a Bayesian framework with Markov chain Monte Carlo algorithms to conduct statistical inference. This approach is validated in simulation studies where both the finite sample performance and asymptotic properties are evaluated and compared with the model with fully observed data and that with a misspecified ignorable missing mechanism. Our proposed methods are finally carried out on the ADNI1 dataset, which turns out to capture both of those clinical risk factors and imaging regions consistent with the existing literature that exhibits clinical significance. Supplementary materials for this article, including a standardized description of the materials available for reproducing the work, are available as an online supplement.}, }
@article {pmid33618651, year = {2021}, author = {Mooko, T and Bala, A and Tripathy, S and Kumar, CS and Mahadevappa, CP and Chaudhary, SK and Matsabisa, MG}, title = {Cannabis Sativa L. Flower and Bud Extracts inhibited In vitro Cholinesterases and b-Secretase Enzymes Activities: Possible Mechanisms of Cannabis use in Alzheimer Disease.}, journal = {Endocrine, metabolic & immune disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/1871530321666210222124349}, pmid = {33618651}, issn = {2212-3873}, abstract = {BACKGROUND: There are anecdotal claims on the use of Cannabis sativa L. in the treatment of Alzheimer's disease, but there is lack of scientific data to support the efficacy and safety of Cannabis sativa L. for Alzheimer's disease.
AIM: The aim of the study was to evaluate the effect of aerial parts of Cannabis sativa L. on the cholinesterases and β-secretase enzyme activity as one of the possible mechanisms of Alzheimer's disease.
METHODS: The phytochemical and heavy metal contents were analysed. The extracts were screened for acetylcholinesterase, butyrylcholinesterase and β-secretase activity. Cytotoxicity of extracts was performed in normal vero and pre-adipocytes cell lines. The extracts were characterized using high performance thin layer chromatography and high-performance liquid chromatography for their chemical fingerprints. Alkaloids, flavonoids and glycosides were present amongst the tested phytochemicals. Cannabidiol concentrations were comparatively high in the hexane and dichloromethane than in dichloromethane: methanol (1:1) and methanol extracts.
RESULTS: Hexane and dichloromethane extracts showed a better inhibitory potential towards cholinesterase activity, while water, hexane, dichloromethane: methanol (1:1) and methanol showed an inhibitory potential towards β-secretase enzyme activity. All extracts showed no cytotoxic effect on pre-adipocytes and vero cells after 24- and 48-hours of exposure.
CONCLUSION: Therefore, this may explain the mechanism through which AD symptoms may be treated and managed by Cannabis sativa L. extracts.}, }
@article {pmid33613890, year = {2020}, author = {Fahanik-Babaei, J and Baluchnejadmojarad, T and Roghani, M}, title = {Differential Effect of Amyloid Beta1-40 on Short-term and Long-term Plasticity in Dentate Gyrus of a Rat Model of Alzheimer Disease.}, journal = {Basic and clinical neuroscience}, volume = {11}, number = {4}, pages = {517-524}, pmid = {33613890}, issn = {2008-126X}, abstract = {Introduction: Synaptic plasticity is inappropriately affected by neurodegenerative diseases, including Alzheimer Disease (AD). In this study, we examined the effect of intrahippocampal amyloid-beta (Aβ1-40) on dentate gyrus Long-term Potentiation (LTP) and presynaptic short-term plasticity in a rat model of AD.
Methods: The experimental groups in this research included the control with no treatment, sham-operated receiving the vehicle (normal saline), and Aβ-lesioned groups. For modeling AD, aggregated Aβ1-40 (10 μg/2 μl on each side) was injected into the hippocampal CA1. Three weeks later, Population Spike (PS) amplitude and slope ratios were determined at different Inter-pulse Intervals (IPI) of 10, 20, 30, and 50 ms as a valid indicator of the short-term presynaptic facilitation and/or depression. In addition, PS amplitude and slope were taken as an index of long-term synaptic plasticity after application of High-frequency Stimulation (HFS) to induce LTP in the medial perforant-dentate gyrus pathway.
Results: No significant differences were noted amongst the experimental groups regarding fEPSP slope and paired-pulse indices as indicators of short-term plasticity. In contrast, fEPSP slope and PS amplitude significantly decreased following the application of HFS in Aβ-injected group. In addition, there was no significant difference between the control and sham-operated groups regarding the mentioned parameters.
Conclusion: Findings of this study clearly demonstrated that microinjection of Aβ1-40 into the CA1 could impair LTP in dentate gyrus but could not modify short-term plasticity.}, }
@article {pmid33613888, year = {2020}, author = {Fahimi Truski, F and Ghotbeddin, Z and Tabandeh, MR and Pourmahdi Borujeni, M}, title = {Crocin Treatment after Maternal Hypoxia Attenuates Spatial Memory Impairment and Expression of BACE1 and HIF-1α in Rat Offspring Brain.}, journal = {Basic and clinical neuroscience}, volume = {11}, number = {4}, pages = {499-506}, pmid = {33613888}, issn = {2008-126X}, abstract = {Introduction: Hypoxia via expression of Hypoxia-Inducible Factor-1 (HIF-1) is an important and effective factor in the onset and progression of memory disorders, such as Alzheimer Disease (AD). The activity of β-secretase (BACE1) is increased in hypoxia conditions. BACE1 triggers a cascade of pathological events resulting in AD. Crocin acts as a memoryimproving agent but its molecular mechanism is not well-known. Therefore, in this study, the effect of crocin on spatial memory, HIF-1α, and BACE1 gene expression was investigated in rat offspring under maternal hypoxia.
Methods: Female pregnant rats on the 20th day of pregnancy were divided into 4 groups, including sham, crocin-treated, hypoxia, and hypoxia group treated with crocin. In the hypoxia groups, pregnant rats were exposed to 7% oxygen and 93% nitrogen intensity for 3 h. In the crocin-treated group, crocin (30 mg/kg) was injected at P14-28 (i.p). At the end, Morris water maze was used to assess spatial memory and real-time polymerase chain reaction was performed to measure the expression of BACE1 and HIF-1α genes in the brain of offspring.
Results: Maternal hypoxia impaired memory compared with the sham group. However, crocin treatment improved cognitive behavior. HIF-1α and BACE1 expressions were upregulated in the brain of offspring in the hypoxia group. Crocin treatment could attenuate the expression of both genes.
Conclusion: According to our results, down-regulation of HIF-1α and BACE1 gene expressions in the brain of rat offspring after crocin treatment can be suggested as a molecular mechanism for crocin to improve spatial memory.}, }
@article {pmid33611334, year = {2021}, author = {Liu, MN and Liou, YJ and Wang, WC and Su, KC and Yeh, HL and Lau, CI and Hu, LY and Tsai, SJ and Chen, HY}, title = {Group Music Intervention Using Percussion Instruments to Reduce Anxiety Among Elderly Male Veterans with Alzheimer Disease.}, journal = {Medical science monitor : international medical journal of experimental and clinical research}, volume = {27}, number = {}, pages = {e928714}, pmid = {33611334}, issn = {1643-3750}, mesh = {Age Factors ; Aged ; Aged, 80 and over ; Alzheimer Disease/psychology/*therapy ; Anxiety/psychology/*therapy ; Anxiety Disorders/psychology/therapy ; Humans ; Male ; Music Therapy/*methods ; Taiwan ; Veterans/*psychology ; }, abstract = {BACKGROUND This study aimed to assess the impact of a group music intervention on anxiety and depression of elderly male veterans with dementia. MATERIAL AND METHODS In total, 50 elderly men with Alzheimer disease were randomly divided into intervention and control groups. Patients in the intervention group attended a 60-minute group music session that used percussion instruments with familiar music in the morning once a week for 12 weeks, whereas those in the control group received a rest and reading session at the same intervals and under the same conditions. The Hamilton Anxiety Rating Scale and Geriatric Depression Scale were used to assess anxiety and depression at baseline, week 6, and week 12. The Primary Measures of Music Audiation (PMMA) was used to assess musical aptitude at the baseline. RESULTS A significant reduction in the anxiety level following the 12-week music sessions was observed in the intervention group (P<.001), but there was no significant change in the control group. However, the change in depressive symptoms between the 2 groups was nonsignificant. In the intervention group, when stratifying patients based on music aptitude determined through PMMA assessment, patients with high PMMA scores had significantly reduced anxiety symptoms over time compared with those with low scores. CONCLUSIONS For elderly male veterans with dementia, participating in a group music intervention reduced anxiety symptoms. In patients with high musical aptitude, the treatment effects on anxiety reduction were satisfactory. Measures of music aptitude may provide valuable information regarding patients' response to music intervention.}, }
@article {pmid33602092, year = {2020}, author = {Vasconcelos-Filho, FSL and da Rocha-E-Silva, RC and Martins, JER and Godinho, WDN and da Costa, VV and Ribeiro, JKC and da Silva, CA and Ceccatto, VM and Soares, PM and Evangelista, JSAM}, title = {Neuroprotector Effect of Daily 8-Minutes of High-Intensity Interval Training in Rat Aβ1-42 Alzheimer Disease Model.}, journal = {Current Alzheimer research}, volume = {17}, number = {14}, pages = {1320-1333}, doi = {10.2174/1567205018666210218161856}, pmid = {33602092}, issn = {1875-5828}, abstract = {BACKGROUND: Alzheimer's disease (AD) is the most common and irreversible neurodegenerative disorder, and amyloid peptide plays a central role in its pathogenesis. Physical training contributes as a beneficial adaptation to AD. However, these effects may be underestimated because much of the literature used fixed training prescription variables (intensity and volume) throughout the protocol. Moreover, researchers poorly understand whether chronic high-intensity interval training (HIIT) exerts similar effects on the brain tissue of individuals with AD.
OBJECTIVE: This study evaluated the effect of 8 minutes of HIIT with incremental overload in an AD model.
METHODS: Forty male Wistar rats were divided into four groups: an untrained Sham group, Sham trained group, Aβ1-42 (Alzheimer's) untrained group, and Aβ1-42 (Alzheimer's) trained group (n=10 rats per group). Animals underwent stereotactic surgery and received a hippocampal injection of Aβ1-42 or a saline solution. Seven days after surgery, two weeks of treadmill adaptation followed by a maximal running test (MRT) was performed. Then, animals were subjected to eight weeks of HIIT. Rats were sacrificed 24 h after the behavioral tests (open field and Morris water maze), hippocampal tissue was extracted to analyze the redox balance and BDNF/TrkB pathway, and neuritic plaques (NP) were detected by evaluating silver impregnation.
RESULTS: The AD trained group presented a physical capacity amelioration every two weeks and locomotor, learning, and memory improvements (p<0.05). These effects were accompanied by increased CAT and SOD levels, followed by decreased lipid peroxidation (p<0.05). Furthermore, increased activation of the BDNF/TrkB (p<0.05) pathway and decreased NP was observed.
CONCLUSION: Based on these results, MRT was essential for an excellent chronic training protocol prescription and overload adjustment. Therefore, 8 minutes of HIIT daily for 8 weeks may reduce behavioral deficits by promoting a positive redox balance and increased activity of the BDNF/TrkB pathway that may contribute to NP attenuation.}, }
@article {pmid33602090, year = {2020}, author = {Siafaka, PI and Mutlu, G and Okur, NÜ}, title = {Alzheimer's Disease and its Related Dementia Types: A Review on Their Management Via Nanotechnology Based Therapeutic Strategies.}, journal = {Current Alzheimer research}, volume = {17}, number = {14}, pages = {1239-1261}, doi = {10.2174/1567205018666210218160812}, pmid = {33602090}, issn = {1875-5828}, abstract = {BACKGROUND: Dementia and its related types such as Alzheimer's disease, vascular dementia and mixed dementia belong to brain associated diseases, resulting in long-term progressive memory loss. These diseases are so severe that can affect a person's daily routine. Up to date, treatment of dementia is still an unmet challenge due to their complex pathophysiology and unavailable efficient pharmacological approaches. The use of nanotechnology based pharmaceutical products could possibly improve the management of dementia given that nanocarriers could more efficiently deliver drugs to the brain.
OBJECTIVE: The objective of this study is to provide the current nanotechnology based drug delivery systems for the treatment of various dementia types. In addition, the current diagnosis biomarkers for the mentioned dementia types along with their available pharmacological treatment are being discussed.
METHODS: An extensive review of the current nanosystems such as brain drug delivery systems against Alzheimer's disease, vascular dementia and mixed dementia was performed. Moreover, nanotheranostics as possible imaging markers for such dementias were also reported.
RESULTS: The field of nanotechnology is quite advantageous for targeting dementia given that nanoscale drug delivery systems easily penetrate the blood brain barrier and circulate in the body for prolonged time. These nanoformulations consist of polymeric nanoparticles, solid lipid nanoparticles, nanostructured lipid carriers, microemulsions, nanoemulsions, and liquid crystals. The delivery of the nanotherapeutics can be achieved via various administration routes such as transdermal, injectable, oral, and more importantly, through the intranasal route. Nonetheless, the nanocarriers are mostly limited to Alzheimer's disease targeting; thus, nanocarriers for other types of dementia should be developed.
CONCLUSION: To conclude, understanding the mechanism of neurodegeneration and reviewing the current drug delivery systems for Alzheimer's disease and other dementia types are significant for medical and pharmaceutical society to produce efficient therapeutic choices and novel strategies based on multifunctional and biocompatible nanocarriers, which can deliver the drug sufficiently into the brain.}, }
@article {pmid33586916, year = {2021}, author = {Ghotbeddin, Z and Tabandeh, MR and Pourmahdi Borujeni, M and Fahimi Truski, F and Zalaki Ghorbani Pour, MR and Tabrizian, L}, title = {Crocin mitigated cognitive impairment and brain molecular alterations induced by different intensities of prenatal hypoxia in neonatal rats.}, journal = {Brain and behavior}, volume = {11}, number = {4}, pages = {e02078}, pmid = {33586916}, issn = {2162-3279}, mesh = {*Amyloid Precursor Protein Secretases ; Animals ; Animals, Newborn ; Aspartic Acid Endopeptidases/genetics ; Brain ; Carotenoids ; *Cognitive Dysfunction/drug therapy ; Female ; Hypoxia/drug therapy ; Pregnancy ; Rats ; }, abstract = {INTRODUCTION: Brain hypoxia has important role to the onset and progression of sporadic form of Alzheimer disease via expression of hypoxia-inducible factor-1 (HIF-1). Crocin by anti-amyloidogenic property inhibits β-amyloid formation. However, the molecular mechanism associated with anti-amyloidogenic activity of crocin is unknown. So, the present study was designed to investigate the effect of crocin on cognitive behavior and expression of HIF-1α and β-secretase (BACE1) genes in the brain of neonate rats following different intensities of hypoxia during pregnancy.
MATERIAL AND METHODS: Pregnant female rats were divided into six groups including sham, control crocin treated (CC), hypoxia with three different intensities (H1-H3), and most intense of hypoxic group treated with crocin (H3C) (30 mg/kg; i.p) at P14. Hypoxia induced on the 20th day of pregnancy. Animals in sham and CC were put in hypoxia chamber at the same time of hypoxia group without any hypoxia induction. Morris water maze (MWM) and qRT-PCR were used to evaluate the cognitive behavior and mRNA levels of BACE1 and HIF-1α genes in the brain tissues.
RESULTS: Animal under 7% O2 + 93% N2 condition for 3 hr showed the highest cognitive behavior impairment and upregulated HIF-1α and BACE1 mRNA in brains of offspring (p < .001). Crocin treatment improved memory impairment and attenuated the gene expression of HIF-1α and BACE1 in the brains of neonate rat.
CONCLUSIONS: It was concluded that crocin has beneficial effects on the brain of neonate rats under gestational hypoxia by improvement of memory impairment and molecular alteration related to hypoxia.}, }
@article {pmid33579844, year = {2021}, author = {Yu, E and Liao, Z and Fan, W and Hu, W and Tian, G and Chen, K and Chen, S and Hua, H and Zheng, H and Fang, X and Li, G and Xie, J and Wu, S}, title = {The Economic Burden of Alzheimer's Disease in Zhejiang Province.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {80}, number = {2}, pages = {539-553}, doi = {10.3233/JAD-201285}, pmid = {33579844}, issn = {1875-8908}, abstract = {BACKGROUND: The World Alzheimer Report has described and predicted the economic burden of Alzheimer's disease (AD) patients in detail for four consecutive years. There was a large-scale national survey in China launched by Professor Jianping Jia in 2015, but it did not adequately represent the average economic burden of AD patients in Zhejiang Province.
OBJECTIVE: To investigate the economic burden and main factors influencing Alzheimer's disease (AD) in Zhejiang Province.
METHODS: We recruited 830 patients from 10 cities in Zhejiang Province, evaluated their per capita and total cost related to AD treatment and care in 2017, and analyzed the main factors affecting economic burden from the perspective of demographic characteristics and disease severity.
RESULTS: In 2017, per capita cost of AD was 114,343.7 yuan, while the total cost was 27.53 billion yuan, accounting for 0.77% of Zhejiang Province's GDP (5176.8 billion yuan). Total cost, direct medical cost, and indirect cost have different correlations with age, education level, type of work, marital status, comorbidity, and disease severity.
CONCLUSION: The economic burden of AD in Zhejiang Province is heavy, similar to the national burden, and interventions based on demographic characteristics and disease severity can help reduce it.}, }
@article {pmid33577362, year = {2021}, author = {Ratto, F and Franchini, F and Musicco, M and Caruso, G and Di Santo, SG}, title = {A narrative review on the potential of tomato and lycopene for the prevention of Alzheimer's disease and other dementias.}, journal = {Critical reviews in food science and nutrition}, volume = {}, number = {}, pages = {1-12}, doi = {10.1080/10408398.2021.1880363}, pmid = {33577362}, issn = {1549-7852}, abstract = {Oxidative stress is a major factor in aging and is implicated in the pathogenesis of tumors, diabetes mellitus, cardiovascular and neurodegenerative diseases, including Alzheimer Disease (AD). Bioactive constituents of tomato as polyphenols and carotenoids, among which lycopene (LYC) are effective in reducing markers of oxidative stress, and appear to have a protective modulator role on the pathogenetic mechanisms, cognitive symptoms and behavioral manifestations of these diseases in cell cultures and animal models. Epidemiological evidence indicates a consistent association between the intake of tomatoes and reduced cardiovascular and neoplastic risk. LYC deficiency is common in elders and AD patients and it is strongly predictive of mortality and poor cardiovascular (CV) outcomes. Dietary intake of tomatoes seems to be more effective than tomato/LYC supplementation. Limited evidence from human intervention trials suggests that increasing tomato intake, besides improving CV markers, enhances cognitive performances. In this narrative review, we analyze the existing evidence on the beneficial effects of tomatoes on AD-related processes or risk factors. Results support the development of promising nutritional strategies to increase the levels of tomato consumption for the prevention or treatment of AD and other dementias. Extensive well-structured research, however, is mandatory to confirm the neuroprotective effects of tomato/LYC in humans.}, }
@article {pmid33573114, year = {2021}, author = {Garad, M and Edelmann, E and Leßmann, V}, title = {Impairment of Spike-Timing-Dependent Plasticity at Schaffer Collateral-CA1 Synapses in Adult APP/PS1 Mice Depends on Proximity of Aβ Plaques.}, journal = {International journal of molecular sciences}, volume = {22}, number = {3}, pages = {}, pmid = {33573114}, issn = {1422-0067}, support = {Project No. 643417, jointly supported by BMBF and Horizon 2020//EU Joint Programme - Neurodegenerative Disease Research/ ; }, abstract = {Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder characterized by progressive and irreversible cognitive decline, with no disease-modifying therapy until today. Spike timing-dependent plasticity (STDP) is a Hebbian form of synaptic plasticity, and a strong candidate to underlie learning and memory at the single neuron level. Although several studies reported impaired long-term potentiation (LTP) in the hippocampus in AD mouse models, the impact of amyloid-β (Aβ) pathology on STDP in the hippocampus is not known. Using whole cell patch clamp recordings in CA1 pyramidal neurons of acute transversal hippocampal slices, we investigated timing-dependent (t-) LTP induced by STDP paradigms at Schaffer collateral (SC)-CA1 synapses in slices of 6-month-old adult APP/PS1 AD model mice. Our results show that t-LTP can be induced even in fully developed adult mice with different and even low repeat STDP paradigms. Further, adult APP/PS1 mice displayed intact t-LTP induced by 1 presynaptic EPSP paired with 4 postsynaptic APs (6× 1:4) or 1 presynaptic EPSP paired with 1 postsynaptic AP (100× 1:1) STDP paradigms when the position of Aβ plaques relative to recorded CA1 neurons in the slice were not considered. However, when Aβ plaques were live stained with the fluorescent dye methoxy-X04, we observed that in CA1 neurons with their somata <200 µm away from the border of the nearest Aβ plaque, t-LTP induced by 6× 1:4 stimulation was significantly impaired, while t-LTP was unaltered in CA1 neurons >200 µm away from plaques. Treatment of APP/PS1 mice with the anti-inflammatory drug fingolimod that we previously showed to alleviate synaptic deficits in this AD mouse model did not rescue the impaired t-LTP. Our data reveal that overexpression of APP and PS1 mutations in AD model mice disrupts t-LTP in an Aβ plaque distance-dependent manner, but cannot be improved by fingolimod (FTY720) that has been shown to rescue conventional LTP in CA1 of APP/PS1 mice.}, }
@article {pmid33570733, year = {2021}, author = {Saleem, U and Akhtar, R and Anwar, F and Shah, MA and Chaudary, Z and Ayaz, M and Ahmad, B}, title = {Neuroprotective potential of Malva neglecta is mediated via down-regulation of cholinesterase and modulation of oxidative stress markers.}, journal = {Metabolic brain disease}, volume = {36}, number = {5}, pages = {889-900}, pmid = {33570733}, issn = {1573-7365}, abstract = {Alzheimer's disease affects daily routine due to loss of memory and decline in cognition. In vitro data showed acetylcholine esterase inhibition activity of Malva neglecta but no in vivo evidence is available. The current study aims to investigate the anti-Alzheimer's activity of Malva neglecta methanolic extract in the AlCl3-induced Alzheimer disease rats' model. Thirty Wistar rats were divided into six groups and respective doses were given orally for 21 days. Behavioural observations were recorded and biochemical analysis was performed on brain homogenate. Improvement in memory and cognition was noted in treated rats as compared to disease control. A dose-dependent decrease (0.530 ± 0.009 at 200 mg/kg, 0.212 ± 0.007 at 400 mg/kg, 0.173 ± 0.005 at 600 mg/kg) in AChE activity was noted in the treatment groups with reference to disease control value (1.572 ± 0.013). This decrease in AChE activity is linked with an increase in acetylcholine in the brain which plays a key role in retaining memory. Oxidative stress biomarkers; GSH (66.77 ± 0.01 at 600 mg/kg), SOD (26.60 ± 0.10 at 600 mg/kg), CAT (21.46 ± 0.01 at 600 mg/kg) levels were increased with a decrease in MDA (103.33 ±0.49 at 600 mg/kg) level in a dose-dependently manner in the treatment groups as compared to disease control respective values. It is concluded that Malva neglecta could ameliorate Alzheimer's symptoms possibly by decreasing AChE activity and oxidative stress.}, }
@article {pmid33560671, year = {2021}, author = {Kawas, CH and Legdeur, N and Corrada, MM}, title = {What have we learned from cognition in the oldest-old.}, journal = {Current opinion in neurology}, volume = {34}, number = {2}, pages = {258-265}, pmid = {33560671}, issn = {1473-6551}, support = {R01 AG021055/AG/NIA NIH HHS/United States ; RF1 AG056519/AG/NIA NIH HHS/United States ; }, abstract = {PURPOSE OF REVIEW: People over 90 are the fastest growing segment of the population with the highest rates of dementia. This review highlights recent findings that provide insight to our understanding of dementia and cognition at all ages.
RECENT FINDINGS: Risk factors for Alzheimer's disease (AD) and dementia differ by age, with some factors, like the development of hypertension, actually becoming protective in the oldest-old. At least half of all dementia in this age group is due to non AD pathologies, including microinfarcts, hippocampal sclerosis and TDP-43. The number of pathologic changes found in the brain is related to both risk and severity of dementia, but many people in this age group appear to be 'resilient' to these pathologies. Resilience to Alzheimer pathology, in part, may be related to absence of other pathologies, and imaging and spinal fluid biomarkers for AD have limited utility in this age group.
SUMMARY: Studies of dementia in the oldest-old are important for our understanding and eventual treatment or prevention of dementia at all ages.}, }
@article {pmid33554551, year = {2021}, author = {Vernerová, A and Kujovská Krčmová, L and Melichar, B and Švec, F}, title = {Non-invasive determination of uric acid in human saliva in the diagnosis of serious disorders.}, journal = {Clinical chemistry and laboratory medicine}, volume = {59}, number = {5}, pages = {797-812}, doi = {10.1515/cclm-2020-1533}, pmid = {33554551}, issn = {1437-4331}, abstract = {This review summarizes and critically evaluates the published approaches and recent trends in sample pre-treatment, as well as both separation and non-separation techniques used for the determination of uric acid (UA) in saliva. UA is the final product of purine nucleotide catabolism in humans. UA concentrations in biological fluids such as serum, plasma, and urine represent an important biomarker of diseases including gout, hyperuricemia, or disorders associated with oxidative stress. Previous studies reported correlation between UA concentrations detected in saliva and in the blood. The interest in UA has been increasing during the past 20 years from a single publication in 2000 to 34 papers in 2019 according to MEDLINE search using term "uric acid in saliva". The evaluation of salivary UA levels can contribute to non-invasive diagnosis of many serious diseases. Increased salivary UA concentration is associated with cancer, HIV, gout, and hypertension. In contrast, low UA levels are associated with Alzheimer disease, progression of multiple sclerosis, and mild cognitive impairment.}, }
@article {pmid33549728, year = {2021}, author = {Donoso, A and González-Durán, J and Muñoz, AA and González, PA and Agurto-Muñoz, C}, title = {"Therapeutic uses of natural astaxanthin: An evidence-based review focused on human clinical trials".}, journal = {Pharmacological research}, volume = {166}, number = {}, pages = {105479}, doi = {10.1016/j.phrs.2021.105479}, pmid = {33549728}, issn = {1096-1186}, abstract = {Astaxanthin is a natural C40 carotenoid with numerous reported biological functions, most of them associated with its antioxidant and anti-inflammatory activity, standing out from other antioxidants as it has shown the highest oxygen radical absorbance capacity (ORAC), 100-500 times higher than ⍺-tocopherol and a 10 times higher free radical inhibitory activity than related antioxidants (α-tocopherol, α-carotene, β -carotene, lutein and lycopene). In vitro and in vivo studies have associated astaxanthin's unique molecular features with several health benefits, including neuroprotective, cardioprotective and antitumoral properties, suggesting its therapeutic potential for the prevention or co-treatment of dementia, Alzheimer, Parkinson, cardiovascular diseases and cancer. Benefits on skin and eye health promotion have also been reported, highlighting its potential for the prevention of skin photo-aging and the treatment of eye diseases like glaucoma, cataracts and uveitis. In this review, we summarize and discuss the currently available evidence on astaxanthin benefits, with a particular focus on human clinical trials, including a brief description of the potential mechanisms of action responsible for its biological activities.}, }
@article {pmid33549409, year = {2021}, author = {Domingues, R and Pereira, C and Cruz, MT and Silva, A}, title = {Therapies for Alzheimer's disease: a metabolic perspective.}, journal = {Molecular genetics and metabolism}, volume = {132}, number = {3}, pages = {162-172}, doi = {10.1016/j.ymgme.2021.01.011}, pmid = {33549409}, issn = {1096-7206}, mesh = {Alzheimer Disease/metabolism/pathology/*therapy ; Brain/*metabolism/pathology ; Citric Acid Cycle/genetics ; Glucose/*metabolism ; Humans ; Insulin/*genetics/metabolism ; Insulin Resistance/genetics ; Mitochondria/genetics/metabolism ; Oxidative Stress/genetics ; }, abstract = {Alzheimer's disease (AD) is one of the most common forms of dementia in the elderly. Currently, there are over 50 million cases of dementia worldwide and it is expected that it will reach 136 million by 2050. AD is described as a neurodegenerative disease that gradually compromises memory and learning capacity. Patients often exhibit brain glucose hypometabolism and are more susceptible to develop type 2 diabetes or insulin resistance in comparison with age-matched controls. This suggests that there is a link between both pathologies. Glucose metabolism and the tricarboxylic acid cycle are tightly related to mitochondrial performance and energy production. Impairment of both these pathways can evoke oxidative damage on mitochondria and key proteins linked to several hallmarks of AD. Glycation is also another type of post-translational modification often reported in AD, which might impair the function of proteins that participate in metabolic pathways thought to be involved in this illness. Despite needing further research, therapies based on insulin treatment, usage of anti-diabetes drugs or some form of dietary intervention, have shown to be promising therapeutic approaches for AD in its early stages of progression and will be unveiled in this paper.}, }
@article {pmid33549267, year = {2021}, author = {Thiyagalingam, S and Kulinski, AE and Thorsteinsdottir, B and Shindelar, KL and Takahashi, PY}, title = {Dysphagia in Older Adults.}, journal = {Mayo Clinic proceedings}, volume = {96}, number = {2}, pages = {488-497}, doi = {10.1016/j.mayocp.2020.08.001}, pmid = {33549267}, issn = {1942-5546}, mesh = {Aged ; Deglutition Disorders/*diagnosis/*etiology/*therapy ; *Geriatric Assessment ; Humans ; }, abstract = {Dysphagia, which is a geriatric syndrome affecting 10% to 33% of older adults, is commonly seen in older adults who have experienced a stroke or neurodegenerative diseases such as Alzheimer or Parkinson disease. Patients diagnosed as having dysphagia can experience malnutrition, pneumonia, and dehydration. Patients can also experience increased rates of mortality and long-term care admission. Providers can identify the specific type of dysphagia for treatment in approximately 80% of patients by asking 5 questions in the patient's history: What happens when you try to swallow? Do you have trouble chewing? Do you have difficulty swallowing solids, liquids, or both? Describe the symptom onset, duration, and frequency? What are the associated symptoms? Providers can then request a videofluoroscopic swallow study or a fiberoptic endoscopic evaluation of swallowing for further evaluation of oropharyngeal dysphagia. If providers are diagnosing esophageal dysphagia, barium esophagraphy or esophagogastroduodenoscopy (EGD) can be used as part of the assessment. Patients can be treated for oropharyngeal dysphagia by using compensatory interventions, including behavioral changes, oral care, dietary modification, or rehabilitative interventions such as exercises and therapeutic oral trials. Providers often address treatment of esophageal dysphagia by managing the underlying etiology, which could include removal of caustic medications or using EGD as a therapeutic modality for esophageal rings. High-quality, large research studies are necessary to further manage the diagnosis and appropriate treatment of this growing geriatric syndrome.}, }
@article {pmid33549256, year = {2021}, author = {Hsiao, SH and Hwang, TJ and Lin, FJ and Sheu, JJ and Wu, CH}, title = {The Association Between the Use of Cholinesterase Inhibitors and Cardiovascular Events Among Older Patients With Alzheimer Disease.}, journal = {Mayo Clinic proceedings}, volume = {96}, number = {2}, pages = {350-362}, doi = {10.1016/j.mayocp.2020.05.048}, pmid = {33549256}, issn = {1942-5546}, mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/*drug therapy ; Cardiovascular Diseases/*epidemiology ; Cholinesterase Inhibitors/administration & dosage/*therapeutic use ; Dose-Response Relationship, Drug ; Female ; Humans ; Male ; Middle Aged ; Propensity Score ; Retrospective Studies ; Taiwan/epidemiology ; }, abstract = {OBJECTIVE: To evaluate the association between the use of cholinesterase inhibitors (ChEIs) and incident cardiovascular events (CVEs) among older patients with Alzheimer disease (AD).
PATIENTS AND METHODS: This retrospective cohort study was conducted with a new-user design and active-comparator design. The data source was the 2005-2014 Full Population file from the Health and Welfare Database in Taiwan. Patients were included if they were aged 50 years or older and had been diagnosed with AD between January 1, 2006, and December 31, 2010. The association between ChEI use and the risk of CVEs was investigated in patients with AD. Among the ChEI users, the risk of CVEs was further compared between patients with different cumulative doses and different ChEI treatment strategies. The propensity score method, which included matching and inverse probability of treatment weighting, was used to balance the potential confounders. A Cox proportional hazards model with competing risks was used to estimate the hazard ratio of CVEs.
RESULTS: The study included 6070 patients with AD. After covariate adjustment, ChEI users had a significantly lower risk of CVEs than nonusers (hazard ratio, 0.57; 95% CI, 0.51 to 0.62). Among ChEI users, patients with a high cumulative dose had a significantly lower risk of CVEs than those with a low cumulative dose (hazard ratio, 0.82; 95% CI, 0.70 to 0.96).
CONCLUSION: The use of ChEIs was associated with a decreased risk of incident CVEs among patients with AD. The cardioprotective effect of ChEIs showed a dose-response relationship.}, }
@article {pmid33547659, year = {2021}, author = {Živković, L and Bajić, V and Čabarkapa-Pirković, A and Dekanski, D and Forbes-Hernández, TY and Zlatković-Švenda, M and Perry, G and Spremo-Potparević, B}, title = {Strawberry (Fragaria ananassa duch.) Alba extract attenuates DNA damage in lymphocytes of patients with Alzheimer's disease.}, journal = {Journal of food biochemistry}, volume = {45}, number = {4}, pages = {e13637}, doi = {10.1111/jfbc.13637}, pmid = {33547659}, issn = {1745-4514}, mesh = {Aged ; *Alzheimer Disease/drug therapy ; DNA Damage ; *Fragaria ; Humans ; Lymphocytes ; Plant Extracts/pharmacology/therapeutic use ; }, abstract = {Increased levels of oxidative stress and oxidative DNA damage are common features in the pathology of Alzheimer's disease (AD) found in neurons and peripheral cells like peripheral blood lymphocytes (PBL). Natural products such as strawberry cultivar Alba are an important source of bioactive nutrients that could help in lowering both the oxidative stress and DNA damage levels. The objective was to estimate the effects of Alba extract on DNA damage in peripheral blood lymphocytes of sporadic AD (aged 60-84 years) patients, and healthy elderly (aged 69-83 years) and young (aged 21-30 years) individuals in in vitro conditions. Comet assay was used as a sensitive technique for the evaluation of PBL DNA damage levels. Reduction of basal DNA damage level in PBL was shown in the young group after the incubation with Alba extract ranging from 25 to 200 μg/ml, with 100 μg/ml being the most effective concentration. Selected Alba extract of 100 μg/ml was further used for PBL treatment of AD and healthy elderly age matched group, displaying potential to significantly attenuate DNA damage levels in both groups (p < .05). Alba extract displayed biological activity against oxidative DNA damage, suggesting that its functional ingredients may have beneficial health effects. PRACTICAL APPLICATIONS: The data obtained in this preliminary study displayed that strawberry Alba extract is efficient against DNA damage induced by endogenous and exogenous oxidative stress in peripheral blood lymphocytes of Alzheimer`s disease in vitro. An active area of future research of Alba cultivar should be to determine the trials in in vivo systems. Our findings also suggest that Alba cultivar's functional ingredients potentially may have beneficial health effects in AD.}, }
@article {pmid33542683, year = {2020}, author = {Salobrar-García, E and López-Cuenca, I and Sánchez-Puebla, L and de Hoz, R and Fernández-Albarral, JA and Ramírez, AI and Bravo-Ferrer, I and Medina, V and Moro, MA and Saido, TC and Saito, T and Salazar, JJ and Ramírez, JM}, title = {Retinal Thickness Changes Over Time in a Murine AD Model APP NL-F/NL-F.}, journal = {Frontiers in aging neuroscience}, volume = {12}, number = {}, pages = {625642}, pmid = {33542683}, issn = {1663-4365}, abstract = {Background: Alzheimer's disease (AD) may present retinal changes before brain pathology, suggesting the retina as an accessible biomarker of AD. The present work is a diachronic study using spectral domain optical coherence tomography (SD-OCT) to determine the total retinal thickness and retinal nerve fiber layer (RNFL) thickness in an APPNL-F/NL-F mouse model of AD at 6, 9, 12, 15, 17, and 20 months old compared to wild type (WT) animals. Methods: Total retinal thickness and RNFL thickness were determined. The mean total retinal thickness was analyzed following the Early Treatment Diabetic Retinopathy Study sectors. RNFL was measured in six sectors of axonal ring scans around the optic nerve. Results: In the APPNL-F/NL-F group compared to WT animals, the total retinal thickness changes observed were the following: (i) At 6-months-old, a significant thinning in the outer temporal sector was observed; (ii) at 15-months-old a significant thinning in the inner temporal and in the inner and outer inferior retinal sectors was noticed; (iii) at 17-months-old, a significant thickening in the inferior and nasal sectors was found in both inner and outer rings; and (iv) at 20-months-old, a significant thinning in the inner ring of nasal, temporal, and inferior retina and in the outer ring of superior and temporal retina was seen. In RNFL thickness, there was significant thinning in the global analysis and in nasal and inner-temporal sectors at 6 months old. Thinning was also found in the supero-temporal and nasal sectors and global value at 20 months old. Conclusions: In the APPNL-F/NL-F AD model, the retinal thickness showed thinning, possibly produced by neurodegeneration alternating with thickening caused by deposits and neuroinflammation in some areas of the retina. These changes over time are similar to those observed in the human retina and could be a biomarker for AD. The APPNL-F/NL-F AD model may help us better understand the different retinal changes during the progression of AD.}, }
@article {pmid33540840, year = {2021}, author = {Fragoso-Morales, LG and Correa-Basurto, J and Rosales-Hernández, MC}, title = {Implication of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase and Its Inhibitors in Alzheimer's Disease Murine Models.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {2}, pages = {}, pmid = {33540840}, issn = {2076-3921}, support = {CB286653, 254600 and 782//Consejo Nacional de Ciencia y Tecnología/ ; SIP20195089//SIPCOFAA-IPN/ ; }, abstract = {Alzheimer's disease (AD) is one of the main human dementias around the world which is constantly increasing every year due to several factors (age, genetics, environment, etc.) and there are no prevention or treatment options to cure it. AD is characterized by memory loss associated with oxidative stress (OS) in brain cells (neurons, astrocytes, microglia, etc.). OS can be produced by amyloid beta (Aβ) protein aggregation and its interaction with metals, mitochondrial damage and alterations between antioxidants and oxidant enzymes such as nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. NADPH oxidase produces reactive oxygen species (ROS) and it is overexpressed in AD, producing large amounts of superoxide anions and hydrogen peroxide which damage brain cells and the vasculature. In addition, it has been reported that NADPH oxidase causes an imbalance of pH which could also influence in the amyloid beta (Aβ) production. Therefore, NADPH oxidase had been proposed as a therapeutic target in AD. However, there are no drugs for AD treatment such as an NADPH oxidase inhibitor despite great efforts made to stabilize the ROS production using antioxidant molecules. So, in this work, we will focus our attention on NADPH oxidase (NOX2 and NOX4) in AD as well as in AD models and later discuss the use of NADPH oxidase inhibitor compounds in AD.}, }
@article {pmid33523405, year = {2021}, author = {Pereira, AKDS and Santos, IA and da Silva, WW and Nogueira, FAR and Bergamini, FRG and Jardim, ACG and Corbi, PP}, title = {Memantine hydrochloride: a drug to be repurposed against Chikungunya virus?.}, journal = {Pharmacological reports : PR}, volume = {73}, number = {3}, pages = {954-961}, pmid = {33523405}, issn = {1734-1140}, abstract = {BACKGROUND: Chikungunya fever is an endemic disease caused by the Chikungunya virus (CHIKV) to which there is no vaccine or effective antiviral drug treatment so far. Our study aimed to evaluate the potential anti-CHIKV activity of memantine hydrochloride (mtnH), a drug from the class of the aminoadamantanes approved for the treatment of Alzheimer´s disease, as a possible drug to be repurposed to the treatment of Chikungunya fever.
METHODS: MtnH antiviral activity against CHIKV was determined by infecting BHK-21 cells with CHIKV-nanoluc, a virus carrying the marker nanoluciferase reporter, in the presence or absence of mtnH at concentrations ranging from 500 to 1.45 µM. The effective concentration of 50% inhibition (EC50) was calculated. Cell viability assay (determination of CC50) was also performed employing BHK-21 cells. Mutagenic assays were performed by the Salmonella Typhimurium/microsome assay (Ames test).
RESULTS: MtnH presented a CC50 of 248.4 ± 31.9 µM and an EC50 of 32.4 ± 4 µM against CHIKV in vitro. The calculated selectivity index (SI) was 7.67. MtnH did not induce genetic mutation in Salmonella strains with or without an external metabolizing system.
CONCLUSION: With the data herein presented, it is possible to hypothesize mtnH as a viable candidate to be repurposed as an anti-CHIKV drug. Clinical assays are, therefore, encouraged due to the promising in vitro results. The drug memantine hydrochloride is herein personified with a doubt: as a prior regulated drug against Alzheimer, could it follow the path against Chikungunya virus too?}, }
@article {pmid33513837, year = {2021}, author = {Munir, R and Zia-Ur-Rehman, M and Murtaza, S and Zaib, S and Javid, N and Awan, SJ and Iftikhar, K and Athar, MM and Khan, I}, title = {Microwave-Assisted Synthesis of (Piperidin-1-yl)quinolin-3-yl)methylene)hydrazinecarbothioamides as Potent Inhibitors of Cholinesterases: A Biochemical and In Silico Approach.}, journal = {Molecules (Basel, Switzerland)}, volume = {26}, number = {3}, pages = {}, pmid = {33513837}, issn = {1420-3049}, support = {12-33715-2PS1-501//Higher Education Commision, Pakistan/ ; }, mesh = {Acetylcholinesterase/metabolism ; Alzheimer Disease/drug therapy/metabolism ; Butyrylcholinesterase/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cholinesterase Inhibitors/*pharmacology ; Cholinesterases/*metabolism ; Hep G2 Cells ; Heterocyclic Compounds/pharmacology ; Humans ; Hydrazines/*pharmacology ; Microwaves ; Molecular Docking Simulation ; Quinolines/pharmacology ; Structure-Activity Relationship ; Thioamides/*pharmacology ; }, abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder, characterized by central cognitive dysfunction, memory loss, and intellectual decline poses a major public health problem affecting millions of people around the globe. Despite several clinically approved drugs and development of anti-Alzheimer's heterocyclic structural leads, the treatment of AD requires safer hybrid therapeutics with characteristic structural and biochemical properties. In this endeavor, we herein report a microwave-assisted synthesis of a library of quinoline thiosemicarbazones endowed with a piperidine moiety, achieved via the condensation of 6/8-methyl-2-(piperidin-1-yl)quinoline-3-carbaldehydes and (un)substituted thiosemicarbazides. The target N-heterocyclic products were isolated in excellent yields. The structures of all the synthesized compounds were fully established using readily available spectroscopic techniques (FTIR, 1H- and 13C-NMR). Anti-Alzheimer potential of the synthesized heterocyclic compounds was evaluated using acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. The in vitro biochemical assay results revealed several compounds as potent inhibitors of both enzymes. Among them, five compounds exhibited IC50 values less than 20 μM. N-(3-chlorophenyl)-2-((8-methyl-2-(piperidin-1-yl)quinolin-3-yl)methylene)hydrazine carbothioamide emerged as the most potent dual inhibitor of AChE and BChE with IC50 values of 9.68 and 11.59 μM, respectively. Various informative structure-activity relationship (SAR) analyses were also concluded indicating the critical role of substitution pattern on the inhibitory efficacy of the tested derivatives. In vitro results were further validated through molecular docking analysis where interactive behavior of the potent inhibitors within the active pocket of enzymes was established. Quinoline thiosemicarbazones were also tested for their cytotoxicity using MTT assay against HepG2 cells. Among the 26 novel compounds, there were five cytotoxical and 18 showed proliferative properties.}, }
@article {pmid33512104, year = {2020}, author = {Arsenault-Lapierre, G and Godard-Sebillotte, C and Sourial, N and Couturier, Y and Bouchard, P and Rozo, LR and Pilon, C and Bergman, H and Vedel, I}, title = {.}, journal = {Sante publique (Vandoeuvre-les-Nancy, France)}, volume = {32}, number = {4}, pages = {375-380}, doi = {10.3917/spub.204.0375}, pmid = {33512104}, issn = {0995-3914}, mesh = {*Alzheimer Disease/diagnosis/epidemiology/therapy ; Canada ; Family Practice ; Humans ; *Primary Health Care ; Quebec ; }, abstract = {Many countries have answered the call from the World Health Organization, and developed or implemented Alzheimer Plans. Some plans anchored the majority of the care for persons living with dementia in specialized care settings, while others anchored it in primary care. In this article we present the Quebec Alzheimer Plan, which is being implemented in Family Medicine Groups, primary care interdisciplinary clinics, across the Canadian province. The Quebec Alzheimer Plan aims to enable primary healthcare teams of physicians, nurses and/or social workers to provide access to personalized, coordinated assessment and treatment services for people living with dementia and their caregivers. The Quebec Alzheimer Plan enables and empowers primary care clinicians to detect, diagnose, treat and follow-up the vast majority of patients/caregivers. A major strength of the Quebec Alzheimer Plan strategy is the embedded evaluation to inform implementation and its flexibility to allow local adaptations. We are discussing that it is feasible and advantageous to anchor dementia care in an interprofessional primary care setting.}, }
@article {pmid33508797, year = {2021}, author = {Lin, CH and Chiu, CC and Lane, HY}, title = {Trough Melatonin Levels Differ between Early and Late Phases of Alzheimer Disease.}, journal = {Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology}, volume = {19}, number = {1}, pages = {135-144}, pmid = {33508797}, issn = {1738-1088}, abstract = {Objective: Melatonin has been considered to have an essential role in the pathophysiology of Alzheimer's disease (AD) for its regulatory function on circadian rhythm and interaction with glutamate for the modulation of learning and memory. Previous studies revealed that melatonin levels decreased in patients with AD. However, melatonin supplement didn't show promising efficacy for AD. This study compared trough melatonin levels among elderly people with different severities of cognitive deficits.
Methods: We enrolled 270 elder individuals (consisting four groups: healthy elderly, amnestic mild cognitive impairment [MCI], mild AD, and moderate-severe AD) in the learning cohort. Trough melatonin levels in plasma were measured using ELISA. Cognitive function was evaluated by Clinical Dementia Rating Scale (CDR) and Mini-Mental State Examination (MMSE). An independent testing cohort, also consisting of four groups, was enrolled for ascertainment.
Results: In the learning cohort, trough melatonin levels decreased in the MCI group but elevated in the mild and moderate to severe AD groups. Trough melatonin levels were associated with CDR and MMSE in MCI or AD patients significantly. In the testing cohort, the results were similar to those in the learning cohort.
Conclusion: This study demonstrated that trough melatonin levels in the peripheral blood were decreased in MCI but increased with the severity of AD. The finding supports the trials indicating that melatonin showed efficacy only in MCI but not in AD. Whether trough melatonin level has potential to be a treatment response biomarker for AD, especially its early phase needs further studies.}, }
@article {pmid33504676, year = {2020}, author = {Yuan, Q and Lin, ZX and Wu, W and Albert, WN and Zee, BCY}, title = {Huperzine A in treatment of amyloid-β-associated neuropathology in a mouse model of Alzheimer disease: abridged secondary publication.}, journal = {Hong Kong medical journal = Xianggang yi xue za zhi}, volume = {26 Suppl 8}, number = {6}, pages = {34-37}, pmid = {33504676}, issn = {1024-2708}, }
@article {pmid33502736, year = {2021}, author = {Rezaei Rad, F and Ghahvechi Akbari, M and Zamani, M and Bayat, S and Zamani, M}, title = {Pharmacogenetic and Association Studies on the Influence of HLA Alleles and Rivastigmine on the Iranian Patients with Late-Onset Alzheimer's Disease.}, journal = {Molecular neurobiology}, volume = {58}, number = {6}, pages = {2792-2802}, pmid = {33502736}, issn = {1559-1182}, support = {40225//Tehran University of Medical Sciences and Health Services/ ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting cognitive function. A number of allelic genes from HLA complex have shown variable associations with AD in different populations. In this study, we investigated the association of DQB1*06:00/x, DRB1*04:00/x, DRB1*15:00/x, and B*07:00/x genotypes with AD and their relevance to the efficacy of rivastigmine treatment in the Iranian population. Our findings suggest that DQB1*06:00/x genotype offers strong protection against AD (P = 0.0074), while B*07:00/x genotype imposes a significant susceptibility for sporadic Alzheimer's disease (SAD) (P = 0.009). Interestingly, B*07:00/x genotype does not show any apparent associations with familial Alzheimer's disease (FAD). Our studies also suggest a pharmacogenetic relationship between drug treatment and presence of a particular genotype in the Iranian LOAD patient population. The Clinical Dementia Rating analysis showed that LOAD patients carrying DRB1*04:00/x genotype tend to display a downward trend in the disease severity and symptoms after 2-year follow-up with rivastigmine treatment. Moreover, in our total patient population, the carriers of DQB1*06:00/x and B*07:00/x alleles have better and worse responses to rivastigmine respectively. We also measured the clinical relevance of the testing for these genotypes employing prevalence-corrected positive predictive value (PcPPV) formula. The PcPPV of testing for DQB1*06:00/x in the Iranian LOAD patients was 1.17% which means that people carrying this genotype have half of the probability of the absolute risk for developing LOAD, whereas the PcPPV of testing for B*07:00/x was 4.45% for SAD, which can be interpreted as a doubling chance for developing LOAD among the Iranian population carrying this genotype. These results also suggest that DQβ1 peptide containing positively charged AAs histidine30 and arginine55 and HLA class I β chain containing negatively charges aspartic acid114 and glutamic acid45,152 in their binding groove plays important roles in protection against and susceptibility for LOAD respectively.}, }
@article {pmid33502110, year = {2021}, author = {Bektašević, M and Politeo, O and Carev, I}, title = {Comparative Study of Chemical Composition, Cholinesterase Inhibition and Antioxidant Potential of Mentha pulegium L. Essential Oil.}, journal = {Chemistry & biodiversity}, volume = {18}, number = {3}, pages = {e2000935}, doi = {10.1002/cbdv.202000935}, pmid = {33502110}, issn = {1612-1880}, support = {//Faculty of Science, University of Split, Croatia/ ; 04-14-3804-1/12//FMON Bosnia and Herzegovina/ ; IP-2014-09-6897//Croatian Science Foundation/ ; }, mesh = {Acetylcholinesterase/metabolism ; Animals ; Antioxidants/chemistry/isolation & purification/*pharmacology ; Biphenyl Compounds/antagonists & inhibitors ; Butyrylcholinesterase/metabolism ; Cholinesterase Inhibitors/chemistry/isolation & purification/*pharmacology ; Dose-Response Relationship, Drug ; Electrophorus ; Horses ; Mentha pulegium/*chemistry ; Molecular Structure ; Oils, Volatile/chemistry/isolation & purification/*pharmacology ; Picrates/antagonists & inhibitors ; Stereoisomerism ; Structure-Activity Relationship ; }, abstract = {Perennial plant Mentha pulegium L. (pennyroyal, Lamiaceae) can be found in Europe and Mediterranean. In areas where it thrives, M. pulegium is used in nutrition and as medicinal plant. Essential oil of M. pulegium is also a frequent constituent of foods and fragrances, because of mint-like odor. Regarding the use of M. pulegium in traditional medicine and nutrition, as well as fact that essential oils are potential sources of bioactive components, this study was conducted to examine the chemical composition of essential oil of M. pulegium wild growing in Bosnia and Herzegovina and its biological activity. The chemical profile testing was made using GC/MS and GC/FID technique. Potential of cholinesterase inhibition was tested by Ellman's assay. The antioxidant activity was tested by DPPH and FRAP assay. The dominant components in analyzed oil were pulegone 54.4 %, p-menthone 14.0 % and piperitenone 12.8 %. Good antioxidant activity and moderate cholinesterase inhibition potential of tested essential oil indicates to possibility of its use in treatment of diseases related to free radicals, Alzheimer disease and as lipid protecting antioxidant.}, }
@article {pmid33497068, year = {2021}, author = {}, title = {Clinical Consensus Statement: Association of Anticholinergic Medication Use and Cognition in Women With Overactive Bladder.}, journal = {Female pelvic medicine & reconstructive surgery}, volume = {27}, number = {2}, pages = {69-71}, doi = {10.1097/SPV.0000000000001008}, pmid = {33497068}, issn = {2154-4212}, abstract = {ABSTRACT: Overactive bladder affects a significant portion of the overall population and has substantial impact on daily activities and quality of life. First-line treatment of overactive bladder includes behavioral therapies, which may be combined with pharmacologic management as indicated. Anticholinergic medications and β-3 agonists are often used as initial pharmacologic therapy, but caution should be taken in prescribing anticholinergic medications in frail or cognitively impaired patients. Recently, additional concerns have emerged regarding prolonged use of anticholinergic medications and the associated risk of cognitive impairment, dementia, and Alzheimer disease in the general population. Given the available evidence, which has shown significant associations between anticholinergic medication use and increased risk of cognitive impairment and dementia, providers should counsel on the associated risks, prescribe the lowest effective dose, and consider alternative medications in patients at risk.}, }
@article {pmid33495373, year = {2021}, author = {Joseph-Mathurin, N and Wang, G and Kantarci, K and Jack, CR and McDade, E and Hassenstab, J and Blazey, TM and Gordon, BA and Su, Y and Chen, G and Massoumzadeh, P and Hornbeck, RC and Allegri, RF and Ances, BM and Berman, SB and Brickman, AM and Brooks, WS and Cash, DM and Chhatwal, JP and Chui, HC and Correia, S and Cruchaga, C and Farlow, MR and Fox, NC and Fulham, M and Ghetti, B and Graff-Radford, NR and Johnson, KA and Karch, CM and Laske, C and Lee, AKW and Levin, J and Masters, CL and Noble, JM and O'Connor, A and Perrin, RJ and Preboske, GM and Ringman, JM and Rowe, CC and Salloway, S and Saykin, AJ and Schofield, PR and Shimada, H and Shoji, M and Suzuki, K and Villemagne, VL and Xiong, C and Yakushev, I and Morris, JC and Bateman, RJ and Benzinger, TLS and , }, title = {Longitudinal Accumulation of Cerebral Microhemorrhages in Dominantly Inherited Alzheimer Disease.}, journal = {Neurology}, volume = {96}, number = {12}, pages = {e1632-e1645}, pmid = {33495373}, issn = {1526-632X}, support = {U01 AG032438/AG/NIA NIH HHS/United States ; K01 AG053474/AG/NIA NIH HHS/United States ; UF1 AG032438/AG/NIA NIH HHS/United States ; R01 AG052550/AG/NIA NIH HHS/United States ; U19 AG032438/AG/NIA NIH HHS/United States ; U01 AG042791/AG/NIA NIH HHS/United States ; R01 EB009352/EB/NIBIB NIH HHS/United States ; P30 NS098577/NS/NINDS NIH HHS/United States ; }, mesh = {Adult ; Alzheimer Disease/*complications/*pathology ; Brain/pathology ; Cerebral Hemorrhage/*epidemiology/etiology/pathology ; Female ; Humans ; Longitudinal Studies ; Magnetic Resonance Imaging ; Male ; Middle Aged ; }, abstract = {OBJECTIVE: To investigate the inherent clinical risks associated with the presence of cerebral microhemorrhages (CMHs) or cerebral microbleeds and characterize individuals at high risk for developing hemorrhagic amyloid-related imaging abnormality (ARIA-H), we longitudinally evaluated families with dominantly inherited Alzheimer disease (DIAD).
METHODS: Mutation carriers (n = 310) and noncarriers (n = 201) underwent neuroimaging, including gradient echo MRI sequences to detect CMHs, and neuropsychological and clinical assessments. Cross-sectional and longitudinal analyses evaluated relationships between CMHs and neuroimaging and clinical markers of disease.
RESULTS: Three percent of noncarriers and 8% of carriers developed CMHs primarily located in lobar areas. Carriers with CMHs were older, had higher diastolic blood pressure and Hachinski ischemic scores, and more clinical, cognitive, and motor impairments than those without CMHs. APOE ε4 status was not associated with the prevalence or incidence of CMHs. Prevalent or incident CMHs predicted faster change in Clinical Dementia Rating although not composite cognitive measure, cortical thickness, hippocampal volume, or white matter lesions. Critically, the presence of 2 or more CMHs was associated with a significant risk for development of additional CMHs over time (8.95 ± 10.04 per year).
CONCLUSION: Our study highlights factors associated with the development of CMHs in individuals with DIAD. CMHs are a part of the underlying disease process in DIAD and are significantly associated with dementia. This highlights that in participants in treatment trials exposed to drugs, which carry the risk of ARIA-H as a complication, it may be challenging to separate natural incidence of CMHs from drug-related CMHs.}, }
@article {pmid33494672, year = {2021}, author = {Saha, S and Pal, D and Nimse, SB}, title = {Recent Advances in the Discovery of GSK-3 Inhibitors from Synthetic Origin in the Treatment of Neurological Disorders.}, journal = {Current drug targets}, volume = {22}, number = {12}, pages = {1437-1462}, doi = {10.2174/1389450122666210120143953}, pmid = {33494672}, issn = {1873-5592}, abstract = {BACKGROUND: Glycogen synthase kinase 3 (GSK-3) is a serine/threonine kinase enzyme that controls neuronal functions such as neurite outgrowth, synapse formation, neurotransmission, and neurogenesis. The enzyme has two subunits as GSK-3α and GSK-3β. 4ACC, 1Q3D, 3AFG, 1UV5, and 1Q5K are the important GSK-3 receptors isolated from Homo sapiens and Mus musculus. This enzyme mainly phosphorylates Tau protein with the increased amount in neuronal fibres together with beta-amyloid plaques that cause neuronal diseases like Alzheimer's, Parkinson's and many more.
OBJECTIVE: We investigated the developments of various synthetic GSK-3 inhibitors responsible for the prevention and treatment of neurological disorders, like Alzheimer's disease, bipolar disorders, acting as antidepressants, neuroprotective, etc. Results and Conclusion: It has been observed that structures of the GSK-3 inhibitors are comprised of benzopyridine, benzothiazole, pyrazole, pyrazine, dioxolo-benzoxazine, oxadiazole, and benzimidazole in the skeletal with cyclopropyl amide, phenyl carbamothioate, 3-[(propan- 2-yl)oxy]propan-1-amine in the side chain. The molecules were evaluated against the effectivity of GSK-3, human adenosine kinase, cyclin-dependent kinase, and phosphodiesterase-4 along with tail suspension test forced swim test, percent neuronal survival and other cognitive behaviours. The observations confirmed the remarkable effects of the synthesized molecules to conquer Alzheimer, Parkinson's depression, psychosis and other forms of neurological disorders.}, }
@article {pmid33492880, year = {2021}, author = {Ross, SM}, title = {Coconut Oil: Effects of Medium-Chain Triglycerides for Prevention and Treatment of Alzheimer Disease.}, journal = {Holistic nursing practice}, volume = {35}, number = {1}, pages = {49-50}, doi = {10.1097/HNP.0000000000000425}, pmid = {33492880}, issn = {1550-5138}, mesh = {Alzheimer Disease/*drug therapy/*prevention & control ; Coconut Oil/administration & dosage/*pharmacology ; Humans ; Triglycerides/*analysis ; }, }
@article {pmid33490645, year = {2021}, author = {Kikuchi, H and Harata, K and Madhyastha, H and Kuribayashi, F}, title = {Ellagic acid and its fermentative derivative urolithin A show reverse effects on the gp91-phox gene expression, resulting in opposite alterations in all-trans retinoic acid-induced superoxide generating activity of U937 cells.}, journal = {Biochemistry and biophysics reports}, volume = {25}, number = {}, pages = {100891}, pmid = {33490645}, issn = {2405-5808}, abstract = {Ellagitannins (esters composed of glucose and ellagic acid) are hydrolyzed to generate ellagic acid in gut followed by conversion of ellagic acid to urolithins such as urolithin A by intestinal bacteria. Since urolithins are absorbed by gut easier than ellagitannins and ellagic acid, and show various physiological activities (e.g. anti-cancer, anti-cardiovascular disease, anti-diabetes mellitus, anti-obesity and anti-Alzheimer disease activities), they are expected as excellent health-promoting phytochemicals. Here, using human monoblast U937 cells, we investigated the effect of ellagic acid and urolithin A on the superoxide anion (O2 -)-generating system of phagocytes, which is consisted of five specific protein factors (membrane proteins: p22-phox and gp91-phox, cytosolic proteins: p40-phox, p47-phox and p67-phox). Twenty micromolar of urolithin A enhanced the all-trans retinoic acid (ATRA)-induced O2 --generating activity (to ~175%) while 20 μM ellagic acid inhibited the ATRA-induced O2 --generating activity (to ~70%). Semiquantitative RT-PCR showed that transcription level of gp91-phox was certainly decreased (to ~70%) in ATRA plus ellagic acid-treated cells, while that of gp91-phox was significantly increased (to ~160%) in ATRA plus urolithin A-treated cells. Chromatin immunoprecipitation assay suggested that urolithin A enhanced acetylations of Lys-9 residues of histone H3 within chromatin surrounding the promoter region of gp91-phox gene, but ellagic acid suppressed the acetylations. Immunoblotting also revealed that ATRA plus urolithin A-treatment up-regulated protein levels of p22-phox (to ~160%) and gp91-phox (to ~170%) although ATRA plus ellagic acid-treatment down-regulated protein levels of p22-phox (to ~70%) and gp91-phox (to ~60%). These results suggested that conversion of ellagic acid to urolithin A in gut may bring about reverse effects on the gp91-phox gene expression, resulting in opposite alterations in O2 --generating activity of intestinal macrophages.}, }
@article {pmid33478054, year = {2021}, author = {Turkez, H and Cacciatore, I and Marinelli, L and Fornasari, E and Aslan, ME and Cadirci, K and Kahraman, CY and Caglar, O and Tatar, A and Di Biase, G and Hacimuftuoglu, A and Di Stefano, A and Mardinoglu, A}, title = {Glycyl-L-Prolyl-L-Glutamate Pseudotripeptides for Treatment of Alzheimer's Disease.}, journal = {Biomolecules}, volume = {11}, number = {1}, pages = {}, pmid = {33478054}, issn = {2218-273X}, mesh = {Alzheimer Disease/*drug therapy/genetics ; Amyloid beta-Peptides/metabolism ; Antioxidants/metabolism ; Apoptosis/drug effects ; Cell Death ; Cell Differentiation/drug effects ; Cell Line, Tumor ; Drug Design ; Humans ; Models, Biological ; Necrosis ; Neuroprotective Agents/pharmacology ; Oligopeptides/chemistry/pharmacology/*therapeutic use ; Oxidation-Reduction/drug effects ; Peptidomimetics/pharmacology ; }, abstract = {So far, there is no effective disease-modifying therapies for Alzheimer's Disease (AD) in clinical practice. In this context, glycine-L-proline-L-glutamate (GPE) and its analogs may open the way for developing a novel molecule for treating neurodegenerative disorders, including AD. In turn, this study was aimed to investigate the neuroprotective potentials exerted by three novel GPE peptidomimetics (GPE1, GPE2, and GPE3) using an in vitro AD model. Anti-Alzheimer potentials were determined using a wide array of techniques, such as measurements of mitochondrial viability (MTT) and lactate dehydrogenase (LDH) release assays, determination of acetylcholinesterase (AChE), α-secretase and β-secretase activities, comparisons of total antioxidant capacity (TAC) and total oxidative status (TOS) levels, flow cytometric and microscopic detection of apoptotic and necrotic neuronal death, and investigating gene expression responses via PCR arrays involving 64 critical genes related to 10 different pathways. Our analysis showed that GPE peptidomimetics modulate oxidative stress, ACh depletion, α-secretase inactivation, apoptotic, and necrotic cell death. In vitro results suggested that treatments with novel GPE analogs might be promising therapeutic agents for treatment and/or or prevention of AD.}, }
@article {pmid33477684, year = {2021}, author = {Nieraad, H and de Bruin, N and Arne, O and Hofmann, MCJ and Gurke, R and Schmidt, D and Ritter, M and Parnham, MJ and Geisslinger, G}, title = {Effects of Alzheimer-Like Pathology on Homocysteine and Homocysteic Acid Levels-An Exploratory In Vivo Kinetic Study.}, journal = {International journal of molecular sciences}, volume = {22}, number = {2}, pages = {}, pmid = {33477684}, issn = {1422-0067}, abstract = {Hyperhomocysteinemia has been suggested potentially to contribute to a variety of pathologies, such as Alzheimer's disease (AD). While the impact of hyperhomocysteinemia on AD has been investigated extensively, there are scarce data on the effect of AD on hyperhomocysteinemia. The aim of this in vivo study was to investigate the kinetics of homocysteine (HCys) and homocysteic acid (HCA) and effects of AD-like pathology on the endogenous levels. The mice received a B-vitamin deficient diet for eight weeks, followed by the return to a balanced control diet for another eight weeks. Serum, urine, and brain tissues of AppNL-G-F knock-in and C57BL/6J wild type mice were analyzed for HCys and HCA using LC-MS/MS methods. Hyperhomocysteinemic levels were found in wild type and knock-in mice due to the consumption of the deficient diet for eight weeks, followed by a rapid normalization of the levels after the return to control chow. Hyperhomocysteinemic AppNL-G-F mice had significantly higher HCys in all matrices, but not HCA, compared to wild type control. Higher serum concentrations were associated with elevated levels in both the brain and in urine. Our findings confirm a significant impact of AD-like pathology on hyperhomocysteinemia in the AppNL-G-F mouse model. The immediate normalization of HCys and HCA after the supply of B-vitamins strengthens the idea of a B-vitamin intervention as a potentially preventive treatment option for HCys-related disorders such as AD.}, }
@article {pmid33476770, year = {2021}, author = {Mani, S and Swargiary, G and Chadha, R}, title = {Mitophagy impairment in neurodegenerative diseases: Pathogenesis and therapeutic interventions.}, journal = {Mitochondrion}, volume = {57}, number = {}, pages = {270-293}, doi = {10.1016/j.mito.2021.01.001}, pmid = {33476770}, issn = {1872-8278}, abstract = {Neurons are specialized cells, requiring a lot of energy for its proper functioning. Mitochondria are the key cellular organelles and produce most of the energy in the form of ATP, required for all the crucial functions of neurons. Hence, the regulation of mitochondrial biogenesis and quality control is important for maintaining neuronal health. As a part of mitochondrial quality control, the aged and damaged mitochondria are removed through a selective mode of autophagy called mitophagy. However, in different pathological conditions, this process is impaired in neuronal cells and lead to a variety of neurodegenerative disease (NDD). Various studies indicate that specific protein aggregates, the characteristics of different NDDs, affect this process of mitophagy, adding to the severity and progression of diseases. Though, the detailed process of this association is yet to be explored. In light of the significant role of impaired mitophagy in NDDs, further studies have also investigated a large number of therapeutic strategies to target mitophagy in these diseases. Our current review summarizes the abnormalities in different mitophagy pathways and their association with different NDDs. We have also elaborated upon various novel therapeutic strategies and their limitations to enhance mitophagy in NDDs that may help in the management of symptoms and increasing the life expectancy of NDD patients. Thus, our study provides an overview of mitophagy in NDDs and emphasizes the need to elucidate the mechanism of impaired mitophagy prevalent across different NDDs in future research. This will help designing better treatment options with high efficacy and specificity.}, }
@article {pmid33469351, year = {2021}, author = {Nagy, EN and Ali, AY and Behiry, ME and Naguib, MM and Elsayed, MM}, title = {Impact of Combined Photo-Biomodulation and Aerobic Exercise on Cognitive Function and Quality-of-Life in Elderly Alzheimer Patients with Anemia: A Randomized Clinical Trial.}, journal = {International journal of general medicine}, volume = {14}, number = {}, pages = {141-152}, pmid = {33469351}, issn = {1178-7074}, abstract = {Purpose: Few data are available on the positive impact of photo-biomodulation (PBM) using low-level laser therapy as a complementary treatment for improving the cognitive function and optimizing the hemoglobin (Hb) level and oxygen carrying capacity in anemic elderly patients and consequently improving the quality-of-life. The present study aimed to evaluate a new, safe, and easy therapeutic approach to improve Alzheimer's disease-related symptoms that interfere with the whole life activities and social interaction of elderly patients.
Patients and Methods: In this placebo-controlled clinical trial, 60 elderly patients suffering from anemia and mild cognitive dysfunction were randomly assigned into two equal groups to receive active or placebo low-level laser in addition to a moderate-intensity aerobic exercise over a 12-week period. Hb level as well as cognitive and functional tests were reassessed for any change after 12 weeks of intervention.
Results: By the end of this study, both groups showed significant improvements in Hb level, Montreal Cognitive Assessment Scale (MoCa - B basic), Quality-of-Life for Alzheimer's Disease scale, and Berg Balance scale scores along with significant reduction in body mass index (BMI) and waist-hip ratio (WHR) (P<0.0001). The experimental group which received active low-level laser in addition to moderate-intensity aerobic exercise showed more significant results compared to the control group which received placebo low-level laser in addition to moderate-intensity aerobic exercise in all the measured outcomes (P<0.001).
Conclusion: Combined low-level laser therapy and moderate-intensity aerobic exercises are more effective in improving the cognitive function and quality-of-life of Alzheimer's disease patients.
Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT04496778.}, }
@article {pmid33466168, year = {2021}, author = {Guan, X and Zhang, L and Li, X and Hou, H and Bi, S and Wang, K}, title = {Effectiveness comparisons of acupuncture treatments for vascular dementia: A protocol for systematic review and network meta-analysis.}, journal = {Medicine}, volume = {100}, number = {2}, pages = {e24079}, doi = {10.1097/MD.0000000000024079}, pmid = {33466168}, issn = {1536-5964}, support = {81303028//National Natural Science Foundation of China for Youth/ ; 2014GSF119038//Key Technology Research and Development Program of Shandong/ ; ZR2015HL114//Shandong Province Natural Science Foundation joint Special project/ ; 2017-040//State Administration of Traditional Chinese Medicine of the People's Republic of China/ ; 2019-0107//State Administration of Traditional Chinese Medicine of the People's Republic of China/ ; 2019-0094//State Administration of Traditional Chinese Medicine of the People's Republic of China/ ; }, mesh = {Acupuncture Therapy/*methods ; Comparative Effectiveness Research ; Dementia, Vascular/*therapy ; Humans ; Network Meta-Analysis ; Randomized Controlled Trials as Topic ; Research Design ; Systematic Reviews as Topic ; Treatment Outcome ; }, abstract = {BACKGROUND: Vascular dementia (VD) is the second most common form of dementia in the world. Acupuncture therapy has been widely used in clinical treatment. Based on the available evidence, we will rank different acupuncture therapy to determine the most effective acupuncture therapy.
METHODS: We will search the following database, including PubMed, Embase, Cochrane, Web of Science, China National Knowledge Infrastructure, Wanfang Database, Chinese Biomedical Literature Database and Chinese Scientific Journals Database database, in order to collect randomized controlled trials on acupuncture in the treatment of VD. We will use Stata 14.2 and WinBUGS 1.4.3 software for Bayesian network meta-analysis and finally evaluated the level of evidence of the results.
RESULTS: This study will compare and rank the effectiveness of acupuncture in the treatment of vascular dementia. Outcome indicators included Alzheimer Disease Assessment Scale-Cognitive section and Mini-mental State Examination, Activity of Daily Living, Blessed dementia scale, Hastgawa Dementia Scale, and adverse events.
CONCLUSION: Our study will provide support for clinical practice.
INPLASY REGISTRATION NUMBER: INPLASY2020110088.}, }
@article {pmid33464300, year = {2021}, author = {Sperling, R and Henley, D and Aisen, PS and Raman, R and Donohue, MC and Ernstrom, K and Rafii, MS and Streffer, J and Shi, Y and Karcher, K and Raghavan, N and Tymofyeyev, Y and Bogert, J and Brashear, HR and Novak, G and Thipphawong, J and Saad, ZS and Kolb, H and Rofael, H and Sanga, P and Romano, G}, title = {Findings of Efficacy, Safety, and Biomarker Outcomes of Atabecestat in Preclinical Alzheimer Disease: A Truncated Randomized Phase 2b/3 Clinical Trial.}, journal = {JAMA neurology}, volume = {78}, number = {3}, pages = {293-301}, doi = {10.1001/jamaneurol.2020.4857}, pmid = {33464300}, issn = {2168-6157}, abstract = {Importance: Atabecestat, a nonselective oral β-secretase inhibitor, was evaluated in the EARLY trial for slowing cognitive decline in participants with preclinical Alzheimer disease. Preliminary analyses suggested dose-related cognitive worsening and neuropsychiatric adverse events (AEs).
Objective: To report efficacy, safety, and biomarker findings in the EARLY trial, both on and off atabecestat treatment, with focus on potential recovery of effects on cognition and behavior.
Randomized, double-blind, placebo-controlled, phase 2b/3 study conducted from November 2015 to December 2018 after being stopped prematurely. The study was conducted at 143 centers across 14 countries. Participants were permitted to be followed off-treatment by the original protocol, collecting safety and efficacy data. From 4464 screened participants, 557 amyloid-positive, cognitively normal (Clinical Dementia Rating of 0; aged 60-85 years) participants (approximately 34% of originally planned 1650) were randomized before the trial sponsor stopped enrollment.
Interventions: Participants were randomized (1:1:1) to atabecestat, 5 mg (n = 189), 25 mg (n = 183), or placebo (n = 185).
Main Outcomes and Measures: Primary outcome: change from baseline in Preclinical Alzheimer Cognitive Composite score. Secondary outcomes: change from baseline in the Cognitive Function Index and the Repeatable Battery for the Assessment of Neuropsychological Status total scale score. Safety was monitored throughout the study.
Results: Of 557 participants, 341 were women (61.2%); mean (SD) age was 70.4 (5.56) years. In May 2018, study medication was stopped early owing to hepatic-related AEs; participants were followed up off-treatment for 6 months. Atabecestat, 25 mg, showed significant cognitive worsening vs placebo for Preclinical Alzheimer Cognitive Composite at month 6 (least-square mean difference, -1.09; 95% CI, -1.66 to -0.53; P < .001) and month 12 (least-square mean, -1.62; 95% CI, -2.49 to -0.76; P < .001), and at month 3 for Repeatable Battery for the Assessment of Neuropsychological Status (least-square mean, -3.70; 95% CI, -5.76 to -1.63; P < .001). Cognitive Function Index participant report showed nonsignificant worsening at month 12. Systemic and neuropsychiatric-related treatment-emergent AEs were greater in atabecestat groups vs placebo. After stopping treatment, follow-up cognitive testing and AE assessment provided evidence of reversibility of drug-induced cognitive worsening and AEs in atabecestat groups.
Conclusions and Relevance: Atabecestat treatment was associated with dose-related cognitive worsening as early as 3 months and presence of neuropsychiatric treatment-emergent AEs, with evidence of reversibility after 6 months off treatment.
Trial Registration: ClinicalTrials.gov Identifier: NCT02569398.}, }
@article {pmid33458891, year = {2021}, author = {Liss, JL and Seleri Assunção, S and Cummings, J and Atri, A and Geldmacher, DS and Candela, SF and Devanand, DP and Fillit, HM and Susman, J and Mintzer, J and Bittner, T and Brunton, SA and Kerwin, DR and Jackson, WC and Small, GW and Grossberg, GT and Clevenger, CK and Cotter, V and Stefanacci, R and Wise-Brown, A and Sabbagh, MN}, title = {Practical recommendations for timely, accurate diagnosis of symptomatic Alzheimer's disease (MCI and dementia) in primary care: a review and synthesis.}, journal = {Journal of internal medicine}, volume = {290}, number = {2}, pages = {310-334}, pmid = {33458891}, issn = {1365-2796}, support = {//Genentech/ ; }, abstract = {The critical role of primary care clinicians (PCCs) in Alzheimer's disease (AD) prevention, diagnosis and management must evolve as new treatment paradigms and disease-modifying therapies (DMTs) emerge. Our understanding of AD has grown substantially: no longer conceptualized as a late-in-life syndrome of cognitive and functional impairments, we now recognize that AD pathology builds silently for decades before cognitive impairment is detectable. Clinically, AD first manifests subtly as mild cognitive impairment (MCI) due to AD before progressing to dementia. Emerging optimism for improved outcomes in AD stems from a focus on preventive interventions in midlife and timely, biomarker-confirmed diagnosis at early signs of cognitive deficits (i.e. MCI due to AD and mild AD dementia). A timely AD diagnosis is particularly important for optimizing patient care and enabling the appropriate use of anticipated DMTs. An accelerating challenge for PCCs and AD specialists will be to respond to innovations in diagnostics and therapy for AD in a system that is not currently well positioned to do so. To overcome these challenges, PCCs and AD specialists must collaborate closely to navigate and optimize dynamically evolving AD care in the face of new opportunities. In the spirit of this collaboration, we summarize here some prominent and influential models that inform our current understanding of AD. We also advocate for timely and accurate (i.e. biomarker-defined) diagnosis of early AD. In doing so, we consider evolving issues related to prevention, detecting emerging cognitive impairment and the role of biomarkers in the clinic.}, }
@article {pmid33450772, year = {2021}, author = {Tabrizian, K and Amelinia, F and Belaran, M and Pourheidar, S and Mirzaei, H and Fanoudi, S}, title = {Tadalafil Reversed H-89 - and Scopolamine - Induced Spatial Learning Impairments in Male Rats.}, journal = {Drug research}, volume = {71}, number = {5}, pages = {275-283}, doi = {10.1055/a-1345-7832}, pmid = {33450772}, issn = {2194-9387}, abstract = {Accumulated evidence shows that the cAMP and cGMP signaling pathway plays an important role in memory function and neuronal plasticity. Phosphodiesterase 5 (PDE5) is a hopeful therapeutic target in AD (Alzheimer disease), and PDE5 inhibition may be a good therapeutic strategy for the treatment of AD. In the present study, the four-day bilateral intra-hippocampal infusion of H-89 as a protein kinase AII inhibitor (10 µM/side) and intra-peritoneal injections of tadalafil (20 mg/kg) and scopolamine (0.5 mg/kg) alone and also on combination on spatial learning in Morris water maze (MWM) were investigated. DMSO and saline were used as controls for H-89 and other mentioned drugs, respectively. Rats were trained for 4 days; each day included one block of four trials. Post- training probe trial tests were performed on day 5. Administration of H-89 and scopolamine led to a significant impairment in spatial learning compared to their related controls. But, combination of tadalafil/H-89 or tadalafil/scopolamine reversed H-89 or scopolamine- induced spatial learning deficits in MWM. Taken together, these results showed the probable regulatory effects of cGMP on cholinergic and cAMP/PKA signaling pathways in co-administrations of these mentioned drugs on spatial learning in MWM.}, }
@article {pmid33450186, year = {2021}, author = {Wang, C and Zhang, M and Garcia, G and Tian, E and Cui, Q and Chen, X and Sun, G and Wang, J and Arumugaswami, V and Shi, Y}, title = {ApoE-Isoform-Dependent SARS-CoV-2 Neurotropism and Cellular Response.}, journal = {Cell stem cell}, volume = {28}, number = {2}, pages = {331-342.e5}, pmid = {33450186}, issn = {1875-9777}, support = {R56 AG061171/AG/NIA NIH HHS/United States ; R01 AG056305/AG/NIA NIH HHS/United States ; P30 CA033572/CA/NCI NIH HHS/United States ; RF1 AG061794/AG/NIA NIH HHS/United States ; R21 AI129471/AI/NIAID NIH HHS/United States ; }, mesh = {Adenosine Monophosphate/analogs & derivatives/pharmacology ; Alanine/analogs & derivatives/pharmacology ; Animals ; Antiviral Agents/pharmacology ; Apolipoproteins E/*metabolism ; Astrocytes/drug effects/pathology/virology ; Brain/*pathology/*virology ; COVID-19/*virology ; Cell Differentiation ; Chlorocebus aethiops ; Humans ; Induced Pluripotent Stem Cells/*virology ; Nerve Degeneration/pathology ; Neurites/pathology ; Neurons/drug effects/pathology/virology ; Organoids/drug effects/pathology/virology ; Protein Isoforms/metabolism ; SARS-CoV-2/*physiology ; Synapses/pathology ; Tropism/*physiology ; Vero Cells ; }, abstract = {ApoE4, a strong genetic risk factor for Alzheimer disease, has been associated with increased risk for severe COVID-19. However, it is unclear whether ApoE4 alters COVID-19 susceptibility or severity, and the role of direct viral infection in brain cells remains obscure. We tested the neurotropism of SARS-CoV2 in human-induced pluripotent stem cell (hiPSC) models and observed low-grade infection of neurons and astrocytes that is boosted in neuron-astrocyte co-cultures and organoids. We then generated isogenic ApoE3/3 and ApoE4/4 hiPSCs and found an increased rate of SARS-CoV-2 infection in ApoE4/4 neurons and astrocytes. ApoE4 astrocytes exhibited enlarged size and elevated nuclear fragmentation upon SARS-CoV-2 infection. Finally, we show that remdesivir treatment inhibits SARS-CoV2 infection of hiPSC neurons and astrocytes. These findings suggest that ApoE4 may play a causal role in COVID-19 severity. Understanding how risk factors impact COVID-19 susceptibility and severity will help us understand the potential long-term effects in different patient populations.}, }
@article {pmid33441550, year = {2021}, author = {Hashimoto, Y and Kusakari, S and Nawa, M and Okamoto, K and Toyama, Y and Matsuoka, M}, title = {Restoration of the reduced CLSP activity alleviates memory impairment in Alzheimer disease.}, journal = {Translational psychiatry}, volume = {11}, number = {1}, pages = {44}, pmid = {33441550}, issn = {2158-3188}, support = {P30 AG028377/AG/NIA NIH HHS/United States ; }, mesh = {Aged ; *Alzheimer Disease ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/genetics ; Animals ; Brain/metabolism ; Disease Models, Animal ; Humans ; Memory Disorders ; Mice ; Mice, Transgenic ; Neurons/metabolism ; Presenilin-1 ; }, abstract = {Calmodulin-like skin protein (CLSP), a secreted peptide, inhibits neuronal death in cell-based Alzheimer's disease (AD) models and transgenic overexpression of the CLSP gene suppresses synaptic loss and memory impairment in AD model mice, APPswe/PS1dE9 double transgenic mice (APP/PS1 mice). Despite the anticipated role of CLSP as an AD-suppressing factor, it remains unanswered whether the insufficiency of the CLSP activity is linked to the AD pathogenesis. In this study, we first show that adiponectin, a CLSP potentiator/protector, dominantly determines the CLSP activity in the central nervous system where there are sufficient concentrations of CLSP, higher concentrations of CLSP inhibitors such as apolipoprotein E, and smaller concentrations of adiponectin. We next show that both the levels of brain adiponectin and the intraneuronal levels of SH3BP5, an important effector of the CLSP signal, are reduced in both AD patients and APP/PS1 mice. Finally, the restoration of the CLSP activity by subcutaneous injection of a hybrid peptide named CLSPCOL consisting of CLSP(1-61) and the collagen-homologous region of adiponectin, which has more potent neuroprotective activity than CLSP, is insensitive to the suppression by the CLSP inhibitors, and is efficiently recruited into brains, alleviates dementia and synaptic loss in the aged APP/PS1 mice. Collectively, these results suggest that the reduction in the CLSP activity, likely caused by the reduction in the levels of adiponectin, leads to the insufficient protection of neurons from neurotoxicity in the AD brains and the restoration of the CLSP activity is a promising strategy for the treatment of AD.}, }
@article {pmid33437626, year = {2021}, author = {Yao, X and Sun, C and Fan, B and Zhao, C and Zhang, Y and Duan, H and Pang, Y and Shen, W and Li, B and Wang, X and Liu, C and Zhou, H and Kong, X and Feng, S}, title = {Neurotropin exerts neuroprotective effects after spinal cord injury by inhibiting apoptosis and modulating cytokines.}, journal = {Journal of orthopaedic translation}, volume = {26}, number = {}, pages = {74-83}, pmid = {33437626}, issn = {2214-031X}, abstract = {Background/objective: Spinal cord injury (SCI) severely and irreversibly damages the central nervous system. Neurotropin (NTP), a nonprotein extract obtained from inflamed rabbit skin inoculated with vaccinia virus, is a drug that has been used for more than sixty years to alleviate neuropathic pain. It also reportedly exerts a neuroprotective role in peripheral nerves and in response to various central nervous system diseases, such as brain injury and Alzheimer disease. However, whether NTP promotes SCI recovery remains unknown. This study evaluated NTP's effects after SCI and explored its underlying mechanisms in a rat contusion model of SCI.
Method: NTP was intraperitoneally administered to adult female Wistar rats subjected to contusion-induced SCI. Functional recovery was evaluated with behavioural scores and electrophysiological examinations. Tissue recovery was assessed with magnetic resonance imaging as well as histological staining with haematoxylin and eosin and Luxol Fast Blue. Neuronal survival and gliosis were observed after NeuN and glial fibrillary acidic protein immunofluorescence. Levels of apoptosis were demonstrated with TdT-mediated dUTP nick-end labeling (TUNEL) staining, Caspase-3 and B-cell lymphoma-2 (Bcl-2) Western blot, and Annexin V/propidium iodide flow cytometry. A protein antibody chip analysis was performed to evaluate the expression levels of 67 rat cytokines.
Results: NTP treatment improved the hindlimb locomotor recovery of the injured animals as well as their electrophysiological outcomes after SCI. A dosage of 50 NTP units/kg was found to optimize the efficacy of NTP. Magnetic resonance imaging revealed that lesion sizes decreased after NTP treatment. The haematoxylin and eosin and Luxol Fast Blue staining showed significant increases in the amount of spared tissue. The NeuN and glial fibrillary acidic protein immunofluorescence revealed that NTP treatment increased neuronal survival and reduced gliosis in tissue samples obtained from the lesion's epicentre. That NTP inhibited apoptosis was confirmed by the decreased number of TUNEL-positive cells, level of Caspase-3 expression, and number of Annexin V/propidium iodide-positive cells, as well as the increased level of Bcl-2 expression. The protein array analysis identified 28 differentially expressed proteins in the NTP group, and the gene ontology (GO) analysis showed that the enriched differentially expressed proteins implicate janus kinase-signal transducer and activator of transcription (JAK-STAT) signalling pathways. The expression levels of proinflammatory cytokines such as interleukin 6, thymus chemokine-1(TCK-1), and lipopolysaccharide-induced CXC chemokine (LIX) decreased after NTP treatment, whereas the levels of prorepair cytokine hepatocyte growth factor and adiponectin increased.
Conclusion: Our research provides evidence that NTP can improve functional outcomes and alleviate secondary injury after SCI by inhibiting apoptosis and modulating cytokines.
The multicomponent NTP might have broad target spectra in SCI pathophysiology and halt the secondary injury cascade. As a safe drug that features sixty years of clinical use as an analgesic, translating this demonstrated efficacy of NTP to addressing SCI in human patients may potentially be accelerated.}, }
@article {pmid33433143, year = {2021}, author = {Lee, ZF and Huang, TH and Chen, SP and Cheng, IH}, title = {Altered nociception in Alzheimer disease is associated with striatal-enriched protein tyrosine phosphatase signaling.}, journal = {Pain}, volume = {162}, number = {6}, pages = {1669-1680}, doi = {10.1097/j.pain.0000000000002180}, pmid = {33433143}, issn = {1872-6623}, mesh = {*Alzheimer Disease/complications/genetics ; Amyloid beta-Peptides ; Amyloid beta-Protein Precursor/genetics ; Animals ; Disease Models, Animal ; Humans ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Nociception ; Protein Tyrosine Phosphatases ; Quality of Life ; }, abstract = {ABSTRACT: Alzheimer disease (AD) is the most common form of dementia, accounting for approximately 60% of cases. In addition to memory loss, changes in pain sensitivity are found in a substantial proportion of patients with AD. However, the mechanism of nociception deficits in AD is still unclear. Here, we hypothesize that the nociception abnormality in AD is due to the aberrant activation of striatal-enriched protein tyrosine phosphatase (STEP) signaling, which modulates proteins related to nociception transduction. Our results indicated that the transgenic mice carrying human amyloid precursor protein (APP) gene had lower sensitivity to mechanical and thermal stimulation than the wild-type group at the ages of 6, 9, and 12 months. These APP mice exhibited elevated STEP activity and decreased phosphorylation of proteins involved in nociception transduction in hippocampi. The pharmacological inhibition of STEP activity using TC-2153 further reversed nociception and cognitive deficits in the APP mice. Moreover, the phosphorylation of nociception-related proteins in the APP mice was also rescued after STEP inhibitor treatment, indicating the key role of STEP in nociception alteration. In summary, this study identifies a mechanism for the reduced nociceptive sensitivity in an AD mouse model that could serve as a therapeutic target to improve the quality of life for patients with AD.}, }
@article {pmid33427873, year = {2021}, author = {Moscoso, A and Grothe, MJ and Ashton, NJ and Karikari, TK and Lantero Rodríguez, J and Snellman, A and Suárez-Calvet, M and Blennow, K and Zetterberg, H and Schöll, M and , }, title = {Longitudinal Associations of Blood Phosphorylated Tau181 and Neurofilament Light Chain With Neurodegeneration in Alzheimer Disease.}, journal = {JAMA neurology}, volume = {78}, number = {4}, pages = {396-406}, doi = {10.1001/jamaneurol.2020.4986}, pmid = {33427873}, issn = {2168-6157}, abstract = {Importance: Plasma phosphorylated tau at threonine 181 (p-tau181) has been proposed as an easily accessible biomarker for the detection of Alzheimer disease (AD) pathology, but its ability to monitor disease progression in AD remains unclear.
Objective: To study the potential of longitudinal plasma p-tau181 measures for assessing neurodegeneration progression and cognitive decline in AD in comparison to plasma neurofilament light chain (NfL), a disease-nonspecific marker of neuronal injury.
This longitudinal cohort study included data from the Alzheimer's Disease Neuroimaging Initiative from February 1, 2007, to June 6, 2016. Follow-up blood sampling was performed for up to 8 years. Plasma p-tau181 measurements were performed in 2020. This was a multicentric observational study of 1113 participants, including cognitively unimpaired participants as well as patients with cognitive impairment (mild cognitive impairment and AD dementia). Participants were eligible for inclusion if they had available plasma p-tau181 and NfL measurements and at least 1 fluorine-18-labeled fluorodeoxyglucose (FDG) positron emission tomography (PET) or structural magnetic resonance imaging scan performed at the same study visit. Exclusion criteria included any significant neurologic disorder other than suspected AD; presence of infection, infarction, or multiple lacunes as detected by magnetic resonance imaging; and any significant systemic condition that could lead to difficulty complying with the protocol.
Exposures: Plasma p-tau181 and NfL measured with single-molecule array technology.
Main Outcomes and Measures: Longitudinal imaging markers of neurodegeneration (FDG PET and structural magnetic resonance imaging) and cognitive test scores (Preclinical Alzheimer Cognitive Composite and Alzheimer Disease Assessment Scale-Cognitive Subscale with 13 tasks). Data were analyzed from June 20 to August 15, 2020.
Results: Of the 1113 participants (mean [SD] age, 74.0 [7.6] years; 600 men [53.9%]; 992 non-Hispanic White participants [89.1%]), a total of 378 individuals (34.0%) were cognitively unimpaired (CU) and 735 participants (66.0%) were cognitively impaired (CImp). Of the CImp group, 537 (73.1%) had mild cognitive impairment, and 198 (26.9%) had AD dementia. Longitudinal changes of plasma p-tau181 were associated with cognitive decline (CU: r = -0.24, P < .001; CImp: r = 0.34, P < .001) and a prospective decrease in glucose metabolism (CU: r = -0.05, P = .48; CImp: r = -0.27, P < .001) and gray matter volume (CU: r = -0.19, P < .001; CImp: r = -0.31, P < .001) in highly AD-characteristic brain regions. These associations were restricted to amyloid-β-positive individuals. Both plasma p-tau181 and NfL were independently associated with cognition and neurodegeneration in brain regions typically affected in AD. However, NfL was also associated with neurodegeneration in brain regions exceeding this AD-typical spatial pattern in amyloid-β-negative participants. Mediation analyses found that approximately 25% to 45% of plasma p-tau181 outcomes on cognition measures were mediated by the neuroimaging-derived markers of neurodegeneration, suggesting links between plasma p-tau181 and cognition independent of these measures.
Conclusions and Relevance: Study findings suggest that plasma p-tau181 was an accessible and scalable marker for predicting and monitoring neurodegeneration and cognitive decline and was, unlike plasma NfL, AD specific. The study findings suggest implications for the use of plasma biomarkers as measures to monitor AD progression in clinical practice and treatment trials.}, }
@article {pmid33420969, year = {2021}, author = {Jalili-Baleh, L and Nadri, H and Forootanfar, H and Küçükkılınç, TT and Ayazgök, B and Sharifzadeh, M and Rahimifard, M and Baeeri, M and Abdollahi, M and Foroumadi, A and Khoobi, M}, title = {Chromone-lipoic acid conjugate: Neuroprotective agent having acceptable butyrylcholinesterase inhibition, antioxidant and copper-chelation activities.}, journal = {Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences}, volume = {29}, number = {1}, pages = {23-38}, pmid = {33420969}, issn = {2008-2231}, support = {971370//The National Institute for Medical Research Development/ ; }, abstract = {PURPOSE: Alzheimer's disease (AD) is a multifaceted neurodegenerative disease. To target simultaneously multiple pathological processes involved in AD, natural-origin compounds with unique characteristics are promising scaffolds to develop novel multi-target compounds in the treatment of different neurodegenerative disease, especially AD. In this study, novel chromone-lipoic acid hybrids were prepared to find a new multifunctional lead structure for the treatment of AD.
METHODS: Chromone-lipoic acid hybrids were prepared through click reaction and their neuroprotection and anticholinesterase activity were fully evaluated. The anti-amyloid aggregation, antioxidant and metal-chelation activities of the best compound were also investigated by standard methods to find a new multi-functional agent against AD.
RESULTS: The primary biological screening demonstrated that all compounds had significant neuroprotection activity against H2O2-induced cell damage in PC12 cells. Compound 19 as the most potent butyrylcholinesterase (BuChE) inhibitor (IC50 = 7.55 μM) having significant neuroprotection activity as level as reference drug was selected for further biological evaluations. Docking and kinetic studies revealed non-competitive mixed-type inhibition of BuChE by compound 19. It could significantly reduce formation of the intracellular reactive oxygen species (ROS) and showed excellent reducing power (85.57 mM Fe+2), comparable with quercetin and lipoic acid. It could also moderately inhibit Aβ aggregation and selectively chelate with copper ions in 2:1 M ratio.
CONCLUSION: Compound 19 could be considered as a hopeful multifunctional agent for the further development gainst AD owing to the acceptable neuroprotective and anti-BuChE activity, moderate anti-Aβ aggregation activity, outstanding antioxidant activity as well as selective copper chelation ability. A new chromone-lipoic acid hybrid was synthesized as anti-Alzheimer agent with BuChE inhibitory activity, anti-Aβ aggregation, metal-chelation and antioxidant properties.}, }
@article {pmid33419465, year = {2021}, author = {Tan, MS and Yang, YX and Xu, W and Wang, HF and Tan, L and Zuo, CT and Dong, Q and Tan, L and Suckling, J and Yu, JT and , }, title = {Associations of Alzheimer's disease risk variants with gene expression, amyloidosis, tauopathy, and neurodegeneration.}, journal = {Alzheimer's research & therapy}, volume = {13}, number = {1}, pages = {15}, pmid = {33419465}, issn = {1758-9193}, mesh = {*Alzheimer Disease/genetics ; *Amyloidosis/genetics ; Gene Expression ; Genome-Wide Association Study ; Humans ; *Tauopathies/genetics ; }, abstract = {BACKGROUND: Genome-wide association studies have identified more than 30 Alzheimer's disease (AD) risk genes, although the detailed mechanism through which all these genes are associated with AD pathogenesis remains unknown. We comprehensively evaluate the roles of the variants in top 30 non-APOE AD risk genes, based on whether these variants were associated with altered mRNA transcript levels, as well as brain amyloidosis, tauopathy, and neurodegeneration.
METHODS: Human brain gene expression data were obtained from the UK Brain Expression Consortium (UKBEC), while other data used in our study were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. We examined the association of AD risk allele carrier status with the levels of gene expression in blood and brain regions and tested the association with brain amyloidosis, tauopathy, and neurodegeneration at baseline, using a multivariable linear regression model. Next, we analyzed the longitudinal effects of these variants on the change rates of pathology using a mixed effect model.
RESULTS: Altogether, 27 variants were detected to be associated with the altered expression of 21 nearby genes in blood and brain regions. Eleven variants (especially novel variants in ADAM10, IGHV1-68, and SLC24A4/RIN3) were associated with brain amyloidosis, 7 variants (especially in INPP5D, PTK2B) with brain tauopathy, and 8 variants (especially in ECHDC3, HS3ST1) with brain neurodegeneration. Variants in ADAMTS1, BZRAP1-AS1, CELF1, CD2AP, and SLC24A4/RIN3 participated in more than one cerebral pathological process.
CONCLUSIONS: Genetic variants might play functional roles and suggest potential mechanisms in AD pathogenesis, which opens doors to uncover novel targets for AD treatment.}, }
@article {pmid33416500, year = {2021}, author = {Moussavi, Z and Rutherford, G and Lithgow, B and Millikin, C and Modirrousta, M and Mansouri, B and Wang, X and Omelan, C and Fellows, L and Fitzgerald, P and Koski, L}, title = {Repeated Transcranial Magnetic Stimulation for Improving Cognition in Patients With Alzheimer Disease: Protocol for a Randomized, Double-Blind, Placebo-Controlled Trial.}, journal = {JMIR research protocols}, volume = {10}, number = {1}, pages = {e25144}, pmid = {33416500}, issn = {1929-0748}, abstract = {BACKGROUND: Alzheimer disease has no known cure. As existing pharmacologic interventions only modestly slow cognitive decline, there is a need for new treatments. Recent trials of repetitive transcranial magnetic stimulation (rTMS) have reported encouraging results for improving or stabilizing cognition in patients diagnosed with Alzheimer dementia. However, owing to small samples and lack of a well-controlled double-blind design, the results to date are inconclusive. This paper presents the protocol for a large placebo-controlled double-blind study designed with sufficient statistical rigor to measure the efficacy of rTMS treatment in patients with Alzheimer dementia.
OBJECTIVE: The objectives are to (1) recruit and enroll up to 200 eligible participants, (2) estimate the difference in treatment effects between active treatment and sham treatment, (3) estimate the difference in treatment effects between two doses of rTMS applications, (4) estimate the duration of treatment effects among responders to active rTMS treatment, and (5) estimate the effect of dementia severity on treatment outcomes among patients receiving active rTMS treatment.
METHODS: We have designed our study to be a double-blind, randomized, placebo-controlled clinical trial investigating the short- and long-term (up to 6 months) benefits of active rTMS treatment at two doses (10 sessions over 2 weeks and 20 sessions over 4 weeks) compared with sham rTMS treatment. The study will include patients aged ≥55 years who are diagnosed with Alzheimer disease at an early to moderate stage and have no history of seizures and no major depression. The primary outcome measure is the change in the Alzheimer Disease Assessment Scale-Cognitive Subscale score from pretreatment to posttreatment. Secondary outcomes are changes in performance on tests of frontal lobe functioning (Stroop test and verbal fluency), changes in neuropsychiatric symptoms (Neuropsychiatric Inventory Questionnaire), and changes in activities of daily living (Alzheimer Disease Co-operative Study-Activities of Daily Living Inventory). Tolerability of the intervention will be assessed using a modification of the Treatment Satisfaction Questionnaire for Medication. We assess participants at baseline and 3, 5, 8, 16, and 24 weeks after the intervention.
RESULTS: As of November 1, 2020, we have screened 523 individuals, out of which 133 were eligible and have been enrolled. Out of the 133 individuals, 104 have completed the study. Moreover, as of November 1, 2020, there has been no serious adverse event. We anticipate that rTMS will considerably improve cognitive function, with effects lasting up to 3 months. Moreover, we expect rTMS to be a well-tolerated treatment with no serious side effect.
CONCLUSIONS: This protocol design will allow to address both the rTMS active treatment dose and its short- and long-term effects compared with sham treatment in large samples.
TRIAL REGISTRATION: ClinicalTrials.gov NCT02908815; https://clinicaltrials.gov/ct2/show/NCT02908815.
DERR1-10.2196/25144.}, }
@article {pmid33410119, year = {2021}, author = {Herr, M and Ankri, J and Diard, C and Hiance-Delahaye, A}, title = {Removal of Drugs for Alzheimer's Disease from the List of Reimbursable Drugs in France: Analysis of Change in Drug Use, Disease Management and Cognition Using the National Alzheimer Data Bank (BNA).}, journal = {Drugs & aging}, volume = {38}, number = {1}, pages = {63-74}, pmid = {33410119}, issn = {1179-1969}, abstract = {BACKGROUND: Because of insufficient data about their benefit-risk ratio in real life, drugs used for Alzheimer's disease (AD; cholinesterase inhibitors and memantine) were withdrawn from the list of reimbursable drugs in France on 1 August 2018.
OBJECTIVES: In this context, this study aimed to investigate the effects of the removal of AD drugs from the list of reimbursed drugs among patients followed in memory centres in France, in terms of prevalence and factors associated with drug discontinuation and evolution of disease management and cognition after drug discontinuation.
METHODS: This is an observational study based on data from the National Alzheimer Data Bank ('Banque Nationale Alzheimer' [BNA]), which centralizes information about patients consulting in memory centres. The drug discontinuation rate was estimated among patients receiving AD drugs at the last visit before the end of reimbursement. Factors associated with drug discontinuation were investigated among sociodemographic and disease characteristics, as well as among the use of healthcare resources before the end of reimbursement. We compared the evolution of disease management (psychotropic drugs and non-pharmacological interventions) and Mini-Mental State Examination (MMSE) score during the year following the end of reimbursement among patients with a diagnosis of AD.
RESULTS: Among the 19,380 patients of the study sample (62.5% females, mean age 81 years, 86.8% with a diagnosis of AD), 19.5% discontinued their treatment after the end of reimbursement. The main factors associated with drug discontinuation were the type of dementia and lower MMSE level. Compared with patients with a diagnosis of AD, those with vascular dementia were more likely to stop their treatment, whereas those with dementia with Lewy bodies were less likely to discontinue. Among patients with a diagnosis of AD, drug discontinuation was associated with increased use of psychotropic medications, especially antidepressants, and non-pharmacological interventions afterwards, but there was no difference regarding the evolution of MMSE score.
CONCLUSION: This study provides real-life information about the use of AD drugs after they were withdrawn from reimbursement in France and shows that drug discontinuation was limited among patients followed in memory centres and accompanied by increased use of other healthcare resources.}, }
@article {pmid33404280, year = {2021}, author = {Wani, A and Al Rihani, SB and Sharma, A and Weadick, B and Govindarajan, R and Khan, SU and Sharma, PR and Dogra, A and Nandi, U and Reddy, CN and Bharate, SS and Singh, G and Bharate, SB and Vishwakarma, RA and Kaddoumi, A and Kumar, A}, title = {Crocetin promotes clearance of amyloid-β by inducing autophagy via the STK11/LKB1-mediated AMPK pathway.}, journal = {Autophagy}, volume = {}, number = {}, pages = {1-20}, doi = {10.1080/15548627.2021.1872187}, pmid = {33404280}, issn = {1554-8635}, abstract = {Alzheimer disease (AD) is usually accompanied by two prominent pathological features, cerebral accumulation of amyloid-β (Aβ) plaques and presence of MAPT/tau neurofibrillary tangles. Dysregulated clearance of Aβ largely contributes to its accumulation and plaque formation in the brain. Macroautophagy/autophagy is a lysosomal degradative process, which plays an important role in the clearance of Aβ. Failure of autophagic clearance of Aβ is currently acknowledged as a contributing factor to increased accumulation of Aβ in AD brains. In this study, we have identified crocetin, a pharmacologically active constituent from the flower stigmas of Crocus sativus, as a potential inducer of autophagy in AD. In the cellular model, crocetin induced autophagy in N9 microglial and primary neuron cells through STK11/LKB1 (serine/threonine kinase 11)-mediated AMP-activated protein kinase (AMPK) pathway activation. Autophagy induction by crocetin significantly increased Aβ clearance in N9 cells. Moreover, crocetin crossed the blood-brain barrier and induced autophagy in the brains' hippocampi of wild-type male C57BL/6 mice. Further studies in transgenic male 5XFAD mice, as a model of AD, revealed that one-month treatment with crocetin significantly reduced Aβ levels and neuroinflammation in the mice brains and improved memory function by inducing autophagy that was mediated by AMPK pathway activation. Our findings support further development of crocetin as a pharmacological inducer of autophagy to prevent, slow down progression, and/or treat AD.}, }
@article {pmid33402424, year = {2021}, author = {Taudte, N and Linnert, M and Rahfeld, JU and Piechotta, A and Ramsbeck, D and Buchholz, M and Kolenko, P and Parthier, C and Houston, JA and Veillard, F and Eick, S and Potempa, J and Schilling, S and Demuth, HU and Stubbs, MT}, title = {Mammalian-like type II glutaminyl cyclases in Porphyromonas gingivalis and other oral pathogenic bacteria as targets for treatment of periodontitis.}, journal = {The Journal of biological chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1074/jbc.RA120.016836}, pmid = {33402424}, issn = {1083-351X}, abstract = {The development of a targeted therapy would significantly improve the treatment of periodontitis and its associated diseases including Alzheimer Disease, rheumatoid arthritis, and cardiovascular diseases. Glutaminyl cyclases (QCs) from the oral pathogens Porphyromonas gingivalis, Tannerella forsythia and Prevotella intermedia represent attractive target enzymes for small-molecule inhibitor development, as their action is likely to stabilize essential periplasmic and outer membrane proteins by N-terminal pyroglutamination. In contrast to other microbial QCs that utilize so-called type I enzymes, these oral pathogens possess sequences corresponding to type II QCs, observed hitherto only in animals. However, whether differences between these bacteroidal QCs and animal QCs are sufficient to enable development of selective inhibitors is not clear. To learn more, we recombinantly expressed all three QCs. They exhibit comparable catalytic efficiencies and are inhibited by metal chelators. Crystal structures of the enzymes from P. gingivalis (PgQC) and T. forsythia (TfQC) reveal a tertiary structure composed of an eight-stranded β-sheet surrounded by seven α-helices, typical of animal type II QCs. In each case, an active site Zn ion is tetrahedrally coordinated by conserved residues. Nevertheless, significant differences to mammalian enzymes are found around the active site of the bacteroidal enzymes. Application of a PgQC-selective inhibitor described here for the first time results in growth inhibition of two P. gingivalis clinical isolates in a dose dependent manner. The insights gained by these studies will assist in the development of highly specific small-molecule bacteroidal QC inhibitors, paving the way for alternative therapies against periodontitis and associated diseases.}, }
@article {pmid33397589, year = {2021}, author = {Jonathan, MC and Adrián, SH and Gonzalo, A}, title = {Type II nuclear receptors with potential role in Alzheimer disease.}, journal = {Molecular aspects of medicine}, volume = {78}, number = {}, pages = {100940}, doi = {10.1016/j.mam.2020.100940}, pmid = {33397589}, issn = {1872-9452}, abstract = {Nuclear receptors are ligand-activated transcription factors that can modulated cellular processes involved in the development, homeostasis, cell proliferation, metabolism, and reproduction through the control of the specific genetic and molecular program. In the central nervous system, they are key regulators of neural stem cell fate decisions and can modulate the physiology of different brain cells. Over the past decades, a large body of evidence has supported that nuclear receptors are potential therapeutic targets for the treatment of neurodegenerative disorders such as Alzheimer's disease, the most common dementia worldwide, and the main cause of disability in later life. This disease is characterized by the progressive accumulation of amyloid-beta peptides and hyperphosphorylated tau protein that can explain alterations in synaptic transmission and plasticity; loss of dendritic spines; increased in reactive microglia and inflammation; reduction of neuronal stem cells number; myelin and vascular alterations that finally leads to increased neuronal death. Here, we present a review of type II no steroidal nuclear receptors that form obligatory heterodimers with the Retinoid X Receptor (RXR) and its potential in the therapeutic of AD. Activation of type II nuclear receptor by synthetic agonist leads to transcriptional regulation of specific genes that acts counteracting against the detrimental effects of amyloid-beta peptides and hyperphosphorylated tau in neuronal cells recovering the functionality of the synapses. But also, activation of type II nuclear receptor leads to modifications in APP metabolism, repression of inflammatory cascade and inductors of the generation of neuronal stem cells and progenitor cells supporting its potential therapeutics role for Alzheimer's disease.}, }
@article {pmid33396647, year = {2020}, author = {Fernández-Fierro, A and Funes, SC and Rios, M and Covián, C and González, J and Kalergis, AM}, title = {Immune Modulation by Inhibitors of the HO System.}, journal = {International journal of molecular sciences}, volume = {22}, number = {1}, pages = {}, pmid = {33396647}, issn = {1422-0067}, support = {P09/016-F//Instituto Milenio en Inmunología e Inmunoterapia/ ; 1190830//Fondo Nacional de Desarrollo Científico y Tecnológico/ ; I781902009//Agencia Nacional de Investigación y Desarrollo/ ; }, abstract = {The heme oxygenase (HO) system involves three isoforms of this enzyme, HO-1, HO-2, and HO-3. The three of them display the same catalytic activity, oxidating the heme group to produce biliverdin, ferrous iron, and carbon monoxide (CO). HO-1 is the isoform most widely studied in proinflammatory diseases because treatments that overexpress this enzyme promote the generation of anti-inflammatory products. However, neonatal jaundice (hyperbilirubinemia) derived from HO overexpression led to the development of inhibitors, such as those based on metaloproto- and meso-porphyrins inhibitors with competitive activity. Further, non-competitive inhibitors have also been identified, such as synthetic and natural imidazole-dioxolane-based, small synthetic molecules, inhibitors of the enzyme regulation pathway, and genetic engineering using iRNA or CRISPR cas9. Despite most of the applications of the HO inhibitors being related to metabolic diseases, the beneficial effects of these molecules in immune-mediated diseases have also emerged. Different medical implications, including cancer, Alzheimer´s disease, and infections, are discussed in this article and as to how the selective inhibition of HO isoforms may contribute to the treatment of these ailments.}, }
@article {pmid33390886, year = {2020}, author = {Zhou, Y and Chen, Y and Xu, C and Zhang, H and Lin, C}, title = {TLR4 Targeting as a Promising Therapeutic Strategy for Alzheimer Disease Treatment.}, journal = {Frontiers in neuroscience}, volume = {14}, number = {}, pages = {602508}, pmid = {33390886}, issn = {1662-4548}, abstract = {Alzheimer disease (AD) is a devastating neurodegenerative disorder characterized by extracellular accumulation of amyloid-beta and formation of intracellular neurofibrillary tangles. Microglia activation and neuroinflammation play important roles in the pathogenesis of AD; Toll-like receptor 4 (TLR4)-a key component of the innate immune system-in microglia is also thought to be involved based on the observed association between TLR gene polymorphisms and AD risk. TLR4 has been shown to exert both detrimental and beneficial effects on AD-related pathologies. In preclinical models, experimental manipulations targeting TLR4 were shown to improve learning and memory, which was related to inhibition of pro-inflammatory cytokine release and reduction of oxidative stress. In this review, we summarize the key evidence supporting TLR4 as a promising therapeutic target in AD treatment.}, }
@article {pmid33361021, year = {2020}, author = {Yang, H and Han, W and Li, H}, title = {Efficacy and safety of MAO-B inhibitor versus donepezil in Chinese elderly stroke patients with Alzheimer disease: A potential therapeutic option.}, journal = {Pakistan journal of pharmaceutical sciences}, volume = {33}, number = {3(Special)}, pages = {1349-1354}, pmid = {33361021}, issn = {1011-601X}, mesh = {Age Factors ; Aged ; Alzheimer Disease/complications/diagnosis/*drug therapy/psychology ; China ; Cholinesterase Inhibitors/adverse effects/*therapeutic use ; Cognition/*drug effects ; Donepezil/adverse effects/*therapeutic use ; Female ; Humans ; Male ; Monoamine Oxidase Inhibitors/adverse effects/*therapeutic use ; Nootropic Agents/adverse effects/*therapeutic use ; Pilot Projects ; Random Allocation ; Selegiline/adverse effects/*therapeutic use ; Stroke/*complications/diagnosis/psychology ; Time Factors ; Treatment Outcome ; }, abstract = {This pilot study designed to evaluate the efficacy and safety of MAO-B inhibitor in comparison with Donepezil (DNP) in elderly Chinese patients with Alzheimer disease (AD). In the present clinical trial, Chinese elderly patients aged ≥65 years with a confirmed diagnosis of AD were enrolled. The patients received MAO-B inhibitor (Selegiline 5 mg) or DNP 10 mg daily (reference) for 6 months. The efficacy and safety data were collected from 120 patients (60 patients in each group) every 3 weeks until 6 months. The primary endpoints were to assess the change in cognitive score from baseline in both the treatment group. The result of the present study showed that the patients treated with MAO-B inhibitor and DNP have similar efficacy and safety profile Considering the clinical benefit, mean (SD) improvement in sign and symptoms was numerically greater in DNP-treated patients as compared to MAO-B inhibitor at endpoint visit (SIB: 12.3 (3.7) vs 11.3 (4.2); AD severity: 14.2 (3.5); CIBIS+/CIBIC: 10.2 (2.7) vs 9.4 (3.2); ADCS-ADL: 14.3 (4.2) vs 13.2 (3.4); MMSE: 14.3 (3.7) vs 12.2 (3.2), P>0.05 respectively for each comparison). However, a statistical difference in terms of clinical benefit was similar between both the treatment groups (p>0.05). Overall, both the study drugs were found comparable in relieving the symptoms of AD (severity score after end of treatment: 14.2 vs 13.4 respectively; p >0.05). This indicates that MAO-B inhibitor is a potential target for the treatment of AD in China. The results of the present study may help to design a large clinical trial to evaluate the efficacy and safety of MAO-B inhibitor in comparison with DNP in AD patients.}, }
@article {pmid33359918, year = {2021}, author = {Singh, N and Yadav, SS and Rao, AS and Nandal, A and Kumar, S and Ganaie, SA and Narasihman, B}, title = {Review on anticancerous therapeutic potential of Withania somnifera (L.) Dunal.}, journal = {Journal of ethnopharmacology}, volume = {270}, number = {}, pages = {113704}, doi = {10.1016/j.jep.2020.113704}, pmid = {33359918}, issn = {1872-7573}, mesh = {Animals ; Antineoplastic Agents/adverse effects/chemistry/*pharmacology/*therapeutic use ; Apoptosis/drug effects ; Humans ; Medicine, Ayurvedic ; Neoplasms/*drug therapy ; Plant Extracts/adverse effects/chemistry/*pharmacology/*therapeutic use ; Withania/*chemistry ; }, abstract = {Withania somnifera, commonly known as Ashwagandha, is an important medicinal herb belonging to family Solanaceae. It is widely used in folkloric and Ayurvedic medicines since antiquity. Traditionally, the plant is highly practiced throughout the globe as immunomodulator, anti-inflammatory, anti-stress, anti-parkinson, anti-alzheimer, cardio protective, neural and physical health enhancer, neurodefensive, anti-diabetic, aphrodisiac, memory boosting etc. The plant is also effective in combating various types of cancer and other related problems of colon, mammary, lung, prostate, skin, blood, liver and kidney.
AIM OF THIS REVIEW: The present review represents the critical assessment of the literature available on the anticancerous role of W. somnifera. The present study throws light on its diverse chemical compounds and the possible mechanisms of action involved. This review also suggests further research strategies to harness the therapeutic potential of this plant.
MATERIALS AND METHODS: The present review is the outcome of a systematic search of scientific literature about 'Withania somnifera and its role in cancer prevention'. The scientific databases viz. Google Scholar, Science Direct, Pubmed and Web of Science were searched from 2001 to 2019. Textbooks, magazines and newspapers were also consulted. This review summarizes all the published literature about its therapeutic potential for the treatment of different types of cancers.
RESULTS: W. somnifera has been widely used in traditional and ayurvedic medicines for treatment of numerous problems related to health and vitality. The plant is a reservoir of diverse phytoconstituents like alkaloids, steroids, flavonoids, phenolics, nitrogen containing compounds and trace elements. Withanolides are the major alkaloids which renders its anticancer potential due to its highly oxygenated nature. The plant is highly effective in combating various types of cancers viz. colon, mammary, lung, prostate, skin, blood, liver and kidney. Previous studies depict that this plant is more effective against breast cancer followed by colon, lung, prostate and blood cancer. Furthermore, from different clinical studies it has been observed that the active constituents of the plant like withaferin-A, withanolide-D have least toxic effects.
CONCLUSION: The present review confirms the various medicinal values of W. somnifera without any significant side effects. Withaferin-A (WA) and Withanolides are its most promising anticancer compounds that play a major role in apoptosis induction. Keeping in mind the anticancerous potential of this plant, it is suggested that this plant may further be investigated and more clinical studies can be performed.}, }
@article {pmid33356266, year = {2021}, author = {Viayna, E and Coquelle, N and Cieslikiewicz-Bouet, M and Cisternas, P and Oliva, CA and Sánchez-López, E and Ettcheto, M and Bartolini, M and De Simone, A and Ricchini, M and Rendina, M and Pons, M and Firuzi, O and Pérez, B and Saso, L and Andrisano, V and Nachon, F and Brazzolotto, X and García, ML and Camins, A and Silman, I and Jean, L and Inestrosa, NC and Colletier, JP and Renard, PY and Muñoz-Torrero, D}, title = {Discovery of a Potent Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase with Antioxidant Activity that Alleviates Alzheimer-like Pathology in Old APP/PS1 Mice.}, journal = {Journal of medicinal chemistry}, volume = {64}, number = {1}, pages = {812-839}, doi = {10.1021/acs.jmedchem.0c01775}, pmid = {33356266}, issn = {1520-4804}, mesh = {Acetylcholinesterase/chemistry/*metabolism ; Alzheimer Disease/drug therapy/pathology ; Amyloid/metabolism ; Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism ; Animals ; Antioxidants/chemistry/*metabolism/pharmacology/therapeutic use ; Aspartic Acid Endopeptidases/antagonists & inhibitors/metabolism ; Binding Sites ; Brain/drug effects/metabolism ; Butyrylcholinesterase/chemistry/*metabolism ; Cholinesterase Inhibitors/*chemistry/metabolism/pharmacology/therapeutic use ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Molecular Docking Simulation ; Oxidative Stress/drug effects ; Structure-Activity Relationship ; Tissue Distribution ; }, abstract = {The combination of the scaffolds of the cholinesterase inhibitor huprine Y and the antioxidant capsaicin results in compounds with nanomolar potencies toward human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) that retain or improve the antioxidant properties of capsaicin. Crystal structures of their complexes with AChE and BChE revealed the molecular basis for their high potency. Brain penetration was confirmed by biodistribution studies in C57BL6 mice, with one compound (5i) displaying better brain/plasma ratio than donepezil. Chronic treatment of 10 month-old APP/PS1 mice with 5i (2 mg/kg, i.p., 3 times per week, 4 weeks) rescued learning and memory impairments, as measured by three different behavioral tests, delayed the Alzheimer-like pathology progression, as suggested by a significantly reduced Aβ42/Aβ40 ratio in the hippocampus, improved basal synaptic efficacy, and significantly reduced hippocampal oxidative stress and neuroinflammation. Compound 5i emerges as an interesting anti-Alzheimer lead with beneficial effects on cognitive symptoms and on some underlying disease mechanisms.}, }
@article {pmid33352990, year = {2020}, author = {Herrero-Labrador, R and Trueba-Saiz, A and Martinez-Rachadell, L and Fernandez de Sevilla, ME and Zegarra-Valdivia, JA and Pignatelli, J and Diaz-Pacheco, S and Fernandez, AM and Torres Aleman, I}, title = {Circulating Insulin-Like Growth Factor I is Involved in the Effect of High Fat Diet on Peripheral Amyloid β Clearance.}, journal = {International journal of molecular sciences}, volume = {21}, number = {24}, pages = {}, pmid = {33352990}, issn = {1422-0067}, support = {PIE14/00061//Ciberned/ ; SAF2013-40710-R (AEI/FEDER, UE)//Mineco/ ; }, mesh = {Alzheimer Disease/etiology/metabolism/pathology ; Amyloid beta-Peptides/*metabolism ; Amyloid beta-Protein Precursor/metabolism ; Animals ; Biomarkers ; Brain/metabolism/pathology ; *Diet, High-Fat ; Disease Models, Animal ; Hepatocytes/metabolism ; Insulin-Like Growth Factor I/*metabolism ; Mice ; Mice, Transgenic ; Overweight ; }, abstract = {Obesity is a risk factor for Alzheimer's disease (AD), but underlying mechanisms are not clear. We analyzed peripheral clearance of amyloid β (Aβ) in overweight mice because its systemic elimination may impact brain Aβ load, a major landmark of AD pathology. We also analyzed whether circulating insulin-like growth factor I (IGF-I) intervenes in the effects of overweight as this growth factor modulates brain Aβ clearance and is increased in the serum of overweight mice. Overweight mice showed increased Aβ accumulation by the liver, the major site of elimination of systemic Aβ, but unaltered brain Aβ levels. We also found that Aβ accumulation by hepatocytes is stimulated by IGF-I, and that mice with low serum IGF-I levels show reduced liver Aβ accumulation-ameliorated by IGF-I administration, and unchanged brain Aβ levels. In the brain, IGF-I favored the association of its receptor (IGF-IR) with the Aβ precursor protein (APP), and at the same time, stimulated non-amyloidogenic processing of APP in astrocytes, as indicated by an increased sAPPα/sAPPβ ratio after IGF-I treatment. Since serum IGF-I enters into the brain in an activity-dependent manner, we analyzed in overweight mice the effect of brain activation by environmental enrichment (EE) on brain IGF-IR phosphorylation and its association to APP, as a readout of IGF-I activity. After EE, significantly reduced brain IGF-IR phosphorylation and APP/IGF-IR association were found in overweight mice as compared to lean controls. Collectively, these results indicate that a high-fat diet influences peripheral clearance of Aβ without affecting brain Aβ load. Increased serum IGF-I likely contributes to enhanced peripheral Aβ clearance in overweight mice, without affecting brain Aβ load probably because its brain entrance is reduced.}, }
@article {pmid33348472, year = {2021}, author = {Yang, P and Knight, WC and Li, H and Guo, Y and Perlmutter, JS and Benzinger, TLS and Morris, JC and Xu, J}, title = {Dopamine D1 + D3 receptor density may correlate with parkinson disease clinical features.}, journal = {Annals of clinical and translational neurology}, volume = {8}, number = {1}, pages = {224-237}, pmid = {33348472}, issn = {2328-9503}, support = {P30 AG066444/AG/NIA NIH HHS/United States ; R01 AG052550/GF/NIH HHS/United States ; R01 NS092865/GF/NIH HHS/United States ; R03 AG070474/AG/NIA NIH HHS/United States ; R01 NS092865/NS/NINDS NIH HHS/United States ; R03 NS090214/NS/NINDS NIH HHS/United States ; P50 AG06644/GF/NIH HHS/United States ; }, abstract = {OBJECTIVE: Dopamine D2-like receptors - mainly dopamine D2 receptors (D2R) and dopamine D3 receptors (D3R) - are believed to be greatly involved in the pathology of Parkinson disease (PD) progression. However, these receptors have not been precisely examined in PD patients. Our aim was to quantitatively calculate the exact densities of dopamine D1 receptors (D1R), D2R, and D3R in control, Alzheimer disease (AD), and Lewy body disease (LBD) patients (including PD, Dementia with Lewy bodies, and Parkinson disease dementia); and analyze the relationship between dopamine receptors and clinical PD manifestations.
METHODS: We analyzed the densities of D1R, D2R, and D3R in the striatum and substantia nigra (SN) using a novel quantitative autoradiography procedure previously developed by our group. We also examined the expression of D2R and D3R mRNA in the striatum by in situ hybridization.
RESULTS: The results showed that although no differences of striatal D1R were found among all groups; D2R was significantly decreased in the striatum of PD patients when compared with control and AD patients. Some clinical manifestations: age of onset, PD stage, dopamine responsiveness, and survival time after onset; showed a better correlation with striatal D1R + D3R densities combined compared to D1R or D3R alone.
INTERPRETATION: There is a possibility that we may infer the results in diagnosis, treatment, and prognosis of PD by detecting D1R + D3R as opposed to using dopamine D1 or D3 receptors alone. This is especially true for elderly patients with low D2R expression as is common in this disease.}, }
@article {pmid33344795, year = {2020}, author = {Olawande, TI and Ajayi, MP and Amoo, EO and Olawole-Isaac, A}, title = {Treatment pathways of Alzheimer in Nigeria.}, journal = {Heliyon}, volume = {6}, number = {12}, pages = {e05724}, pmid = {33344795}, issn = {2405-8440}, abstract = {Alzheimer poses lots of challenges in Low and Middle Income Countries, especially in Nigeria. Globally, the causes of Alzheimer are poorly understood. Cultural factors affect the preference of mental health treatment for treating people living with Alzheimer's disease (PLWA However, Alzheimer's and its gender differentials have been given little consideration in particular. Twenty-four in-depth study was conducted with caregivers and family members/relatives of people living with Alzheimer's (PLWA) residing in the study area. 52.2 percent of respondents were female out of the total while 45.8 percent were male. For male respondents, 40.4%; 49.4 %; 49.2%; 35 % and 28.3% indicated spiritual preference of mental health counseling; traditional; medical practitioner; both traditional and spiritual and psychiatrist respectively. On the other hand, 59.6%; 50.6%; 50.8%; 65% and 70.7% of female respondents indicated spiritual; traditional; medical practitioner; both traditional and spiritual and psychiatrist respectively. This research found that gender disparities primarily affected the mental health intervention care pathways. The availability of mental health resources to support adult mental health were key factors which could influence mental health status.}, }
@article {pmid33344098, year = {2020}, author = {Nienałtowski, T and Krzesiński, P and Baumert, ME and Skoczeń, A and Suska-Kauf, E and Pawłowska, J and Kajetanowicz, A and Grela, K}, title = {4-Methyltetrahydropyran as a Convenient Alternative Solvent for Olefin Metathesis Reaction: Model Studies and Medicinal Chemistry Applications.}, journal = {ACS sustainable chemistry & engineering}, volume = {8}, number = {49}, pages = {18215-18223}, pmid = {33344098}, issn = {2168-0485}, abstract = {A number of metathesis reactions were successfully conducted in 4-methyltetrahydropyran, including both standard model dienes, as well as more complex substrates, such as analogues of biologically active compounds and active pharmaceutical ingredients. To place this solvent in a context of pharmaceutical R + D, larger-scale syntheses of SUAM 1221, a prolyl endopeptidase inhibitor with potential application in Alzheimer disease treatment, and a derivative of sildenafil, an analogue of the popular Viagra drug, were executed. In the latter case, despite all the setup being made in air, the metathesis reaction at a 33 g scale proceeded very well with relatively low catalyst loading and without need of aqueous workup or column chromatography.}, }
@article {pmid33337622, year = {2021}, author = {Zhang, J and Cheng, J and Yang, H}, title = {Effects of Rivastigmine on Brain Functional Networks in Patients With Alzheimer Disease Based on the Graph Theory.}, journal = {Clinical neuropharmacology}, volume = {44}, number = {1}, pages = {9-16}, pmid = {33337622}, issn = {1537-162X}, abstract = {OBJECTIVE: The aim of this study was to explore the effect of rivastigmine on brain function in Alzheimer disease (AD) by analyzing brain functional network based on the graph theory.
METHODS: We enrolled 9 patients with mild to moderate AD who received rivastigmine treatment and 9 healthy controls (HC). Subsequently, we used resting-state functional magnetic resonance imaging data to establish the whole-brain functional network using a graph theory-based analysis. Furthermore, we compared systemic and local network indicators between pre- and posttreatment.
RESULTS: Patients with AD exhibited a posttreatment increase in the Mini-Mental State Examination scores and a decrease in the Alzheimer's Disease Assessment Scale cognitive subscale scores and activities of daily living. The systemic network for HC and patients with AD had good pre- and posttreatment clustering coefficients. There was no change in the Cp, Lp, Gamma, Lambda, and Sigma in patients with AD. There were no significant between-group differences in the pre- and posttreatment systemic network measures. Regarding the regional network, patients with AD showed increased betweenness centrality in the bilateral caudate nucleus and right superior temporal pole after treatment with rivastigmine. However, there was no between-group difference in the pre- and posttreatment betweenness centrality of these regions. There were no significant correlations between regional network measure changes and clinical score alterations in patients with AD.
CONCLUSIONS: There are similar systemic network properties between patients with AD and HC. Rivastigmine cannot alter systemic network attributes in patients with AD. However, it improves the topological properties of regional networks and between-node information transmission in patients with AD.}, }
@article {pmid33336229, year = {2021}, author = {Bouftas, M}, title = {A Systematic Review on the Feasibility of Salivary Biomarkers for Alzheimer's Disease.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {8}, number = {1}, pages = {84-91}, doi = {10.14283/jpad.2020.57}, pmid = {33336229}, issn = {2426-0266}, abstract = {Early AD diagnosis is critical for ameliorating prognosis and treatment. The analysis of CSF biomarkers yields accurate results, but it necessitates a lumbar puncture procedure. Screening for peripheral biomarkers in saliva is advantageous since this medium is noninvasive and inexpensive to obtain. The objective of this systematic review is to analyze saliva biomarker studies which aim to diagnose AD. Titles, abstracts, and reference lists for publications from January 2004 to February 2020 were screened for by searching Google Scholar and PubMed. The inclusion criteria involved published studies that consisted of both AD and control groups. 88 studies were screened, and 20 publications fulfilled the inclusion criteria. These selected publications were scrutinized and included in this review. Aβ42, tau, certain metabolites, and oral microbiota might serve as reliable biomarkers for AD diagnosis. These results showcase the legitimate feasibility of proteomic, metabolomic, and microbiotic compounds in saliva for AD diagnostics in the near future. Supplemental studies must consider standardizing the analytical methods of measuring salivary biomarkers to establish coherence for the selection of valid AD biomarkers. Validation studies will require a large sample size of biomarker-diagnosed individuals for independent populations. This ensures accuracy and rigidity for receiver operating characteristic (ROC) curves that can be set for the most optimal salivary biomarkers in future clinical settings.}, }
@article {pmid33328962, year = {2020}, author = {Yin, Z and Wang, X and Zheng, S and Cao, P and Chen, Y and Yu, M and Liao, C and Zhang, Z and Han, J and Duan, Y and Yang, X and Zhang, S}, title = {LongShengZhi Capsule Attenuates Alzheimer-Like Pathology in APP/PS1 Double Transgenic Mice by Reducing Neuronal Oxidative Stress and Inflammation.}, journal = {Frontiers in aging neuroscience}, volume = {12}, number = {}, pages = {582455}, pmid = {33328962}, issn = {1663-4365}, abstract = {Alzheimer's disease (AD) is the most common form of dementia in the elderly. It may be caused by oxidative stress, inflammation, and cerebrovascular dysfunctions in the brain. LongShengZhi Capsule (LSZ), a traditional Chinese medicine, has been approved by the China Food and Drug Administration for treatment of patients with cardiovascular/cerebrovascular disease. LSZ contains several neuroprotective ingredients, including Hirudo, Astmgali Radix, Carthami Flos (Honghua), Persicae Semen (Taoren), Acori Tatarinowii Rhizoma (Shichangpu), and Acanthopanax Senticosus (Ciwujia). In this study, we aimed to determine the effect of LSZ on the AD process. Double transgenic mice expressing the amyloid-β precursor protein and mutant human presenilin 1 (APP/PS1) to model AD were treated with LSZ for 7 months starting at 2 months of age. LSZ significantly improved the cognition of the mice without adverse effects, indicating its high degree of safety and efficacy after a long-term treatment. LSZ reduced AD biomarker Aβ plaque accumulation by inhibiting β-secretase and γ-secretase gene expression. LSZ also reduced p-Tau expression, cell death, and inflammation in the brain. Consistently, in vitro, LSZ ethanol extract enhanced neuronal viability by reducing L-glutamic acid-induced oxidative stress and inflammation in HT-22 cells. LSZ exerted antioxidative effects by enhancing superoxide dismutase and glutathione peroxidase expression, reduced Aβ accumulation by inhibiting β-secretase and γ-secretase mRNA expression, and decreased p-Tau level by inhibiting NF-κB-mediated inflammation. It also demonstrated neuroprotective effects by regulating the Fas cell surface death receptor/B-cell lymphoma 2/p53 pathway. Taken together, our study demonstrates the antioxidative stress, anti-inflammatory, and neuroprotective effects of LSZ in the AD-like pathological process and suggests it could be a potential medicine for AD treatment.}, }
@article {pmid33327914, year = {2020}, author = {Zhao, Y and Long, Z and Liu, Y and Luo, M and Qiu, Y and Idris, NFB and Song, A and Wang, K and He, G}, title = {Dihydroartemisinin Ameliorates Decreased Neuroplasticity-Associated Proteins and Excessive Neuronal Apoptosis in APP/PS1 Mice.}, journal = {Current Alzheimer research}, volume = {17}, number = {10}, pages = {916-925}, doi = {10.2174/1567205017666201215124746}, pmid = {33327914}, issn = {1875-5828}, abstract = {BACKGROUND: Alzheimer's disease (AD) is one of the worst neurodegenerative disorders worldwide, with extracellular senile plaques (SP), subsequent intracellular neurofibrillary tangles (NFTs) and final neuron loss and synaptic dysfunction as the main pathological characteristics. Excessive apoptosis is the main cause of irreversible neuron loss. Thus, therapeutic intervention for these pathological features has been considered a promising strategy to treat or prevent AD. Dihydroartemisin (DHA) is a widely used first-line drug for malaria. Our previous study showed that DHA treatment significantly accelerated Aβ clearance, improved memory and cognitive deficits in vivo and restored autophagic flux both in vivo and in vitro.
METHODS: The present study intended to explore the neuroprotective effect of DHA on neuron loss in APP/PS1 double-transgenic mice and the underlying mechanisms involved. Transmission electron microscope (TEM) analysis showed that DHA significantly reduced the swollen endoplasmic reticulum (ER) in APP/PS1 mice. Western blot analysis indicated that DHA upregulated the level of NeuN, NeuroD, MAP2, and synaptophysin and promoted neurite outgrowth. Meanwhile, DHA greatly corrected the abnormal levels of Brain-derived neurotrophic factor (BDNF) and rescued the neuronal loss in the hippocampal CA1 area. Western blot analysis revealed that DHA notably down-regulated the protein expression of full length caspase-3, cleaved caspase-3 and Bax. In parallel, the expression of the anti-apoptotic protein Bcl-2 increased after oral DHA treatment.
RESULTS: Altogether, these results indicate that DHA protected AD mice from neuron loss via promoting the expression of BDNF and other neuroplasticity-associated proteins and suppressing the inhibition of neuronal apoptosis.}, }
@article {pmid33327909, year = {2021}, author = {Harakeh, S and Qari, MH and Ramadan, WS and Al Jaouni, SK and Almuhayawi, MS and Al Amri, T and Ashraf, GM and Bharali, DJ and Mousa, SA}, title = {A Novel Nanoformulation of Ellagic Acid is Promising in Restoring Oxidative Homeostasis in Rat Brains with Alzheimer's Disease.}, journal = {Current drug metabolism}, volume = {22}, number = {4}, pages = {299-307}, doi = {10.2174/1389200221666201216170851}, pmid = {33327909}, issn = {1875-5453}, support = {G: 1574-140-1440//King Abdulaziz University/ ; }, abstract = {BACKGROUND: Aluminum toxicity induces neurodegenerative changes in the brain and results in Alzheimer's disease (AD).
OBJECTIVE: Here, the aim was to evaluate the antioxidant therapeutic effects of ellagic acid (EA) and EA-loaded nanoparticles (EA-NP) in an aluminum chloride-induced AD rat model.
METHODS: The nanoparticles' loading of EA was 0.84/1 w/w. The in vitro release kinetics of EA from EA-NP in fetal bovine serum showed 60% release in the first 1-5 hours, followed by sustained release at 60-70% over 6-24 hours. Six groups were implemented; group 1 served as the control, group 2 received EA, group 3 received EA-NP, group 4 was the AD rat model administered AlCl3 (50 mg/kg) for 4 weeks, groups 5 (AD+EA) and 6 (AD+EA-NP) were treated with EA and EA-NP, respectively, for 2 weeks after AlCl3 was stopped. The neurotoxicity in the rat brain was examined by measuring the brain antioxidant biomarkers catalase, glutathione, and total antioxidant activity and lipid peroxidation (thiobarbituric acid, TBA). Histopathological studies using hematoxylin and eosin, cresyl violet, silver stains, and the novel object recognition test were examined.
RESULTS: Data revealed significant increase of antioxidant biomarkers and decreased TBA in the EA-NP group. The pathological hallmarks of AD-vacuolation of the neurons, chromatolysis, neurofibrillary tangles, and the senile plaques in brains of the AD rat model were decreased and restoration of Nissl granules was noted. The calculated discrimination index in the behavioral test increased more in cases treated with EA-NP.
CONCLUSION: The treatment of AD with EA-NP was more effective than EA in alleviating the oxidative neurotoxic effects on AD rat brains.}, }
@article {pmid33322478, year = {2020}, author = {Park, JH and Whang, WK}, title = {Bioassay-Guided Isolation of Anti-Alzheimer Active Components from the Aerial Parts of Hedyotis diffusa and Simultaneous Analysis for Marker Compounds.}, journal = {Molecules (Basel, Switzerland)}, volume = {25}, number = {24}, pages = {}, pmid = {33322478}, issn = {1420-3049}, abstract = {Previous studies have reported that Hedyotis diffusa Willdenow extract shows various biological activities on cerebropathia, such as neuroprotection and short-term memory enhancement. However, there has been a lack of studies on the inhibitory activity on neurodegenerative diseases such as Alzheimer's disease (AD) through enzyme assays of H. diffusa. Therefore, H. diffusa extract and fractions were evaluated for their inhibitory effects through assays of enzymes related to AD, including acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), and β-site amyloid precursor protein cleaving enzyme 1 (BACE1), and on the formation of advanced glycation end-product (AGE). In this study, ten bioactive compounds, including nine iridoid glycosides 1-9 and one flavonol glycoside 10, were isolated from the ethyl acetate and n-butanol fractions of H. diffusa using a bioassay-guided approach. Compound 10 was the strongest inhibitor of cholinesterase, BACE1, and the formation of AGEs of all isolated compounds, while compound 5 had the lowest inhibitory activity. Compounds 3, 6, and 9 exhibited better inhibitory activity than other compounds on AChE, and two pairs of diastereomeric iridoid glycoside structures (compounds 4, 8, and 6, 7) showed higher inhibitory activity than others on BChE. In the BACE1 inhibitory assay, compounds 1-3 were good inhibitors, and compound 10 showed higher inhibitory activity than quercetin, the positive control. Moreover, compounds 1 and 3 were stronger inhibitors of the formation of AGE than aminoguanidine (AMG), the positive control. In conclusion, this study is significant since it demonstrated that the potential inhibitory activity of H. diffusa on enzymes related to AD and showed the potential use for further study as a natural medicine for AD treatment on the basis of the bioactive components isolated from H. diffusa.}, }
@article {pmid33321871, year = {2020}, author = {Morris, R and Armbruster, K and Silva, J and Widell, DJ and Cheng, F}, title = {The Association between the Usage of Non-Steroidal Anti-Inflammatory Drugs and Cognitive Status: Analysis of Longitudinal and Cross-Sectional Studies from the Global Alzheimer's Association Interactive Network and Transcriptomic Data.}, journal = {Brain sciences}, volume = {10}, number = {12}, pages = {}, pmid = {33321871}, issn = {2076-3425}, support = {R03 AG070536/AG/NIA NIH HHS/United States ; 1R03AG070536-01/AG/NIA NIH HHS/United States ; GEENA-Q/ALZ/Alzheimer's Association/United States ; }, abstract = {The degenerative cognitive and physical decline of Alzheimer patients, coupled with the extensive psychological and economic tolls imposed on family members that serve as caretakers, necessitate the discovery of effective cures and preventative measures for age-related cognitive depreciation. In the journey of Alzheimer's disease treatment discovery, several cross-sectional and longitudinal studies have delineated a noticeable association between the use of nonsteroidal anti-inflammatory drugs (NSAIDs), a class of low-cost drugs with minimal side effects, and the alleviation of age-related memory impairment. In this study, four datasets (two cross-sectional and two longitudinal studies) derived from the Global Alzheimer's Association Interactive Network (GAAIN) were analyzed. The significant association between the usage of NSAIDs and better cognitive status was observed. The results agree with the findings of previous studies that the use of NSAIDs may be beneficial in the early stages of Alzheimer's disease. Transcriptomic data show that ibuprofen treatment results in upregulation of several genes involved in arachidonic acid metabolism including PPARγ, Cyp4a12b, Cyp2c66, and Cyp2c37 in the hippocampus. The increase in conversion of arachidonic acid into anti-inflammatory 16C and 18C dicarboxylic acids as well as epoxyeicosatrienoic acids may play a role in reducing the risk of Alzheimer's disease development.}, }
@article {pmid33307058, year = {2021}, author = {Zhao, L and Duan, Z and Wang, Y and Wang, M and Liu, Y and Wang, X and Li, H}, title = {Protective effect of Terminalia chebula Retz. extract against Aβ aggregation and Aβ-induced toxicity in Caenorhabditis elegans.}, journal = {Journal of ethnopharmacology}, volume = {268}, number = {}, pages = {113640}, doi = {10.1016/j.jep.2020.113640}, pmid = {33307058}, issn = {1872-7573}, mesh = {Amyloid beta-Peptides/antagonists & inhibitors/*toxicity ; Animals ; Animals, Genetically Modified ; Caenorhabditis elegans ; Dose-Response Relationship, Drug ; Humans ; Peptide Fragments/antagonists & inhibitors/*toxicity ; Plant Extracts/isolation & purification/pharmacology/*therapeutic use ; Protein Aggregation, Pathological/*chemically induced/pathology/*prevention & control ; *Terminalia ; }, abstract = {Terminalia chebula Retz. (T.chebula) is an important medicinal plant in Tibetan medicine and Ayurveda. T.chebula is known as the "King of Tibetan Medicine", due to its widespread clinical pharmacological activity such as anti-inflammatory, antioxidative, antidiabetic as well as anticancer in lots of in vivo and in vitro models. In this study, we use transgenic and/or RNAi Caenorhabditis elegans (C.elegans) model to simulation the AD pathological features induced by Aβ, to detect the effect of TWE on improving Aβ-induced toxicity and the corresponding molecular mechanism.
AIM OF STUDY: The study aimed to tested the activities and its possible mechanism of T.chebula to against Aβ1-42 induced toxicity and Aβ1-42 aggregation.
MATERIALS AND METHODS: Using transgenic C.elegans strain CL2006 and CL4176 as models respond to paralytic induced by Aβ toxicity. The transcription factors DAF-16 and SKN-1 were analyzed used a fluorescence microscope in transgenic strains (DAF-16:GFP, SKN-1:GFP). The function of DAF-16 and SKN-1 was further investigated using loss-of-function strains by feeding RNA interference (RNAi) bacteria. To evaluate the aggregation level of Aβ in the transgenic C.elegans, Thioflavin S (ThS) staining and WB visualized the levels of Aβ monomers and oligomers.
RESULTS: TWE treatment can significantly improve the paralysis of transgenic C.elegans caused by Aβ aggregation (up to 14%). The Aβ aggregates in transgenic C.elegans are significantly inhibited under TWE exposure (up to 70%). TWE increases the nuclear localization of the key transcription factor DAF-16 and HSF-1, which in turn leads to the expression of downstream Hsp-16.2 protein and exerts its inhibitory effect on Aβ aggregation. Meanwhile, paralysis improved has not observed in SKN-1 mutation and/or RNAi C.elegans.
CONCLUSION: Our results indicate that TWE can protect C.elegans against the Aβ1-42-induced toxicity, inhibition Aβ1-42 aggregation and delaying Aβ-induced paralysis. The neuroprotective effect of TWE involves the activation of DAF-16/HSF-1/Hsp-16.2 pathway.}, }
@article {pmid33307050, year = {2021}, author = {Sharma, A and Cooper, R and Bhardwaj, G and Cannoo, DS}, title = {The genus Nepeta: Traditional uses, phytochemicals and pharmacological properties.}, journal = {Journal of ethnopharmacology}, volume = {268}, number = {}, pages = {113679}, doi = {10.1016/j.jep.2020.113679}, pmid = {33307050}, issn = {1872-7573}, mesh = {Analgesics/isolation & purification/pharmacology/therapeutic use ; Animals ; Anti-Infective Agents/isolation & purification/pharmacology/therapeutic use ; Ethnopharmacology/*methods ; Humans ; Medicine, Traditional/*methods ; *Nepeta ; Phytochemicals/isolation & purification/pharmacology/*therapeutic use ; Plant Extracts/isolation & purification/pharmacology/*therapeutic use ; }, abstract = {Nepeta is a multiregional genus of the "Lamiaceae" (Labiatae or Mint) family. Species of Nepeta are a valuable part of traditional medicine and used extensively, particularly in the Himalayan region of India (Uttarakhand, Himachal Pradesh, Jammu and Kashmir, Leh-Ladakh), Pakistan (Khyber Pakhtunkhwaand Pakistani Kashmir), Nepal (Baglund district), also in China and hilly regions of Turkey and Iran. Nepeta species are extensively used as a remedy against a variety of ailments and conditions like chicken pox, tuberculosis, malaria, pneumonia, influenza, measles, stomach disorders, eye complaints, respiratory disorders, asthma, colds, coughs etc. AIM OF THE REVIEW: The main aim of this review is to present a comprehensive and detailed study on traditional uses, pharmacology, phytochemistry, toxicology of Nepeta species and suggest future direction on the design and conduct of various preparations, either alone or in blends with prevailing conventional remedies. The review also emphasizes encouraging researchers towards the wide range of pharmaceutical applications of the various species of Nepeta for their better use and exploration in the future.
MATERIAL AND METHODS: All the relevant data and information on different species of Nepeta were assembled using different databases, such as Science Direct, Springer, PubMed, Taylor and Francis imprints, Chemspider, Google scholar, review and research articles from peer-reviewed journals and unpublished data. Some select 'grey literature' sources viz. ethnobotanical books, chapters, Wikipedia and webpages were also studied.
RESULTS: A variety of bioactive secondary metabolites and nutraceuticals has been isolated from various species of Nepeta. These bioactive compounds belong to different classes of secondary metabolites, such as phenolic acids and their glycosides (rosmarinic acid, gallic acid, caffeic acid), flavonoids and their glycosides (cirsimaritin, salvigenin, luteolin, apigenin), iridoids (nepetalactones and their derivatives), terpenoids (1,8-cineole, linalool, β-caryophyllene, germacrene D, parnapimaro, β-amyrin, oleanolic acid, ursolic acid), steroids (β-sitosterol, stigmasterol), lignans, amino acids, carbohydrates, volatile oils, etc. The species of the genus Nepeta possess a variety of pharmacological activities namely anti-inflammatory, anti-nociceptive, anti-alzheimer, anticancer and cytotoxic, antioxidant, immunomodulatory, antimicrobial, antifungal, insecticidal and along with other biological activities.
CONCLUSION: The species of the genus Nepeta contains a rich source of various bioactive compounds, which are well tolerated as traditional medicines. In fact, different species of Nepeta are widely used in a variety of traditional medicinal systems all around the world. Owing to the variety of pharmacological properties of Nepeta species, more comprehensive and inclusive clinical trials are necessary for the utilization of different Nepeta species against the treatment of a wide range of ailments. There are also various other uses such as food, cosmetic and agriculture that can be investigated or explored in future. Some of the major domains that can be explored within this genus are the investigation of different species for their unexplored biological potential, isolation and characterization of new bioactive constituents and finally, investigation of new applications and possible commercialization of these bioactive leads. No doubt, there are various viable research domains outside those discussed above, but presently for the purposes of this review we will only emphasize the activities herein.}, }
@article {pmid33290257, year = {2020}, author = {Liu, X and Li, Y and Wang, M and Wang, X and Zhang, L and Peng, T and Liang, W and Wang, Z and Lu, H}, title = {The 1316T>C missenses mutation in MTHFR contributes to MTHFR deficiency by targeting MTHFR to proteasome degradation.}, journal = {Aging}, volume = {13}, number = {1}, pages = {1176-1185}, pmid = {33290257}, issn = {1945-4589}, mesh = {Adolescent ; Alleles ; Ataxia/physiopathology ; Baclofen/therapeutic use ; Brain/diagnostic imaging ; Cognitive Dysfunction/physiopathology ; Female ; Folic Acid/analogs & derivatives/therapeutic use ; Homocystinuria/diagnosis/drug therapy/*genetics/physiopathology ; Humans ; Magnetic Resonance Imaging ; Methionine/therapeutic use ; Methylenetetrahydrofolate Reductase (NADPH2)/*deficiency/genetics/metabolism ; Muscle Hypertonia/drug therapy/physiopathology ; Muscle Relaxants, Central/therapeutic use ; Muscle Spasticity/diagnosis/drug therapy/*genetics/physiopathology ; Mutation, Missense ; Neural Conduction ; Polymorphism, Single Nucleotide ; Proteasome Endopeptidase Complex ; Proteolysis ; Psychotic Disorders/diagnosis/drug therapy/genetics/physiopathology ; Reflex, Abnormal/physiology ; Spine/diagnostic imaging ; Vitamin B 12/therapeutic use ; Vitamin B Complex/therapeutic use ; }, abstract = {5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare hereditary disease characterized by defects in folate and homocysteine metabolism. Individuals with inherited MTHFR gene mutations have a higher tendency to develop neurodegeneration disease as Alzheimer' disease and atherosclerosis. MTHFR is a rate-limiting enzyme catalyzing folate production, various SNPs/mutations in the MTHFR gene have been correlated to MTHFR deficiency. However, the molecular mechanisms underpinning the pathogenic effects of these SNPs/mutations have not been clearly understood. In the present study, we reported a severe MTHFR deficiency patient with late-onset motor dysfunction and sequenced MTHFR gene exons of the family. The patient carries an MD-associating SNP (rs748289202) in one MTHFR allele and the rs545086633 SNP with unknown disease relevance in the other. The rs545086633 SNP (p.Leu439Pro) results in an L439P substitution in MTHFR protein, and drastically decreases mutant protein expression by promoting proteasomal degradation. L439 in MTHFR is highly conserved in vertebrates. Our study demonstrated that p.Leu439Pro in MTHFR is the first mutation causing significant intracellular defects of MTHFR, and rs545086633 should be examined for the in-depth diagnosis and treatment of MD.}, }
@article {pmid33289486, year = {2020}, author = {Gourdon, M and Petit, L and Delpierre, S and Sebbagh-Eczet, M and Estrada, J and Marquis, C and Raynaud-Simon, A and Bonnet-Zamponi, D}, title = {[Overuse of antidepressant in older outpatients with Alzheimer disease and associated disorders: an observational study].}, journal = {Geriatrie et psychologie neuropsychiatrie du vieillissement}, volume = {18}, number = {4}, pages = {395-404}, doi = {10.1684/pnv.2020.0850}, pmid = {33289486}, issn = {2115-7863}, mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/*complications ; Ambulatory Care ; Antidepressive Agents/*therapeutic use ; Cross-Sectional Studies ; Depressive Disorder, Major/*drug therapy/*etiology ; Female ; Humans ; Male ; Prescription Drug Overuse/*statistics & numerical data ; Prospective Studies ; }, abstract = {Forty per cent of French subjects over 65 years old with Alzheimer's disease and related disorders (MATA) are chronically exposed to antidepressants suggesting an overuse of these drugs. The main objective of our study was to estimate the prevalence and factors associated with overuse by antidepressants in this population.
METHODOLOGY: Single-center, prospective, cross-sectional study carried out at the Bretonneau Day Hospital (HDJ) between December, 1st 2014 and May, 31 2015. Consecutive patients with ≥70 years of age, suffering from MATA (according to DSM IV criteria) and current prescription of antidepressant were eligible. Overuse was defined by off-label prescriptions or prescriptions beyond the recommended duration of treatment. It was assessed by the geritrician in charge and validated by an expert committee, blind from the geriatrician's assessment.
RESULTS: Fifty-four patients were included in the study (mean age 82.9 years (+/- 5.4), 70.4% of women, 60% with mild to moderate dementia). The main indication of antidepressant treatment was a major depressive episode (59.3%). The geriatrician could not deal with overuse for 10 cases (18.5%). Inter-rater agreement between geriatricians and expert committee was good (kappa coefficient 0.73 [0.5-0.95]). Finally 33 (61%) of these patients had overuse of antidepressants: 1/3 had an off-label prescription and 2/3 had an exceeded treatment duration. The only factor associated with this overuse was coprescription of psychotropic drugs (p=0.009).
CONCLUSIONS: Antidepressant overuse is common in demented older outpatients, especially overuse due to exceeded treatment duration. It is significantly associated with coprescription with another psychotropic drug, suggesting that it fits into a more global problem of overuse in psychotropic drugs.}, }
@article {pmid33283163, year = {2020}, author = {Pradeep, S and Jain, AS and Dharmashekara, C and Prasad, SK and Kollur, SP and Syed, A and Shivamallu, C}, title = {Alzheimer's Disease and Herbal Combination Therapy: A Comprehensive Review.}, journal = {Journal of Alzheimer's disease reports}, volume = {4}, number = {1}, pages = {417-429}, pmid = {33283163}, issn = {2542-4823}, abstract = {Alzheimer's disease (AD) was first described in 1907 and got its name after Alois Alzheimer, a German psychiatrist and neuropathologist. This disease starts slow, increasing gradually to worsen in the due course of time. AD is mainly characterized by the associated dementia, which is a decline of cognitive effects such as memory, praxis, and orientation. The dementia is further highlighted by the presence of psychological and behavioral symptoms. Additionally, AD is also associated with the multiple interconnected pathways linked neuropathological changes such as the formation of neurofibrillary tangles and amyloid-β plaques inside the brain. AD therapeutics have been of prime concern over the decades, resulting in the elucidation of promising therapeutic targets. The requirement of AD stage dependent optimized conditions has necessitated a combinatorial approach toward treatment. The priority in AD research has remained to develop disease-modifying and development-reducing drugs for treatment regimens followed during the early and later stages, respectively.}, }
@article {pmid33277912, year = {2020}, author = {Leyhe, T and Jucker, M and Nef, T and Sollberger, M and Riese, F and Haba-Rubio, J and Verloo, H and Lüthi, R and Becker, S and Popp, J}, title = {Conference report: dementia research and care and its impact in Switzerland.}, journal = {Swiss medical weekly}, volume = {150}, number = {}, pages = {w20376}, doi = {10.4414/smw.2020.20376}, pmid = {33277912}, issn = {1424-3997}, mesh = {*Alzheimer Disease ; Animals ; *Dementia ; Humans ; Longitudinal Studies ; Mice ; Quality of Life ; Switzerland ; }, abstract = {In October 2019, a Swiss panel of experts met for the Dementia Summit in Brunnen, Switzerland, to discuss the latest scientific findings on basic and clinical research, as well as practical and political approaches to the challenges of dementia disorders in Switzerland. Here, we present the conference summary. To study pathophysiological changes, as well as the underlying mechanism of fluid biomarker changes, excellent experimental approaches, including transgenic mouse models, are available. Current knowledge about presymptomatic disease progression is largely derived from the longitudinal study of individuals with autosomal dominant mutations (Dominantly Inherited Alzheimer Network). Importantly, more than one third of identified dementia risk factors can be modified. For example, sleep disturbances are not only associated with dementia and neurodegeneration in specific brain regions, but also precede cognitive decline and contribute to the development of brain pathology. Regarding the neuropsychological examination of dementia disorders, standardised tests of social cognition, one of the six cognitive domains that must be assessed according to the fifth edition of the Diagnostic and Statistical Manual for Mental Disorders, are missing, but now under development. The most important new therapeutic approach in the treatment of Alzheimer’s disease is the current attempt to prevent β-amyloid accumulation. While until now clinical studies have failed because of side effects or insufficient clinical effectiveness, Biogen recently announced positive results of high doses of aducanumab, a monoclonal antibody against β-amyloid. Other approaches also show promise. In China, sodium oligomannate has been approved to treat Alzheimer's disease. The substance suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression. Assistive technologies for dementia patients can help identify relevant information for care and nursing, as well as measurements for clinical interventions. Dementia patients have a high risk of developing delirium, even in the home environment. Therefore, it is necessary to use and further develop multi-disciplinary and systematic detection and prevention strategies. Homecare models for dementia patients with multidisciplinary teams have been established and evaluated and should be expanded. Dementia is the third-leading cause of death in Switzerland. In palliative care for severe dementia, the improvement of quality of life is of primary importance. The goals of the National Dementia Strategy, to increase the quality of life in those affected and to reduce taboos surrounding the disease, are still unrealised. The need for further national and regional engagement in order to implement the different findings of the strategy has largely been acknowledged, and these implementations have become the core tasks of a national dementia platform.}, }
@article {pmid33270870, year = {2021}, author = {Wegiel, J and Flory, M and Kuchna, I and Nowicki, K and Ma, SY and Wegiel, J and Badmaev, E and Leon, M and Wisniewski, T and Reisberg, B}, title = {Clinicopathological Staging of Dynamics of Neurodegeneration and Neuronal Loss in Alzheimer Disease.}, journal = {Journal of neuropathology and experimental neurology}, volume = {80}, number = {1}, pages = {21-44}, pmid = {33270870}, issn = {1554-6578}, support = {P30 AG066512/AG/NIA NIH HHS/United States ; }, mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/*pathology ; Brain/*pathology ; Cell Death ; Disease Progression ; Female ; Humans ; Male ; Nerve Degeneration/*pathology ; Neurofibrillary Tangles/*pathology ; Neurons/*pathology ; }, abstract = {Clinical and neuropathological staging of Alzheimer disease (AD) neurodegeneration and neuronal loss dynamics is the baseline for identification of treatment targets and timing. The aim of this study of 14 brain regions in 25 subjects diagnosed with AD and 13 age-matched control subjects was to establish the pattern of neurodegeneration, and the severity and rate of neuronal loss in mild cognitive impairment/mild AD (Functional Assessment Staging [FAST] test 3-4), moderate to moderately severe AD (FAST 5-6), and severe AD (FAST 7). The study revealed (1) the most severe neuronal loss in FAST 3-4; (2) the highest rate of neuronal loss in FAST 5-6, to the "critical" point limiting further increase in neuronal loss; (3) progression of neurofibrillary degeneration, but decline of neuronal loss to a floor level in FAST 7; and (4) structure-specific rate of neuronal loss caused by neurofibrillary degeneration and a large pool of neuronal loss caused by other mechanisms. This study defines a range and speed of progression of AD pathology and functional decline that might potentially be prevented by the arrest of neuronal loss, both related and unrelated to neurofibrillary degeneration, during the 9-year duration of mild cognitive impairment/mild AD.}, }
@article {pmid33269389, year = {2021}, author = {Liu, DD and Rivera-Lane, K and Leary, OP and Pertsch, NJ and Niu, T and Camara-Quintana, JQ and Oyelese, AA and Fridley, JS and Gokaslan, ZL}, title = {Supplementation of Screw-Rod C1-C2 Fixation With Posterior Arch Femoral Head Allograft Strut.}, journal = {Operative neurosurgery (Hagerstown, Md.)}, volume = {20}, number = {2}, pages = {226-231}, doi = {10.1093/ons/opaa336}, pmid = {33269389}, issn = {2332-4260}, mesh = {Allografts ; *Atlanto-Axial Joint/diagnostic imaging/surgery ; Bone Screws ; Cervical Vertebrae ; Dietary Supplements ; Femur Head ; Humans ; *Spinal Fusion ; }, abstract = {BACKGROUND: Numerous C1-C2 fixation techniques exist for the treatment of atlantoaxial instability. Limitations of screw-rod and sublaminar wiring techniques include C2 nerve root sacrifice and dural injury, respectively. We present a novel technique that utilizes a femoral head allograft cut with a keyhole that rests posteriorly on the arches of C1 and C2 and straddles the C2 spinous process, secured by sutures.
OBJECTIVE: To offer increased fusion across C1-C2 without the passage of sublaminar wiring or interarticular arthrodesis.
METHODS: A total of 6 patients with atlantoaxial instability underwent C1-C2 fixation using our method from 2015 to 2016. After placement of a C1-C2 screw/rod construct, a cadaveric frozen femoral head allograft was cut into a half-dome with a keyhole and placed over the already decorticated dorsal C1 arch and C2 spinous process. Notches were created in the graft and sutures were placed in the notches and around the rods to secure it firmly in place.
RESULTS: The femoral head's shape allowed for creation of a graft that provides excellent surface area for fusion across C1-C2. There were no intraoperative complications, including dural tears. Postoperatively, no patients had sensorimotor deficits, pain, or occipital neuralgia. 5 patients demonstrated clinical resolution of symptoms by 3 mo and radiographic (computed tomography) evidence of fusion at 1 yr. One patient had good follow-up at 1 mo but died due to complications of Alzheimer disease.
CONCLUSION: The posterior arch femoral head allograft strut technique with securing sutures is a viable option for supplementing screw-rod fixation in the treatment of complex atlantoaxial instability.}, }
@article {pmid33267804, year = {2020}, author = {Huang, CN and Wang, CJ and Lin, CL and Li, HH and Yen, AT and Peng, CH}, title = {Abelmoschus esculentus subfractions attenuate Aβ and tau by regulating DPP-4 and insulin resistance signals.}, journal = {BMC complementary medicine and therapies}, volume = {20}, number = {1}, pages = {370}, pmid = {33267804}, issn = {2662-7671}, support = {108-2320-B241-003//Ministry of Science and Technology/ ; 109-2320-B-040-021//Ministry of Science and Technology/ ; }, mesh = {Abelmoschus ; Alzheimer Disease/metabolism ; Amyloid beta-Peptides/*metabolism ; Cell Line ; Cell Survival/drug effects ; Dipeptidyl Peptidase 4/*metabolism ; Fruit ; Humans ; *Insulin Resistance ; Plant Extracts/*pharmacology ; Taiwan ; tau Proteins/*metabolism ; }, abstract = {BACKGROUND: Insulin resistance could be associated with the development of Alzheimer disease (AD). The neuropathological hallmarks of AD are beta amyloid (Aβ) produced from sequential cleavage initiated by β-secretase and degraded by insulin degradation enzyme (IDE), as well as hyperphosphorylation of tau (p-tau). Insulin action involves the cascades of insulin receptor substrates (IRS) and phosphatidylinositol 3-kinase (PI3K), while phosphorylation of IRS-1 at ser307 (p-ser307IRS-1) hinders the response. Our previous report suggested dipeptidyl peptidase-4 (DPP-4) is crucial to insulin resistance, and the subfractions of Abelmoschus esculentus (AE), F1 and F2, attenuate the signaling. Here we aim to investigate whether AE works to reduce Aβ generation via regulating DPP4 and insulin resistance.
METHODS: The subfractions F1 and F2 were prepared according to a succession of procedures. F1 was composed by quercetin glycosides and triterpene ester, and F2 contained a large amount of polysaccharides. The in vitro insulin resistance model was established by SK-N-MC cell line treated with palmitate. MTT was used to define the dose range, and thereby Western blot, ELISA, and the activity assay were used to detect the putative markers. One-way ANOVA was performed for the statistical analysis.
RESULTS: Treatment of palmitate induced the level of p-ser307IRS-1. Both F1 and F2 effectively decrease p-ser307IRS-1, and recover the expression of p-PI3K. However, the expression of total IRS plunged with 25 μg/mL of F1, while descended steadily with 5 μg/mL of F2. As palmitate increased the levels of Aβ40 and Aβ42, both AE subfractions were effective to reduce Aβ generation of and β-secretase activity, but IDE was not altered in any treatment conditions. The expression of DPP4 was also accompanied with insulin resistance signals. Inhibition of DPP4 attenuated the activity of β-secretase and production of Aβ. Moreover, the present data revealed that both AE subfractions significantly decrease the level of p-Tau.
CONCLUSIONS: In conclusion, we demonstrated that AE would be a potential adjuvant to prevent insulin resistance and the associated pathogenesis of AD, and F2 seems more feasible to be developed.}, }
@article {pmid33260532, year = {2020}, author = {Llano, DA and Issa, LK and Devanarayan, P and Devanarayan, V and Alzheimer's Disease Neuroimaging Initiative Adni, }, title = {Hearing Loss in Alzheimer's Disease Is Associated with Altered Serum Lipidomic Biomarker Profiles.}, journal = {Cells}, volume = {9}, number = {12}, pages = {}, pmid = {33260532}, issn = {2073-4409}, support = {U01 AG024904/AG/NIA NIH HHS/United States ; }, mesh = {Aged ; Aging/blood ; Alzheimer Disease/*blood ; Antioxidants/metabolism ; Biomarkers/*blood ; Female ; Hearing Loss/*blood ; Humans ; Lipidomics/methods ; Lipids/*blood ; Male ; Phosphatidylcholines/blood ; Phosphatidylethanolamines/blood ; }, abstract = {Recent data have found that aging-related hearing loss (ARHL) is associated with the development of Alzheimer's Disease (AD). However, the nature of the relationship between these two disorders is not clear. There are multiple potential factors that link ARHL and AD, and previous investigators have speculated that shared metabolic dysregulation may underlie the propensity to develop both disorders. Here, we investigate the distribution of serum lipidomic biomarkers in AD subjects with or without hearing loss in a publicly available dataset. Serum levels of 349 known lipids from 16 lipid classes were measured in 185 AD patients. Using previously defined co-regulated sets of lipids, both age- and sex-adjusted, we found that lipid sets enriched in phosphatidylcholine and phosphatidylethanolamine showed a strong inverse association with hearing loss. Examination of biochemical classes confirmed these relationships and revealed that serum phosphatidylcholine levels were significantly lower in AD subjects with hearing loss. A similar relationship was not found in normal subjects. These data suggest that a synergistic relationship may exist between AD, hearing loss and metabolic biomarkers, such that in the context of a pathological state such as AD, alterations in serum metabolic profiles are associated with hearing loss. These data also point to a potential role for phosphatidylcholine, a molecule with antioxidant properties, in the underlying pathophysiology of ARHL in the context of AD, which has implications for our understanding and potential treatment of both disorders.}, }
@article {pmid33252082, year = {2021}, author = {Soto-Mercado, V and Mendivil-Perez, M and Jimenez-Del-Rio, M and Velez-Pardo, C}, title = {Multi-Target Effects of the Cannabinoid CP55940 on Familial Alzheimer's Disease PSEN1 E280A Cholinergic-Like Neurons: Role of CB1 Receptor.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {82}, number = {s1}, pages = {S359-S378}, pmid = {33252082}, issn = {1875-8908}, abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by structural damage, death, and functional disruption of cholinergic neurons (ChNs) as a result of intracellular amyloid-β (Aβ) aggregation, extracellular neuritic plaques, and hyperphosphorylation of protein tau (p-Tau) overtime.
OBJECTIVE: To evaluate the effect of the synthetic cannabinoid CP55940 (CP) on PSEN1 E280A cholinergic-like nerve cells (PSEN1 ChLNs)-a natural model of familial AD.
METHODS: Wild type (WT) and PSEN1 ChLNs were exposed to CP (1μM) only or in the presence of the CB1 and CB2 receptors (CB1Rs, CB2Rs) inverse agonist SR141716 (1μM) and SR144528 (1μM) respectively, for 24 h. Untreated or treated neurons were assessed for biochemical and functional analysis.
RESULTS: CP in the presence of both inverse agonists (hereafter SR) almost completely inhibits the aggregation of intracellular sAβPPβf and p-Tau, increases ΔΨm, decreases oxidation of DJ-1Cys106-SH residue, and blocks the activation of c-Jun, p53, PUMA, and caspase-3 independently of CB1Rs signaling in mutant ChLNs. CP also inhibits the generation of reactive oxygen species partially dependent on CB1Rs. Although CP reduced extracellular Aβ42, it was unable to reverse the Ca2+ influx dysregulation as a response to acetylcholine stimuli in mutant ChLNs. Exposure to anti-Aβ antibody 6E10 (1:300) in the absence or presence of SR plus CP completely recovered transient [Ca2+]i signal as a response to acetylcholine in mutant ChLNs.
CONCLUSION: Taken together our findings suggest that the combination of cannabinoids, CB1Rs inverse agonists, and anti-Aβ antibodies might be a promising therapeutic approach for the treatment of familial AD.}, }
@article {pmid33250792, year = {2020}, author = {Owens, AP and Hinds, C and Manyakov, NV and Stavropoulos, TG and Lavelle, G and Gove, D and Diaz-Ponce, A and Aarsland, D}, title = {Selecting Remote Measurement Technologies to Optimize Assessment of Function in Early Alzheimer's Disease: A Case Study.}, journal = {Frontiers in psychiatry}, volume = {11}, number = {}, pages = {582207}, pmid = {33250792}, issn = {1664-0640}, abstract = {Despite the importance of function in early Alzheimer's disease (AD), current measures are outdated and insensitive. Moreover, COVID-19 has heighted the need for remote assessment in older people, who are at higher risk of being infection and are particularly advised to use social distancing measures, yet the importance of diagnosis and treatment of dementia remains unchanged. The emergence of remote measurement technologies (RMTs) allows for more precise and objective measures of function. However, RMT selection is a critical challenge. Therefore, this case study outlines the processes through which we identified relevant functional domains, engaged with stakeholder groups to understand participants' perspectives and worked with technical experts to select relevant RMTs to examine function. After an extensive literature review to select functional domains relevant to AD biomarkers, quality of life, rate of disease progression and loss of independence, functional domains were ranked and grouped by the empirical evidence for each. For all functional domains, we amalgamated feedback from a patient advisory board. The results were prioritized into: highly relevant, relevant, neutral, and less relevant. This prioritized list of functional domains was then passed onto a group of experts in the use of RMTs in clinical and epidemiological studies to complete the selection process, which consisted of: (i) identifying relevant functional domains and RMTs; (ii) synthesizing proposals into final RMT selection, and (iii) verifying the quality of these decisions. Highly relevant functional domains were, "difficulties at work," "spatial navigation and memory," and "planning skills and memory required for task completion." All functional domains were successfully allocated commercially available RMTs that make remote measurement of function feasible. This case study provides a set of prioritized functional domains sensitive to the early stages of AD and a set of RMTs capable of targeting them. RMTs have huge potential to transform the way we assess function in AD-monitoring for change and stability continuously within the home environment, rather than during infrequent clinic visits. Our decomposition of RMT and functional domain selection into identify, synthesize, and verify activities, provides a pragmatic structure with potential to be adapted for use in future RMT selection processes.}, }
@article {pmid33245927, year = {2021}, author = {Almalki, WH and Alzahrani, A and Mahmoud El-Daly, ME and Fadel Ahmed, AHF}, title = {The emerging potential of SIRT-3 in oxidative stress-inflammatory axis associated increased neuroinflammatory component for metabolically impaired neural cell.}, journal = {Chemico-biological interactions}, volume = {333}, number = {}, pages = {109328}, doi = {10.1016/j.cbi.2020.109328}, pmid = {33245927}, issn = {1872-7786}, mesh = {Animals ; Humans ; Inflammation/metabolism/pathology ; Neurodegenerative Diseases/*metabolism/*pathology ; Neurons/*metabolism/pathology ; *Oxidative Stress ; Sirtuin 3/*metabolism ; }, abstract = {People suffering from conditions like epilepsy, where there is an excess of neuron excitement, stroke, and cardiac arrest, where there are oxygen and glucose deprivation, Alzheimer, Parkinson, and Huntington's disease that causes metabolic and also oxidative stress-inflammatory axis; are known to be more vulnerable to disturbances in the metabolism, and there is a lot of inadequacy in defining the inflammation's mechanistic connections, as well as neurodegeneration and the bioenergetic deficiencies in the CNS. We retrieved relevant studies from PubMed/ScienceDirect/Medline/Public library of science/Mendeley/Springer link as well as Google Scholar. We used various keywords both individually and in combination with the literature search. 'Epidemiology of neurodegenerative disorders', 'neurodegenerative diseases associated hyper inflammation', 'Mechanism of inflammation in neuronal cell', 'Involvement of SIRTin inflammation', 'Pathogenesis of mitochondrial associated metabolic impairment in neurons', 'Reactive oxygen species-mediated mitochondrial dysfunction' were a few of the keywords used for the search. PINCH, which is a chronic neuro-inflammatory component that cannot be detected in matured neurons which are healthy, though expressed in oxidative stress inflammatory axis related tauopathy and diseases that cause neurodegeneration. We attempted to study the regulatory mechanisms that cause changes in the bioenergetics and its neuronal defects and mitochondrial subcellular localization that are PINCH protein-mediated on the other handSIRT1, the most intensively studied sirtuin, in oxidative stress-mediated inflammatory consequence for many diseases but very few research data explore the role of SIRT-3 for correction of the chronic neuroinflammatory component. Thus, in this review, we investigate the very recently identified molecules involving in the pathogenesis during stimulated oxidative stress-inflammatory axis in the excitatory neuronal cell which changes brain metabolism. Simultaneously, in CNS neurons of diseases with a component of chronic neuroinflammation which exhibit neuroprotective response, the consequences (mechanistic and biological) of SIRT-3, could be emerging future targets for neurodegenerative disorder treatment with impaired metabolisms.}, }
@article {pmid33245273, year = {2020}, author = {Villarejo-Galende, A and González-Sánchez, M and Blanco-Palmero, VA and Llamas-Velasco, S and Benito-León, J}, title = {Non-steroidal Anti-inflammatory Drugs as Candidates for the Prevention or Treatment of Alzheimer's Disease: Do they Still Have a Role?.}, journal = {Current Alzheimer research}, volume = {17}, number = {11}, pages = {1013-1022}, doi = {10.2174/1567205017666201127163018}, pmid = {33245273}, issn = {1875-5828}, support = {R01 NS039422/NS/NINDS NIH HHS/United States ; }, abstract = {PURPOSE OF REVIEW: To provide an updated analysis of the possible use of non-steroidal anti-inflammatory drugs (NSAIDs) as treatments for Alzheimer´s disease (AD).
RECENT FINDINGS: Neuroinflammation in AD is an active field of research, with increasing evidence from basic and clinical studies for an involvement of innate or adaptive immune responses in the pathophysiology of AD. Few clinical trials with anti-inflammatory drugs have been performed in the last decade, with negative results.
SUMMARY: Besides the information gathered from basic research, epidemiological studies have provided conflicting findings, with most case-control or prevalence studies suggesting an inverse relationship between NSAIDs use and AD, but divided results in prospective population-based incident cohort studies. Clinical trials with different NSAIDs are almost unanimous in reporting an absence of clear benefit in AD.
CONCLUSION: The modulation of inflammatory responses is a promising therapeutic strategy in AD. After three decades of research, it seems that conventional NSAIDs are not the best pharmacological option, both for their lack of clear effects and for an unfavorable side-effect profile in long-term treatment. The development of other anti-inflammatory drugs as candidate treatments in AD may benefit from the knowledge acquired with NSAIDs.}, }
@article {pmid33234100, year = {2020}, author = {Chauhan, PS and Yadav, D and Koul, B and Mohanta, YK and Jin, JO}, title = {Recent Advances in Nanotechnology: A Novel Therapeutic System for the Treatment of Alzheimer's Disease.}, journal = {Current drug metabolism}, volume = {21}, number = {14}, pages = {1144-1151}, doi = {10.2174/1389200221666201124140518}, pmid = {33234100}, issn = {1875-5453}, abstract = {A amyloid-β (Aβ) plaque formation in the brain is known to be the root cause of Alzheimer's disease (AD), which affects the behavior, memory, and cognitive ability in humans. The brain starts undergoing changes several years before the actual appearance of the symptoms. Nanotechnology could prove to be an alternative strategy for treating the disease effectively. It encompasses the diagnosis as well as the therapeutic aspect using validated biomarkers and nano-based drug delivery systems, respectively. A nano-based therapy may provide an alternate strategy, wherein one targets the protofibrillar amyloid-β (Aβ) structures, and this is followed by their disaggregation as random coils. Conventional/routine drug therapies are inefficient in crossing the blood-brain barrier; however, this hurdle can be overcome with the aid of nanoparticles. The present review highlights the various challenges in the diagnosis and treatment of AD. Meticulous and collaborative research using nanotherapeutic systems could provide remarkable breakthroughs in the early-stage diagnosis and therapy of AD.}, }
@article {pmid33224242, year = {2020}, author = {Zamanian-Azodi, M and Rezaei-Tavirani, M and Rezaei-Tavirani, M}, title = {Investigating the Effects of Ibuprofen on the Gene Expression Profile in Hippocampus of Mice Model of Alzheimer's Disease through Bioinformatics Analysis.}, journal = {Iranian journal of pharmaceutical research : IJPR}, volume = {19}, number = {2}, pages = {352-359}, pmid = {33224242}, issn = {1735-0328}, abstract = {Non-steroidal anti-inflammatory drugs (NSAIDs) are identified as effective in many diseases. One of which is neurodegenerative diseases including Alzheimer disease (AD). In this study gross alteration of gene expression in AD mice by ibuprofen treatment is investigated via Protein-protein interaction network (PPI) analysis. Expression profiling of microarray dataset GSE67306 was retrieved from GEO database and analyzed via GEO2R tool. PPI analysis was performed via Cytoscape 3.7.0. and its plug-ins including Network Analyzer, Gene MANIA, and CluePedia. Numbers of 10 central genes including Htr1a, Sstr2, Drd2, Htr1b, Penk, Pomc, Oprm1, Npy, Sst, and Chrm2 were identified as potential biomarkers. However, the role of Penk gene was highlighted. The finding indicates that ibuprofen changes gene expression level of several genes that are involved in AD.}, }
@article {pmid33224224, year = {2020}, author = {Kocakaya, SO and Ertas, A and Yener, I and Ercan, B and Oral, EV and Akdeniz, M and Kaplaner, E and Topcu, G and Kolak, U}, title = {Selective in-vitro Enzymes' Inhibitory Activities of Fingerprints Compounds of Salvia Species and Molecular Docking Simulations.}, journal = {Iranian journal of pharmaceutical research : IJPR}, volume = {19}, number = {2}, pages = {187-198}, pmid = {33224224}, issn = {1735-0328}, abstract = {Recently Nutrition and Food Chemistry researches have been focused on plants and their products or their secondary metabolites having anti-alzheimer, anti-cancer, anti-aging, and antioxidant properties. Among these plants Salvia L. (Lamiaceae) species come into prominence with their booster effects due to high antioxidant contents, which have over 900 species in the world and 98 in Turkey. Some Salvia species are already in use as herbal treatment of vessel stiffness, Dementia like problems and cancer. Recently some species of Salvia are of extensive research topic. In this study, inhibitory potentials of secondary metabolites, rosmarinic acid, salvigenin, salvianolic acid A and B, tanshinone I and IIA, cyrtotanshinone, dihydrotanshinone I, carnosic acid, carnosol, and danshensu sodium salt were investigated against acetylcholinesterase, butyrylcholinesterase, urease and tyrosinase enzymes both in-vitro and in slico in detail. Elevated inhibitory effects on acetyl- and butyryl-cholinesterase of dihydrotanshinone I (IC50: 1.50 ± 0.02 and 0.50 ± 0.01 µg/mL, respectively), carnasol (IC50: 11.15 ± 0.05 ve 3.92 ± 0.03 µg/mL) and carnosic acid (IC50: 31.83 ± 0.65 ve 4.12±0.04 µg/mL) were observed. Furthermore, all other secondary metabolites were active against butyrylcholinesterase. Anti-urease (42.41 ± 0.85%) and anti-tyrosinase (39.82 ± 1.16%) activities of tanshinone I were also observed. Potential inhibitory effects of these molecules on target proteins were investigated using DOCK and molecular dynamics calculations. Dock score analysis and Lipinski parameters were demonstrated that these ligands are potential inhibitors against relevant enzymes. Our findings suggest that Salvia species can be utilized as a ptential source of anti-alzheimer active compounds for designing novel products.}, }
@article {pmid33217524, year = {2021}, author = {Ogunlade, B and Fidelis, OP and Afolayan, OO and Agie, JA}, title = {Neurotherapeutic and antioxidant response of D-ribose-L-Cysteine nutritional dietary supplements on Alzheimer-type hippocampal neurodegeneration induced by cuprizone in adult male wistar rat model.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {147}, number = {}, pages = {111862}, doi = {10.1016/j.fct.2020.111862}, pmid = {33217524}, issn = {1873-6351}, mesh = {Alzheimer Disease/*chemically induced ; Animals ; Antioxidants/metabolism/therapeutic use ; Catalase/metabolism ; Cuprizone/*toxicity ; Cysteine/*analogs & derivatives/therapeutic use ; Diet ; *Dietary Supplements ; Food Contamination ; Glutathione Synthase/metabolism ; Hippocampus/*drug effects ; Male ; Malondialdehyde/metabolism ; Nitric Oxide/metabolism ; Oxidative Stress/drug effects ; Rats ; Rats, Wistar ; Superoxide Dismutase/metabolism ; Thiazolidines/*therapeutic use ; }, abstract = {INTRODUCTION: Cuprizone is a neurotoxicant causing neurodegeneration through enzymes inhibition and oxidative stress. D-Ribose-L-Cysteine (DRLC) is a powerful antioxidant with neuroprotective properties. This study explored the antioxidant response of DRLC against cuprizone-induced behavioral alterations, biochemical imbalance and hippocampal neuronal damage in adult wistar rats.
MATERIALS AND METHODS: Thirty two (32) adult male wistar rats (150-200g) were divided into four groups (n = 8). Group A received normal saline only as placebo; Group B received 0.5% cuprizone diet only; Group C received a combination of 0.5% cuprizone diet and 100 mg/kg bw of DRLC and Group D received 100 mg/kg bw of DRLC only. The administration was done through oral gavage once daily for 45 days. After the last treatment, neurobehavioral tests (Morris Water Maze and Y maze) was conducted; animals sacrificed and brain harvested for histological analysis and biochemical estimations of levels of antioxidants, oxidative stress markers, neurotransmitters and enzyme activitties.
RESULTS: The results showed significant memory decline, hippocampal alterations, decrease levels of antioxidant markers, enzyme and neurotransmitters activities with concomitant increase in norepinephrine and oxidative stress markers in cuprizone induced rats relative to normal but was attenuated with DRLC administration.
CONCLUSION: Cuprizone causes cognitive impairment and neurodegeneration through oxidative stress; however, administration of DRLC ameliorated neuropathological alteration induced by cuprizone.}, }
@article {pmid33204533, year = {2020}, author = {Longhurst, J and Phan, J and Chen, E and Jackson, S and Landers, MR}, title = {Physical Therapy for Gait, Balance, and Cognition in Individuals with Cognitive Impairment: A Retrospective Analysis.}, journal = {Rehabilitation research and practice}, volume = {2020}, number = {}, pages = {8861004}, pmid = {33204533}, issn = {2090-2867}, abstract = {Objectives: The purpose of this study was to determine if a pragmatic physical therapy (PT) program was associated with improved cognition, gait, and balance in individuals with cognitive impairment. This study investigated these associations for individuals with Alzheimer disease (AD), vascular dementia (VaD), dementia with Lewy bodies (DLB), and mild cognitive impairment (MCI) in order to better characterize outcomes to PT for each diagnostic group.
Methods: Data before and after one month of physical therapy were extracted from patient records (67 with AD, 34 with VaD, 35 with DLB, and 37 with MCI). The mean number of PT sessions over a month was 3.4 (±1.8). Outcomes covered the domains of gait, balance, and cognition with multiple outcomes used to measure different constructs within the balance and gait domains.
Results: All groups showed improvements in balance and at least one gait outcome measure. Those with MCI improved in every measure of gait and balance performance. Lastly, cognition as measured by Montreal Cognitive Assessment improved in individuals in the AD, VaD, and MCI groups.
Conclusion: While this retrospective analysis is not appropriate for causal inference, results of one month of physical therapy were associated with decreases in gait, balance, and cognitive impairment in individuals with AD, VaD, DLB<, and MCI. Clinical Implications. While physical therapy is not typically a primary treatment strategy for individuals with cognitive impairment, the results of this study are consistent with the literature that demonstrates improvement from physical therapy for other neurodegenerative diseases. Further clinical and research exploration for physical therapy as a primary treatment strategy in these populations is warranted.}, }
@article {pmid33192051, year = {2020}, author = {Guo, R and Li, L and Su, J and Li, S and Duncan, SE and Liu, Z and Fan, G}, title = {Pharmacological Activity and Mechanism of Tanshinone IIA in Related Diseases.}, journal = {Drug design, development and therapy}, volume = {14}, number = {}, pages = {4735-4748}, pmid = {33192051}, issn = {1177-8881}, mesh = {Abietanes/*pharmacology ; Alzheimer Disease/*drug therapy/metabolism ; Animals ; Anti-Inflammatory Agents/*pharmacology ; Antioxidants/*pharmacology ; Cardiovascular Diseases/*drug therapy/metabolism ; Cell Proliferation/drug effects ; Humans ; Neoplasms/*drug therapy/metabolism/pathology ; }, abstract = {Salvia miltiorrhiza: (Danshen) is a significant (traditional Chinese medication) natural remedy, enhancing blood circulation and clear blood stasis. In this view, it is widely used against several heart diseases, eg, cardiomyopathy, arrhythmia, and congenital heart defects. Tanshinone IIA (tan-IIA) is the main fat-soluble component of Salvia miltiorrhiza. Modern pharmacological study shows that tan-IIA has anti-inflammatory and anti-oxidant activities. Tan-IIA induces remarkable cardioprotective effects via enhancing angiogenesis which may serve as an effective treatment against cardiovascular diseases (CVD). There is also evidence that tan-IIA has extensive immunomodulatory effects and plays a significant role in the development and function of immune cells. Tan-IIA reduces the production of inflammatory mediators and restores abnormal signaling pathways via regulating the function and activation of immune cells. It can also regulate signal transduction pathways, ie, TLR/NF-κB pathway and MAPKs/NF-κB pathway, thereby tan-IIA has an anti-inflammatory, anticoagulant, antithrombotic and neuroprotective role. It plays a protective role in the pathogenesis of cardiovascular disorders (ie, atherosclerosis, hypertension) and Alzheimer's disease. It has also been revealed that tan-IIA has an anti-tumor role by killing various tumor cells, inducing differentiation and apoptosis, and has potential activity against carcinoma progression. In the review of this fact, the tan-IIA role in different diseases and its mechanism have been summarized while its clinical applications are also explored to provide a new perspective of Salvia miltiorrhiza. An extensive study on the mechanism of action of tan-IIA is of great significance for the effective use of Chinese herbal medicine and the promotion of its status and influence on the world.}, }
@article {pmid33189440, year = {2021}, author = {Liu, Z and Zhang, B and Xia, S and Fang, L and Gou, S}, title = {ROS-responsive and multifunctional anti-Alzheimer prodrugs: Tacrine-ibuprofen hybrids via a phenyl boronate linker.}, journal = {European journal of medicinal chemistry}, volume = {212}, number = {}, pages = {112997}, doi = {10.1016/j.ejmech.2020.112997}, pmid = {33189440}, issn = {1768-3254}, mesh = {Acetylcholinesterase/metabolism ; Alzheimer Disease/*drug therapy/metabolism/pathology ; Animals ; Boronic Acids/chemistry/pharmacology ; Cells, Cultured ; Cholinesterase Inhibitors/chemical synthesis/chemistry/*pharmacology ; Cytokines/antagonists & inhibitors/biosynthesis ; Dose-Response Relationship, Drug ; Humans ; Ibuprofen/chemistry/pharmacology ; Lipopolysaccharides/antagonists & inhibitors/pharmacology ; Mice ; Molecular Docking Simulation ; Molecular Structure ; Neuroprotective Agents/chemical synthesis/chemistry/*pharmacology ; Prodrugs/chemical synthesis/chemistry/*pharmacology ; Reactive Oxygen Species/*metabolism ; Structure-Activity Relationship ; Tacrine/chemistry/pharmacology ; }, abstract = {Current drugs available in clinic for Alzheimer's disease (AD) treatment can only alleviate disease symptoms without clearly curing or delaying the process of AD. And some AD drugs failed in Phase III clinical trials are only focused on targeting amyloid-β (Aβ). Therefore, an alternative strategy in AD drug design is meaningful to be involved in the multiple pathogenic factors which can affect each other at multiple levels. Herein, we report a series of ROS-responsive prodrugs based on multi-target-directed ligands (MTDLs) approach, which can specifically release tacrine derivatives and ibuprofen under oxidation of ROS and show acetylcholinesterase (AChE)-inhibiting, neuron-protective and anti-inflammatory effects in extracellular or intracellular assays. Related biological study illustrated that compound 22 was able to permeate blood-brain-barrier (BBB) showing little hepatotoxicity in comparison to tacrine. Besides, 22 hinted a therapeutic clue in AD-treatment by regulating proinflammatory factors (IL-1β and TNF-α) and apoptosis related proteins (Bax, Bcl-2 and cleaved caspase-3). Further spatial memory assays in Aβ-induced AD model showed that 22 enhanced the ability of learning and memory. Our study proves that the strategy of ROS-responsive prodrugs has promise for AD treatments in future and offers a way for AD drug development.}, }
@article {pmid33185582, year = {2021}, author = {de Barros Viana, M and Rosário, BDA and de Fátima Santana de Nazaré, M and Estadella, D and Ribeiro, DA and Socorro de Barros Viana, G}, title = {COVID-19 in age-related neurodegenerative diseases: is there a role for vitamin D3 as a possible therapeutic strategy?.}, journal = {Reviews in the neurosciences}, volume = {32}, number = {2}, pages = {235-247}, doi = {10.1515/revneuro-2020-0074}, pmid = {33185582}, issn = {2191-0200}, mesh = {Age Distribution ; COVID-19/complications/*drug therapy ; Cholecalciferol/*therapeutic use ; Humans ; Neurodegenerative Diseases/*drug therapy/etiology ; SARS-CoV-2/*drug effects/pathogenicity ; }, abstract = {The coronavirus disease (COVID-19), identified in Wuhan, China, on December 2019, was declared a pandemic by the World Health Organization, on March, 2020. Since then, efforts have been gathered to describe its clinical course and to determine preventive measures and treatment strategies. Adults older than 65 years of age are more susceptible to serious clinical symptoms and present higher mortality rates. Angiotensin-converting enzyme 2 (ACE2) is a major receptor for some coronavirus infection, including SARS-COV-2, but is also a crucial determinant in anti-inflammation processes during the renin-angiotensin system (RAS) functioning - converting angiotensin II to angiotensin 1-7. The decline in ACE2 expression that occurs with aging has been associated to the higher morbidity and mortality rates in older adults. These observations highlight the importance of investigating the association between COVID-19 and age-related neurodegenerative disorders, i.e., Parkinson's and Alzheimer's diseases. A possible option to reduce the risk of COVID-19 is vitamin D supplementation, due to its anti-inflammatory and immune-system-modulating effects. It has also been suggested that vitamin D supplementation plays a role in slowing progression of Parkinson and Alzheimer. The present study is a literature review of articles published on the theme COVID-19, Parkinson and Alzheimer's diseases, and the role played by vitamin D. PUBMED, MEDLINE, and EMBASE databases were consulted. Results confirm neurodegenerative and neuroinflammatory effects of COVID-19, aggravated in Parkinson's and Alzheimer's patients, and the important role of vitamin D as a possible therapeutic strategy. Nevertheless, randomized controlled trials and large population studies are still warranted.}, }
@article {pmid33178313, year = {2020}, author = {Liu, F and Zhao, Q and Liu, S and Xu, Y and Zhou, D and Gao, Y and Zhu, L}, title = {Revealing the Pharmacological Mechanism of Acorus tatarinowii in the Treatment of Ischemic Stroke Based on Network Pharmacology.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2020}, number = {}, pages = {3236768}, pmid = {33178313}, issn = {1741-427X}, abstract = {Aim: Stroke is the second significant cause for death, with ischemic stroke (IS) being the main type threatening human being's health. Acorus tatarinowii (AT) is widely used in the treatment of Alzheimer disease, epilepsy, depression, and stroke, which leads to disorders of consciousness disease. However, the systemic mechanism of AT treating IS is unexplicit. This article is supposed to explain why AT has an effect on the treatment of IS in a comprehensive and systematic way by network pharmacology.
Methods and Materials: ADME (absorbed, distributed, metabolized, and excreted) is an important property for screening-related compounds in AT, which were screening out of TCMSP, TCMID, Chemistry Database, and literature from CNKI. Then, these targets related to screened compounds were predicted via Swiss Targets, when AT-related targets database was established. The gene targets related to IS were collected from DisGeNET and GeneCards. IS-AT is a common protein interactive network established by STRING Database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were analysed by IS-AT common target genes. Cytoscape software was used to establish a visualized network for active compounds-core targets and core target proteins-proteins interactive network. Furthermore, we drew a signal pathway picture about its effect to reveal the basic mechanism of AT against IS systematically.
Results: There were 53 active compounds screened from AT, inferring the main therapeutic substances as follows: bisasaricin, 3-cyclohexene-1-methanol-α,α,4-trimethyl,acetate, cis,cis,cis-7,10,13-hexadecatrienal, hydroxyacoronene, nerolidol, galgravin, veraguensin, 2'-o-methyl isoliquiritigenin, gamma-asarone, and alpha-asarone. We obtained 398 related targets, 63 of which were the same as the IS-related genes from targets prediction. Except for GRM2, remaining 62 target genes have an interactive relation, respectively. The top 10 degree core target genes were IL6, TNF, IL1B, TLR4, NOS3, MAPK1, PTGS2, VEGFA, JUN, and MMP9. There were more than 20 terms of biological process, 7 terms of cellular components, and 14 terms of molecular function through GO enrichment analysis and 13 terms of signal pathway from KEGG enrichment analysis based on P < 0.05.
Conclusion: AT had a therapeutic effect for ischemic via multicomponent, multitarget, and multisignal pathway, which provided a novel research aspect for AT against IS.}, }
@article {pmid33173194, year = {2021}, author = {Yang, S and Lim, KH and Kim, SH and Joo, JY}, title = {Molecular landscape of long noncoding RNAs in brain disorders.}, journal = {Molecular psychiatry}, volume = {26}, number = {4}, pages = {1060-1074}, pmid = {33173194}, issn = {1476-5578}, mesh = {Biomarkers ; Humans ; Neurodegenerative Diseases/*genetics ; Neurodevelopmental Disorders/*genetics ; *RNA, Long Noncoding/genetics ; }, abstract = {According to current paradigms, various risk factors, such as genetic mutations, oxidative stress, neural network dysfunction, and abnormal protein degradation, contribute to the progression of brain disorders. Through the cooperation of gene transcripts in biological processes, the study of noncoding RNAs can lead to insights into the cause and treatment of brain disorders. Recently, long noncoding RNAs (lncRNAs) which are longer than 200 nucleotides in length have been suggested as key factors in various brain disorders. Accumulating evidence suggests the potential of lncRNAs as diagnostic or prognostic biomarkers and therapeutic targets. High-throughput screening-based sequencing has been instrumental in identification of lncRNAs that demand new approaches to understanding the progression of brain disorders. In this review, we discuss the recent progress in the study of lncRNAs, and addresses the pathogenesis of brain disorders that involve lncRNAs and describes the associations of lncRNAs with neurodegenerative disorders such as Alzheimer disease (AD), Parkinson disease (PD), and neurodevelopmental disorders. We also discuss potential targets of lncRNAs and their promise as novel therapeutics and biomarkers in brain disorders.}, }
@article {pmid33170159, year = {2020}, author = {Kiani, AK and Miggiano, GAD and Aquilanti, B and Velluti, V and Matera, G and Gagliardi, L and Bertelli, M}, title = {Food supplements based on palmitoylethanolamide plus hydroxytyrosol from olive tree or Bacopa monnieri extracts for neurological diseases.}, journal = {Acta bio-medica : Atenei Parmensis}, volume = {91}, number = {13-S}, pages = {e2020007}, pmid = {33170159}, issn = {2531-6745}, mesh = {Amides ; *Bacopa ; Dietary Supplements ; Ethanolamines ; Humans ; *Nervous System Diseases ; *Olea ; Palmitic Acids ; Phenylethyl Alcohol/analogs & derivatives ; Plant Extracts ; }, abstract = {Neurological disorders like Parkinson disease and Alzheimer disease, spinal cord injury and stroke have some recurrent characteristics such as abnormal protein aggregation, oxidative stress induction, apoptosis, excitotoxicity, perturbation of intracellular Ca2+ homeostasis and inflammation. To date, there are few effective treatments available and the drugs currently used to manage the symptoms have important side effects. Therefore, research studies are focusing on natural phytochemicals present in diet as bioactive molecules potentially useful against neurodegenerative diseases. In this review, we will discuss the neuroprotective role of palmitoylethanolamide, hydroxytyrosol, and Bacopa monnieri extracts against neuroinflammation and neurodegeneration, thereby revealing their remarkable potential as novel therapeutic options for the treatment of neurodegenerative disorders.}, }
@article {pmid33167840, year = {2020}, author = {Carrera-Muñoz, I and Triguero-Cueva, L and Romero-Fábrega, JC and Triviño-Ibáñez, EM and Vilchez-Carrillo, R and Carnero-Pardo, C and Gómez-Río, M}, title = {PET-Amyloid After Inconclusive Cerebrospinal Fluid Biomarkers in Clinical Practice. Is it Necessary to Duplicate Procedures?.}, journal = {Current Alzheimer research}, volume = {17}, number = {8}, pages = {698-708}, doi = {10.2174/1567205017666201109092637}, pmid = {33167840}, issn = {1875-5828}, abstract = {INTRODUCTION: In the absence of a gold standard for in vivo Alzheimer disease (AD) diagnosis, AD biomarkers such as cerebrospinal fluid biomarkers (CSF-B) and PET-Amyloid are considered diagnostically useful in clinical practice guidelines and have consensual appropriate use criteria (AUC). However, little evidence has been published on their utilization in the clinical setting or on approaches to mismatched results. The objective of this work was to evaluate the use of AD biomarkers in clinical practice, focusing on the implementation of PET-Amyloid in cases of inconclusive CSF-B.
METHODS: This naturalistic, ambispective case series included patients fulfilling AUC for CSF-B and PET-Amyloid whose CSF-B results were non-diagnostic (target population), analyzing the diagnostic certainty, the treatment approach, and the relationship between CSF-B and PET-Amyloid results.
RESULTS: Out of 2373 eligible patients, AD biomarkers were studied in 417 (17.6%), most frequently due to cognitive impairment in under 65-year-olds, using CSF-B in 311 patients and PET-Amyloid in 150. CSF-B results were non-diagnostic for 44 patients (52.3% male; aged 60.9±6.6 years), who then underwent PET-Amyloid study, which was positive in 31. A 'k' coefficient of 0.108 was obtained between CSF-B and PET-amyloid (54.5% concordance). In multivariate regression analysis, Aβ42 was the only significant predictor (p= 0.018) of a positive PET-Amyloid result. In the target population, PETAmyloid increased diagnostic confidence by 53.7% (p <0.001) and modified the therapeutic approach in 36.4% of cases.
CONCLUSION: These findings support the duplication of AD biomarkers and demonstrate that the implementation of PET-Amyloid provides an early and certain diagnosis to guide appropriate treatment.}, }
@article {pmid33157972, year = {2020}, author = {Li, WH and Wei, ZW and Liu, XF}, title = {Clinical efficacy of sertraline in the treatment of depression caused by Alzheimer disease: A protocol of systematic review.}, journal = {Medicine}, volume = {99}, number = {45}, pages = {e23076}, doi = {10.1097/MD.0000000000023076}, pmid = {33157972}, issn = {1536-5964}, mesh = {Alzheimer Disease/complications ; Antidepressive Agents/*therapeutic use ; Depression/*drug therapy/etiology ; Humans ; Randomized Controlled Trials as Topic ; *Research Design ; Sertraline/*therapeutic use ; *Systematic Reviews as Topic ; Treatment Outcome ; }, abstract = {BACKGROUND: This study will appraise the clinical efficacy of sertraline in the treatment of depression caused by Alzheimer disease (AD).
METHODS: Comprehensive searches in PUBMED, EMBASE, Cochrane Library, Scopus, AMED, CNKI, and WANGFANG will be performed from inception to the present without language restriction. In addition, other sources will also be searched to avoid losing more potential studies. We will only consider randomized controlled trials that examined the efficacy of sertraline for depression in patients with AD. Two team members will independently undertake literature selection, data collection, and risk of bias assessment. We will use Cochrane Risk of Bias Tool to assess the risk of bias for each eligible trial, and will utilize RevMan 5.3 software to carry out data analysis.
RESULTS: This study will recapitulate high-quality evidence to assess the efficacy of sertraline for the treatment of depression following AD.
CONCLUSION: The findings of this study will help to determine whether or not sertraline is effective for the treatment of depression after AD. OSF REGISTRATION:: osf.io/f29v6.}, }
@article {pmid33151420, year = {2020}, author = {Naik, B and Mehta, A and Shah, M}, title = {Denouements of machine learning and multimodal diagnostic classification of Alzheimer's disease.}, journal = {Visual computing for industry, biomedicine, and art}, volume = {3}, number = {1}, pages = {26}, pmid = {33151420}, issn = {2524-4442}, abstract = {Alzheimer's disease (AD) is the most common type of dementia. The exact cause and treatment of the disease are still unknown. Different neuroimaging modalities, such as magnetic resonance imaging (MRI), positron emission tomography, and single-photon emission computed tomography, have played a significant role in the study of AD. However, the effective diagnosis of AD, as well as mild cognitive impairment (MCI), has recently drawn large attention. Various technological advancements, such as robots, global positioning system technology, sensors, and machine learning (ML) algorithms, have helped improve the diagnostic process of AD. This study aimed to determine the influence of implementing different ML classifiers in MRI and analyze the use of support vector machines with various multimodal scans for classifying patients with AD/MCI and healthy controls. Conclusions have been drawn in terms of employing different classifier techniques and presenting the optimal multimodal paradigm for the classification of AD.}, }
@article {pmid33132939, year = {2020}, author = {Simonetti, A and Pais, C and Jones, M and Cipriani, MC and Janiri, D and Monti, L and Landi, F and Bernabei, R and Liperoti, R and Sani, G}, title = {Neuropsychiatric Symptoms in Elderly With Dementia During COVID-19 Pandemic: Definition, Treatment, and Future Directions.}, journal = {Frontiers in psychiatry}, volume = {11}, number = {}, pages = {579842}, pmid = {33132939}, issn = {1664-0640}, abstract = {Background: Neuropsychiatric symptoms (NPS) of dementia, such as anxiety, depression, agitation, and apathy, are complex, stressful, and costly aspects of care, and are associated to poor health outcomes and caregiver burden. A steep worsening of such symptoms has been reported during Coronavirus Disease 2019 (COVID-19) pandemic. However, their causes, their impact on everyday life, and treatment strategies have not been systematically assessed. Therefore, the aim of this review is to provide a detailed description of behavioral and psychopathological alterations in subjects with dementia during COVID-19 pandemic and the associated management challenges.
Methods: A PubMed search was performed focusing on studies reporting alterations in behavior and mood and treatment strategies for elderly patients with dementia, in accordance with PRISMA guidelines. The following search strategy was utilized: (COVID* OR coronavirus OR "corona vir*" OR SARS-CoV-2) AND (dementia OR demented OR dement* OR alzheimer* OR "pick's disease" OR "lewy body" OR "mild cognitive" OR mild cognitive impairment OR MCI).
Results: Apathy, anxiety and agitation are the most frequently NPS during the COVID-19 pandemic and are mainly triggered by protracted isolation. Most treatment strategies rely on pharmacotherapy; technology is increasingly utilized with mixed results.
Conclusions: NPS of dementia during COVID-19 appear to arise from social restrictions occurring as a consequence of the pandemic. Implementation of caregiver support and the presence of skilled nursing home staff are required to restore social interaction and adjust technological support to the patients' needs.}, }
@article {pmid33131696, year = {2021}, author = {Ai, J and Wang, H and Chu, P and Shopit, A and Niu, M and Ahmad, N and Tesfaldet, T and Wang, FH and Fang, JN and Li, X and Tang, SJ and Qing Ju Han, and Han, G and Peng, J and Tang, Z}, title = {The neuroprotective effects of phosphocreatine on Amyloid Beta 25-35-induced differentiated neuronal cell death through inhibition of AKT /GSK-3β /Tau/APP /CDK5 pathways in vivo and vitro.}, journal = {Free radical biology & medicine}, volume = {162}, number = {}, pages = {181-190}, doi = {10.1016/j.freeradbiomed.2020.10.003}, pmid = {33131696}, issn = {1873-4596}, mesh = {*Amyloid beta-Peptides/toxicity ; Animals ; Apoptosis ; Cell Death ; Glycogen Synthase Kinase 3 beta/genetics ; Mice ; *Neuroprotective Agents/pharmacology ; Phosphocreatine/pharmacology ; Phosphorylation ; Proto-Oncogene Proteins c-akt/genetics/metabolism ; tau Proteins/genetics/metabolism ; }, abstract = {Alzheimer (AD) is a degenerative disease that can lead memory loss and behavioral dysfunction. Aβ protein and phosphorylation of Tau protein are related to the onset of AD. However, at present, its treatment and drugs are limited. The purpose of our study is to evaluate whether phosphocreatine (PCr) could protect neuronal injury induced by Aβ protein in vivo and in vitro through AKT/GSK-3β/Tau/APP/CDK5 pathways. Differentiated PC-12 cells were cultured with Aβ25-35 for 24 h, while the mice were injected with D-Galactose for eight weeks, both of them were pretreated with PCr for 2 h. The results showed PCr could obviously induce cells and hippocampus apoptosis using DAPI and TUNEL. PCr decreased the levels of intercellular reactive oxygen species (ROS) and malondialdehyde (MDA), and increased the activities of superoxide dismutase (SOD). Besides, the apoptosis pathway was detected using Western blot, showing that PCr could significantly reduce caspase-3, caspase-9, Bcl-2/Bax expression in vivo and in vitro. At the same time, PCr could decreased Ca2+ and apoptosis by Flow Cytometry in PC-12 cells. We observed that the morphological alteration of hippocampus injury was mitigated with the pretreatment of PCr. Furthermore, PCr pretreatment could decrease Aβ25-35-induced PC-12 cells apoptosis with APP cDNA transfection, which up-regulated AKT/GSK-3β/CDK5 pathways and induced Tau phosphorylation. In summary, PCr could reduce Aβ25-35 toxicity to protect neuronal cells via AKT/GSK-3β/CDK5 pathways.}, }
@article {pmid33119989, year = {2020}, author = {Tak, K and Sharma, R and Dave, V and Jain, S and Sharma, S}, title = {Clitoria ternatea Mediated Synthesis of Graphene Quantum Dots for the Treatment of Alzheimer's Disease.}, journal = {ACS chemical neuroscience}, volume = {11}, number = {22}, pages = {3741-3748}, doi = {10.1021/acschemneuro.0c00273}, pmid = {33119989}, issn = {1948-7193}, mesh = {*Alzheimer Disease/drug therapy ; *Clitoria ; *Graphite ; *Quantum Dots ; Spectroscopy, Fourier Transform Infrared ; }, abstract = {The main purpose of the present study was to synthesize graphene quantum dots (GQDs)from the flowers of Clitoria ternatea with the help of one-pot microwave-assisted green synthesis for the treatment of Alzheimer's disease. Further, the synthesized graphene quantum dots show a particle size of 10 nm ±1.3, a PDI of 0.354 ± 1.8, and a ζ potential of -46 ± 0.4, indicating the good stability of the quantum dots. With the help of scanning electron microscopy (SEM) and transfer electron microscopy (TEM) examination, the surface microscopic behavior of the synthesized quantum dots was determined. The presence of functional groups in the quantum dots was determined by Fourier-transform infrared spectroscopy (FTIR) study, the chemical state information on the sample was determined with the help of X-ray photoelectron spectroscopy (XPS), and the surface area of the dots was determined with the help of a surface area analyzer. With the help of a radial arm maze and water morris maze assay, the learning and memory capacity of the quantum dots was assessed, and the results show that the ctGQDs significantly decreased the transfer latency to reach the baited arm in 10.37 ± 1.65 s or to the hidden platform in 18.42 ± 0.99 s in 7 days. The synthesized quantum dots show more inhibition of the acetyl cholinesterase enzyme, i.e., 86.32 ± 1.52%, as compared to that of pure donepezil, i.e., 72.46 ± 2.21%. ctGQDs considerably increased the level of glutathione and protein and decreased the level of lipid peroxide and nitric oxide. The histopathological image of ctGQDs shows more preservation of small pyramidal cell and treats the disorganization of the cells. These results suggest that the quantum dots significantly crossed the blood-brain barrier since they were small in size and were effective in reducing Alzheimer-like symptoms in rodents, and thus, it can be concluded that Clitoria ternatea flowers can be used as an adjuvant in the treatment of Alzheimer's.}, }
@article {pmid33115695, year = {2020}, author = {Arduino, I and Iacobazzi, RM and Riganti, C and Lopedota, AA and Perrone, MG and Lopalco, A and Cutrignelli, A and Cantore, M and Laquintana, V and Franco, M and Colabufo, NA and Luurtsema, G and Contino, M and Denora, N}, title = {Induced expression of P-gp and BCRP transporters on brain endothelial cells using transferrin functionalized nanostructured lipid carriers: A first step of a potential strategy for the treatment of Alzheimer's disease.}, journal = {International journal of pharmaceutics}, volume = {591}, number = {}, pages = {120011}, doi = {10.1016/j.ijpharm.2020.120011}, pmid = {33115695}, issn = {1873-3476}, mesh = {ATP Binding Cassette Transporter, Subfamily B/metabolism ; *ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism ; ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism ; *Alzheimer Disease/drug therapy ; Amyloid beta-Peptides ; Blood-Brain Barrier/metabolism ; Brain/metabolism ; Endothelial Cells/metabolism ; Humans ; Lipids ; Neoplasm Proteins/metabolism ; Transferrin ; }, abstract = {P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) are two transporters expressed in human neural stem/progenitor cells and at the Blood-Brain Barrier (BBB) level with decreased activity in the early stage of Alzheimer's disease (AD). Both proteins, have a protective role for the embryonic stem cells in the early developmental step, maintaining them in an undifferentiated state, and limit the access of exogenous and endogenous agents to the brain. Recently, MC111 selected from a P-gp/BCRP ligands library was investigated as multitarget strategy for AD treatment, considering its ability to induce the expression and activity of both proteins. However, MC111 clinical use could be limited for the ubiquitous physiological expression of efflux transporters and its moderate toxicity towards endothelial cells. Therefore, a selective MC111 delivery system based on nanostructured lipid carriers (NLC) functionalized with transferrin were developed. The results proved the formation of NLC with average size about 120 nm and high drug encapsulation efficiency (EE% greater than 50). In vitro studies on hCMEC/D3 cells revealed that the MC111 was selectively released by NLC at BBB level and then inducing the activity and expression of BCRP and P-gp, involved in the clearance of amyloid β peptide on brain endothelial cells.}, }
@article {pmid33114553, year = {2020}, author = {Gavriilaki, M and Kimiskidis, VK and Gavriilaki, E}, title = {Precision Medicine in Neurology: The Inspirational Paradigm of Complement Therapeutics.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {13}, number = {11}, pages = {}, pmid = {33114553}, issn = {1424-8247}, abstract = {Precision medicine has emerged as a central element of healthcare science. Complement, a component of innate immunity known for centuries, has been implicated in the pathophysiology of numerous incurable neurological diseases, emerging as a potential therapeutic target and predictive biomarker. In parallel, the innovative application of the first complement inhibitor in clinical practice as an approved treatment of myasthenia gravis (MG) and neuromyelitis optica spectrum disorders (NMOSD) related with specific antibodies raised hope for the implementation of personalized therapies in detrimental neurological diseases. A thorough literature search was conducted through May 2020 at MEDLINE, EMBASE, Cochrane Library and ClinicalTrials.gov databases based on medical terms (MeSH)" complement system proteins" and "neurologic disease". Complement's role in pathophysiology, monitoring of disease activity and therapy has been investigated in MG, multiple sclerosis, NMOSD, spinal muscular atrophy, amyotrophic lateral sclerosis, Parkinson, Alzheimer, Huntington disease, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, stroke, and epilepsy. Given the complexity of complement diagnostics and therapeutics, this state-of-the-art review aims to provide a brief description of the complement system for the neurologist, an overview of novel complement inhibitors and updates of complement studies in a wide range of neurological disorders.}, }
@article {pmid33114170, year = {2020}, author = {Atlante, A and Amadoro, G and Bobba, A and Latina, V}, title = {Functional Foods: An Approach to Modulate Molecular Mechanisms of Alzheimer's Disease.}, journal = {Cells}, volume = {9}, number = {11}, pages = {}, pmid = {33114170}, issn = {2073-4409}, abstract = {A new epoch is emerging with intense research on nutraceuticals, i.e., "food or food product that provides medical or health benefits including the prevention and treatment of diseases", such as Alzheimer's disease. Nutraceuticals act at different biochemical and metabolic levels and much evidence shows their neuroprotective effects; in particular, they are able to provide protection against mitochondrial damage, oxidative stress, toxicity of β-amyloid and Tau and cell death. They have been shown to influence the composition of the intestinal microbiota significantly contributing to the discovery that differential microorganisms composition is associated with the formation and aggregation of cerebral toxic proteins. Further, the routes of interaction between epigenetic mechanisms and the microbiota-gut-brain axis have been elucidated, thus establishing a modulatory role of diet-induced epigenetic changes of gut microbiota in shaping the brain. This review examines recent scientific literature addressing the beneficial effects of some natural products for which mechanistic evidence to prevent or slowdown AD are available. Even if the road is still long, the results are already exceptional.}, }
@article {pmid33111641, year = {2021}, author = {Zhang, X and Wei, M and Fan, J and Yan, W and Zha, X and Song, H and Wan, R and Yin, Y and Wang, W}, title = {Ischemia-induced upregulation of autophagy preludes dysfunctional lysosomal storage and associated synaptic impairments in neurons.}, journal = {Autophagy}, volume = {17}, number = {6}, pages = {1519-1542}, pmid = {33111641}, issn = {1554-8635}, abstract = {Macroautophagy/autophagy is vital for neuronal homeostasis and functions. Accumulating evidence suggest that autophagy is impaired during cerebral ischemia, contributing to neuronal dysfunction and neurodegeneration. However, the outcomes after transient modification in autophagy machinery are not fully understood. This study investigated the effects of ischemic stress on autophagy and synaptic structures using a rat model of oxygen-glucose deprivation (OGD) in hippocampal neurons and a mouse model of middle cerebral artery occlusion (MCAO). Upon acute ischemia, an initial autophagy modification occurred in an upregulation manner. Following, the number of lysosomes increased, as well as lysosomal volume, indicating dysfunctional lysosomal storage. These changes were prevented by inhibiting autophagy via 3-methyladenine (3-MA) treatment or ATG7 (autophagy related 7) knockdown, or were mimicked by rapamycin (RAPA), a known activator of autophagy. This suggests that dysfunctional lysosomal storage is associated with the early burst of autophagy. Dysfunctional lysosomal storage contributed to autophagy dysfunction because the basal level of MTOR-dependent lysosomal biogenesis in the reperfusion was not sufficient to clear undegraded cargoes after transient autophagy upregulation. Further investigation revealed that impairment of synaptic ultra-structures, accompanied by dysfunctional lysosomal storage, may result from a failure in dynamic turnover of synaptic proteins. This indicates a vital role of autophagy-lysosomal machinery in the maintenance of synaptic structures. This study supports previous evidence that dysfunctional lysosomal storage may occur following the upregulation of autophagy in neurons. Appropriate autophagosome-lysosomal functioning is vital for maintenance of neuronal synaptic function and impacts more than the few known synaptic proteins.Abbreviations: 3-MA: 3-methyladenine; ACTB: actin beta; AD: Alzheimer disease; ALR: autophagic lysosome reformation; ATG7: autophagy related 7; CTSB: cathepsin B; CTSD: cathepsin D; DAPI: 4',6-diamidino-2-phenylindole; DEGs: differentially expressed genes; DMEM: Dulbecco's modified Eagle's medium; DMSO: dimethyl sulfoxide; GO: Gene Ontology; HBSS: Hanks' balanced salt solution; HPCA: hippocalcin; i.c.v: intracerebroventricular; KEGG: kyoto encyclopedia of genes and genomes; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3B/LC3: microtubule-associated protein 1 light chain 3 beta; LSDs: lysosomal storage disorders; MAP2: microtubule-associated protein 2; MCAO: middle cerebral artery occlusion; mCTSB: mature CTSB; mCTSD: mature CTSD; MOI: multiplicity of infection; MTOR: mechanistic target of rapamycin kinase; OGD/R: oxygen-glucose deprivation/reoxygenation; PBS: phosphate-buffered saline; PRKAA/AMPKα: protein kinase AMP-activated catalytic subunit alpha; proCTSD: pro-cathepsin D; RAPA: rapamycin; RNA-seq: RNA sequencing; RPS6KB/p70S6K: ribosomal protein S6 kinase; SDS-PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis; SIM: Structured Illumination Microscopy; SNAP25: synaptosomal-associated protein 25; SQSTM1/p62: sequestosome 1; SYN1: synapsin I; SYT1: synaptotagmin I; TBST: tris-buffered saline Tween-20; TEM: transmission electron microscopy; TFEB: transcription factor EB; tMCAO: transient middle cerebral artery occlusion; TTC: 2,3,5-triphenyltetrazolium chloride; TUBB3: tubulin, beta 3 class III.}, }
@article {pmid33096898, year = {2020}, author = {Manek, E and Darvas, F and Petroianu, GA}, title = {Use of Biodegradable, Chitosan-Based Nanoparticles in the Treatment of Alzheimer's Disease.}, journal = {Molecules (Basel, Switzerland)}, volume = {25}, number = {20}, pages = {}, pmid = {33096898}, issn = {1420-3049}, mesh = {Alzheimer Disease/*drug therapy/metabolism ; Animals ; Chitosan/chemistry/metabolism/*therapeutic use ; Humans ; Nanoparticles/chemistry/metabolism/*therapeutic use ; Neuroprotective Agents/chemistry/metabolism/*therapeutic use ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects more than 24 million people worldwide and represents an immense medical, social and economic burden. While a vast array of active pharmaceutical ingredients (API) is available for the prevention and possibly treatment of AD, applicability is limited by the selective nature of the blood-brain barrier (BBB) as well as by their severe peripheral side effects. A promising solution to these problems is the incorporation of anti-Alzheimer drugs in polymeric nanoparticles (NPs). However, while several polymeric NPs are nontoxic and biocompatible, many of them are not biodegradable and thus not appropriate for CNS-targeting. Among polymeric nanocarriers, chitosan-based NPs emerge as biodegradable yet stable vehicles for the delivery of CNS medications. Furthermore, due to their mucoadhesive character and intrinsic bioactivity, chitosan NPs can not only promote brain penetration of drugs via the olfactory route, but also act as anti-Alzheimer therapeutics themselves. Here we review how chitosan-based NPs could be used to address current challenges in the treatment of AD; with a specific focus on the enhancement of blood-brain barrier penetration of anti-Alzheimer drugs and on the reduction of their peripheral side effects.}, }
@article {pmid33094209, year = {2020}, author = {Bianchi, VE and Rizzi, L and Bresciani, E and Omeljaniuk, RJ and Torsello, A}, title = {Androgen Therapy in Neurodegenerative Diseases.}, journal = {Journal of the Endocrine Society}, volume = {4}, number = {11}, pages = {bvaa120}, pmid = {33094209}, issn = {2472-1972}, abstract = {Neurodegenerative diseases, including Alzheimer disease (AD), Parkinson disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and Huntington disease, are characterized by the loss of neurons as well as neuronal function in multiple regions of the central and peripheral nervous systems. Several studies in animal models have shown that androgens have neuroprotective effects in the brain and stimulate axonal regeneration. The presence of neuronal androgen receptors in the peripheral and central nervous system suggests that androgen therapy might be useful in the treatment of neurodegenerative diseases. To illustrate, androgen therapy reduced inflammation, amyloid-β deposition, and cognitive impairment in patients with AD. As well, improvements in remyelination in MS have been reported; by comparison, only variable results are observed in androgen treatment of PD. In ALS, androgen administration stimulated motoneuron recovery from progressive damage and regenerated both axons and dendrites. Only a few clinical studies are available in human individuals despite the safety and low cost of androgen therapy. Clinical evaluations of the effects of androgen therapy on these devastating diseases using large populations of patients are strongly needed.}, }
@article {pmid33092257, year = {2020}, author = {Borroni, V and Kamerbeek, C and Pediconi, MF and Barrantes, FJ}, title = {Lovastatin Differentially Regulates α7 and α4 Neuronal Nicotinic Acetylcholine Receptor Levels in Rat Hippocampal Neurons.}, journal = {Molecules (Basel, Switzerland)}, volume = {25}, number = {20}, pages = {}, pmid = {33092257}, issn = {1420-3049}, support = {2015/2654//Consejo Nacional de Investigaciones Científicas y Técnicas/ ; }, mesh = {Animals ; Cholesterol/metabolism ; Gene Expression Regulation/drug effects ; Hippocampus/drug effects ; Humans ; Lovastatin/*pharmacology ; Neurons/*drug effects/metabolism ; Neuroprotective Agents/pharmacology ; Rats ; Receptors, Nicotinic/*genetics ; alpha7 Nicotinic Acetylcholine Receptor/*genetics ; }, abstract = {Neuronal α7 and α4β2 are the predominant nicotinic acetylcholine receptor (nAChR) subtypes found in the brain, particularly in the hippocampus. The effects of lovastatin, an inhibitor of cholesterol biosynthesis, on these two nAChRs endogenously expressed in rat hippocampal neuronal cells were evaluated in the 0.01-1 µM range. Chronic (14 days) lovastatin treatment augmented cell-surface levels of α7 and α4 nAChRs, as measured by fluorescence microscopy and radioactive ligand binding assays. This was accompanied in both cases by an increase in total protein receptor levels as determined by Western blots. At low lovastatin concentrations (10-100 nM), the increase in α4 nAChR in neurites was higher than in neuronal cell somata; the opposite occurred at higher (0.5-1 µM) lovastatin concentrations. In contrast, neurite α7 nAChRs raised more than somatic α7 nAChRs at all lovastatin concentrations tested. These results indicate that cholesterol levels homeostatically regulate α7 and α4 nAChR levels in a differential manner through mechanisms that depend on statin concentration and receptor localization. The neuroprotective pleomorphic effects of statins may act by reestablishing the homeostatic equilibrium.}, }
@article {pmid33088260, year = {2020}, author = {Hu, T and Li, S and Liang, WQ and Li, SS and Lu, MN and Chen, B and Zhang, L and Mao, R and Ding, WH and Gao, WW and Chen, SW and XiYang, YB and Zhang, J and Wang, XY}, title = {Notoginsenoside R1-Induced Neuronal Repair in Models of Alzheimer Disease Is Associated With an Alteration in Neuronal Hyperexcitability, Which Is Regulated by Nav.}, journal = {Frontiers in cellular neuroscience}, volume = {14}, number = {}, pages = {280}, pmid = {33088260}, issn = {1662-5102}, abstract = {Alzheimer disease is characterized by a progressive cognitive deficit and may be associated with an aberrant hyperexcitability of the neuronal network. Notoginsenoside R1 (R1), a major activity ingredient from Panax notoginseng, has demonstrated favorable changes in neuronal plasticity and induced neuroprotective effects in brain injuries, resulting from various disorders, however, the underlying mechanisms are still not well understood. In the present study, we aimed to explore the possible neuroprotective effects induced by R1 in a mouse model of AD and the mechanisms underlying these effects. Treatment with R1 significantly improved learning and memory functions and redressed neuronal hyperexcitability in amyloid precursor protein/presenilin-1 mice by altering the numbers and/or distribution of the members of voltage-gated sodium channels (Nav). Moreover, we determined whether R1 contributed to the regulation of neuronal excitability in Aβ-42-injured cells. Results of our study demonstrated that treatment with R1 rescued Aβ1-42-induced injured neurons by increasing cell viability. R1-induced alleviation in neuronal hyperexcitability might be associated with reduced Navβ2 cleavage, which partially reversed the abnormal distribution of Nav1.1α. These results suggested that R1 played a vital role in the recovery of Aβ1-42-induced neuronal injury and hyperexcitability, which is regulated by Nav proteins. Therefore, R1 may be a promising candidate in the treatment of AD.}, }
@article {pmid33086500, year = {2020}, author = {Ullah, R and Ali, G and Ahmad, N and Akram, M and Kumari, G and Amin, MU and Umar, MN}, title = {Attenuation of Spatial Memory in 5xFAD Mice by Halting Cholinesterases, Oxidative Stress and Neuroinflammation Using a Cyclopentanone Derivative.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {13}, number = {10}, pages = {}, pmid = {33086500}, issn = {1424-8247}, abstract = {Alzheimer's disease (AD) is an irreversible and chronic neurological disorder that gradually destroys memory and thinking skills. The research study was designed to investigate the underlying molecular signaling involved in the neuroprotective effects of cyclopentanone derivative i.e., 2-(hydroxyl-(3-nitrophenyl)methyl)cyclopentanone (3NCP) as a therapeutic agent for AD. In this study, In vivo studies were carried out on a well-known 5xFAD mice model using different behavioural test models such as open field, rotarod, Morris water maze (MWM), and Y-maze tests. Furthermore, in vitro cholinesterase inhibition activity assays were carried out. The frontal cortex (FC) and hippocampus (HC) homogenates were tested for the levels/activities of cholinesterases, glutathione (GSH), glutathione S-transferase (GST), and catalase. Furthermore, the hippocampal expression of inflammatory cytokines was observed via RT-PCR and western blot. The results of in vivo studies show an enhancement in the learning behavior. The 3NCP treatment reduced latency time in MWM and Y-maze tests, also increase spontaneous alternation indicate significant effect of 3NCP on memory. Furthermore, open field and rotarod studies revealed that 3NCP does not cause motor coordination deficit. The results of the in vitro studies revealed that the IC50 values of the 3NCP against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were 16.17 and 20.51 µg/mL, respectively. This decline in AChE and BChE was further supported by ex vivo studies. Further, the 3NCP mitigates the GSH level, GST, and catalase activities in HC and FC. The mRNA and protein expression of inflammatory cytokines (IL-1β, IL-6, TNF-α) markedly declined in RT-PCR and western blotting. The results of the current study conclusively demonstrate that 3NCP reduces oxidative stress and mitigates neuroinflammation in 5xFAD mice, implying that 3NCP may be a potential therapeutic candidate for AD treatment in the future.}, }
@article {pmid33081517, year = {2020}, author = {Lam, AD and Noebels, J}, title = {Night Watch on the Titanic: Detecting Early Signs of Epileptogenesis in Alzheimer Disease.}, journal = {Epilepsy currents}, volume = {20}, number = {6}, pages = {369-374}, pmid = {33081517}, issn = {1535-7597}, support = {K23 NS101037/NS/NINDS NIH HHS/United States ; }, abstract = {Aberrant cortical network excitability is an inextricable feature of Alzheimer disease (AD) that can negatively impact memory and accelerate cognitive decline. Surface electroencephalogram spikes and intracranial recordings of nocturnal silent seizures in human AD, coupled with the abnormal neural synchrony that precedes development of behavioral seizures in mouse AD models, build the case for epileptogenesis as an early therapeutic target for AD. Since most individuals with AD do not develop overt seizures, leveraging functional biomarkers of epilepsy risk to stratify a heterogeneous AD patient population for treatment is research priority for successful clinical trial design. Who will benefit from antiseizure interventions, which one, and when should it begin?}, }
@article {pmid33079410, year = {2021}, author = {Khazaei, H and Pesce, M and Patruno, A and Aneva, IY and Farzaei, MH}, title = {Medicinal plants for diabetes associated neurodegenerative diseases: A systematic review of preclinical studies.}, journal = {Phytotherapy research : PTR}, volume = {35}, number = {4}, pages = {1697-1718}, doi = {10.1002/ptr.6903}, pmid = {33079410}, issn = {1099-1573}, mesh = {Animals ; Diabetes Complications/*complications ; Humans ; Mice ; Neurodegenerative Diseases/*drug therapy/*etiology ; Plants, Medicinal/*chemistry ; Rats ; }, abstract = {Diabetes mellitus is a metabolic defect with many complications for the patients. Deaths due to diabetes and its complications are increasing, and one of the most serious consequences are the neurological disorders. Chemical treatments have irreversible side effect and therefore the aim of this study is to evaluate the medicinal plants used for treatment of cognitive impairments and neurodegenerative diseases associated with diabetes in 2004-2020 period. Electronic databases used were PubMed, Scopus and Cochrane library. The keywords used were "diabetes," "plant," "herb," "neurodegenerative," "neurodegeneration," "cognitive," "cognition," "Alzheimer," "dementia." The non-English articles, repetitive articles and review studies were excluded. From total of 3,590 results, 58 articles are included in the study. The results show that many chemical treatments considered for this disease simply control hyperglycemia, but cannot improve the complications of diabetes. Herbal medicine could be more effective due to the high antioxidant activity of some medicinal plants. Biologically active substances of medicinal plants can improve the neurological disorders caused by diabetes via several pathways. The most important pathway is related to antioxidant properties. Other pathways include antiinflammatory, anti-apoptotic, neurotoxicity inhibition, neuronal death, increasing the uptake of glucose by cells and improve neurotransmitters levels involved in learning and memory.}, }
@article {pmid33079159, year = {2020}, author = {Tsou, AY and Bulova, P and Capone, G and Chicoine, B and Gelaro, B and Harville, TO and Martin, BA and McGuire, DE and McKelvey, KD and Peterson, M and Tyler, C and Wells, M and Whitten, MS and , }, title = {Medical Care of Adults With Down Syndrome: A Clinical Guideline.}, journal = {JAMA}, volume = {324}, number = {15}, pages = {1543-1556}, doi = {10.1001/jama.2020.17024}, pmid = {33079159}, issn = {1538-3598}, mesh = {Adult ; Alzheimer Disease/complications/epidemiology ; Cardiovascular Diseases/complications/diagnosis/prevention & control ; Comorbidity ; Diabetes Complications/epidemiology ; Down Syndrome/complications/*therapy ; Evidence-Based Medicine ; Humans ; Mass Screening ; Obesity/complications ; }, abstract = {Importance: Down syndrome is the most common chromosomal condition, and average life expectancy has increased substantially, from 25 years in 1983 to 60 years in 2020. Despite the unique clinical comorbidities among adults with Down syndrome, there are no clinical guidelines for the care of these patients.
Objective: To develop an evidence-based clinical practice guideline for adults with Down syndrome.
Evidence Review: The Global Down Syndrome Foundation Medical Care Guidelines for Adults with Down Syndrome Workgroup (n = 13) developed 10 Population/Intervention/ Comparison/Outcome (PICO) questions for adults with Down syndrome addressing multiple clinical areas including mental health (2 questions), dementia, screening or treatment of diabetes, cardiovascular disease, obesity, osteoporosis, atlantoaxial instability, thyroid disease, and celiac disease. These questions guided the literature search in MEDLINE, EMBASE, PubMed, PsychINFO, Cochrane Library, and the TRIP Database, searched from January 1, 2000, to February 26, 2018, with an updated search through August 6, 2020. Using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology and the Evidence-to-Decision framework, in January 2019, the 13-member Workgroup and 16 additional clinical and scientific experts, nurses, patient representatives, and a methodologist developed clinical recommendations. A statement of good practice was made when there was a high level of certainty that the recommendation would do more good than harm, but there was little direct evidence.
Findings: From 11 295 literature citations associated with 10 PICO questions, 20 relevant studies were identified. An updated search identified 2 additional studies, for a total of 22 included studies (3 systematic reviews, 19 primary studies), which were reviewed and synthesized. Based on this analysis, 14 recommendations and 4 statements of good practice were developed. Overall, the evidence base was limited. Only 1 strong recommendation was formulated: screening for Alzheimer-type dementia starting at age 40 years. Four recommendations (managing risk factors for cardiovascular disease and stroke prevention, screening for obesity, and evaluation for secondary causes of osteoporosis) agreed with existing guidance for individuals without Down syndrome. Two recommendations for diabetes screening recommend earlier initiation of screening and at shorter intervals given the high prevalence and earlier onset in adults with Down syndrome.
Conclusions and Relevance: These evidence-based clinical guidelines provide recommendations to support primary care of adults with Down syndrome. The lack of high-quality evidence limits the strength of the recommendations and highlights the need for additional research.}, }
@article {pmid33070647, year = {2021}, author = {Maurice, T}, title = {Bi-phasic dose response in the preclinical and clinical developments of sigma-1 receptor ligands for the treatment of neurodegenerative disorders.}, journal = {Expert opinion on drug discovery}, volume = {16}, number = {4}, pages = {373-389}, doi = {10.1080/17460441.2021.1838483}, pmid = {33070647}, issn = {1746-045X}, abstract = {Introduction: The sigma-1 receptor (S1R) is attracting much attention for disease-modifying therapies in neurodegenerative diseases. It is a conserved protein, present in plasma and endoplasmic reticulum (ER) membranes and enriched in mitochondria-associated ER membranes (MAMs). It modulates ER-mitochondria Ca2+ transfer and ER stress pathways. Mitochondrial and MAM dysfunctions contribute to neurodegenerative processes in diseases such as Alzheimer, Parkinson, Huntington or Amyotrophic Lateral Sclerosis. Interestingly, the S1R can be activated by small druggable molecules and accumulating preclinical data suggest that S1R agonists are effective protectants in these neurodegenerative diseases.Area covered: In this review, we will present the data showing the high therapeutic potential of S1R drugs for the treatment of neurodegenerative diseases, focusing on pridopidine as a potent and selective S1R agonist under clinical development. Of particular interest is the bi-phasic (bell-shaped) dose-response effect, representing a common feature of all S1R agonists and described in numerous preclinical models in vitro, in vivo and in clinical trials.Expert opinion: S1R agonists modulate inter-organelles communication altered in neurodegenerative diseases and activate intracellular survival pathways. Research will continue growing in the future. The particular cellular nature of this chaperone protein must be better understood to facilitate the clinical developement of promising molecules.}, }
@article {pmid33068737, year = {2020}, author = {Fan, YG and Pang, ZQ and Wu, TY and Zhang, YH and Xuan, WQ and Wang, Z and Yu, X and Li, YC and Guo, C and Wang, ZY}, title = {Vitamin D deficiency exacerbates Alzheimer-like pathologies by reducing antioxidant capacity.}, journal = {Free radical biology & medicine}, volume = {161}, number = {}, pages = {139-149}, doi = {10.1016/j.freeradbiomed.2020.10.007}, pmid = {33068737}, issn = {1873-4596}, mesh = {*Alzheimer Disease/genetics ; Amyloid Precursor Protein Secretases/genetics ; Amyloid beta-Peptides ; Amyloid beta-Protein Precursor/genetics ; Animals ; Antioxidants ; Aspartic Acid Endopeptidases ; Disease Models, Animal ; Humans ; Mice ; Mice, Transgenic ; Presenilin-1 ; *Vitamin D Deficiency ; tau Proteins/genetics ; }, abstract = {Vitamin D (VD) deficiency is prevalent among aging people and Alzheimer's disease (AD) patients. However, the roles of VD deficiency in the pathology of AD remain largely unexplored. In this study, APP/PS1 mice were fed a VD-deficient diet for 13 weeks to evaluate the effects of VD deficiency on the learning and memory functions and the neuropathological characteristics of the mice. Our study revealed that VD deficiency accelerated cognitive impairment in the APP/PS1 mice. Mechanistic studies revealed that VD deficiency promoted glial activation and increased inflammatory factor secretion. Furthermore, VD deficiency increased the production and deposition of Aβ by elevating the expression levels of amyloid precursor protein (APP) and β-site APP cleavage enzyme 1 (BACE1). In addition, VD deficiency increased the phosphorylation of Tau at Thr181, Thr205 and Ser396 by increasing the activities of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3α/β (GSK3α/β) and promoted synaptic dystrophy and neuronal loss. All these effects of VD deficiency may be ascribed to enhanced oxidative stress via the downregulation of superoxide dismutase 1 (SOD1), glutathione peroxidase 4 (GPx4) and cystine/glutamate exchanger (xCT). Taken together, our data suggest that VD deficiency exacerbates Alzheimer-like pathologies via promoting inflammatory stress, increasing Aβ production and elevating Tau phosphorylation by decreasing antioxidant capacity in the brains of APP/PS1 mice. Hence, rescuing the VD status of AD patients should be taken into consideration during the treatment of AD.}, }
@article {pmid33066585, year = {2020}, author = {Veenman, L}, title = {Raloxifene as Treatment for Various Types of Brain Injuries and Neurodegenerative Diseases: A Good Start.}, journal = {International journal of molecular sciences}, volume = {21}, number = {20}, pages = {}, pmid = {33066585}, issn = {1422-0067}, mesh = {Animals ; Brain Injuries/*drug therapy/metabolism ; Humans ; Neurodegenerative Diseases/*drug therapy/metabolism ; Neuroprotective Agents/*therapeutic use ; Raloxifene Hydrochloride/*therapeutic use ; Selective Estrogen Receptor Modulators/*therapeutic use ; }, abstract = {Recent studies have shown that the selective estrogen receptor modulator (SERM) raloxifene had pronounced protective effects against progressing brain damage after traumatic brain injury (TBI) in mice. These studies, indicating beneficial effects of raloxifene for brain health, prompted the study of the history and present state of knowledge of this topic. It appears that, apart from raloxifene, to date, four nonrelated compounds have shown comparable beneficial effects-fucoidan, pifithrin, SMM-189 (5-dihydroxy-phenyl]-phenyl-methanone), and translocator protein (TSPO) ligands. Raloxifene, however, is ahead of the field, as for more than two decades it has been used in medical practice for various chronic ailments in humans. Thus, apart from different types of animal and cell culture studies, it has also been assessed in various human clinical trials, including assaying its effects on mild cognitive impairments. Regarding cell types, raloxifene protects neurons from cell death, prevents glial activation, ameliorates myelin damage, and maintains health of endothelial cells. At whole central nervous system (CNS) levels, raloxifene ameliorated mild cognitive impairments, as seen in clinical trials, and showed beneficial effects in animal models of Parkinson's disease. Moreover, with stroke and TBI in animal models, raloxifene showed curative effects. Furthermore, raloxifene showed healing effects regarding multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) in cell culture. The adverse biological signals typical of these conditions relate to neuronal activity, neurotransmitters and their receptors, plasticity, inflammation, oxidative stress, nitric oxide, calcium homeostasis, cell death, behavioral impairments, etc. Raloxifene favorably modulates these signals toward cell health-on the one hand, by modulating gene expression of the relevant proteins, for example by way of its binding to the cell nuclear estrogen receptors ERα and ERβ (genomic effects) and, on the other hand (nongenomic effects) by modulation of mitochondrial activity, reduction of oxidative stress and programmed cell death, maintaining metabolic balance, degradation of Abeta, and modulation of intracellular cholesterol levels. More specifically regarding Alzheimer's disease, raloxifene may not cure diagnosed Alzheimer's disease. However, the onset of Alzheimer's disease may be delayed or arrested by raloxifene's capability to attenuate mild cognitive impairment. Mild cognitive impairment is a condition that may precede diagnosis of Alzheimer's disease. In this review, relatively new insights are addressed regarding the notion that Alzheimer's disease can be caused by bacterial (as well as viral) infections, together with the most recent findings that raloxifene can counteract infections of at least some bacterial and viral strains. Thus, here, an overview of potential treatments of neurodegenerative disease by raloxifene is presented, and attention is paid to subcellular molecular biological pathways that may be involved.}, }
@article {pmid33065613, year = {2021}, author = {Kagawa, Y and Yamamoto, Y and Ueno, A and Maeda, T and Obi, T}, title = {Impact of CYP2D6, CYP3A5, and ABCB1 Polymorphisms on Plasma Concentrations of Donepezil and Its Metabolite in Patients With Alzheimer Disease.}, journal = {Therapeutic drug monitoring}, volume = {43}, number = {3}, pages = {429-435}, doi = {10.1097/FTD.0000000000000823}, pmid = {33065613}, issn = {1536-3694}, abstract = {BACKGROUND: Donepezil is one of the most commonly prescribed drugs for the treatment of Alzheimer disease. It is predominantly metabolized through CYP2D6 and to a lesser extent by CYP3A4/5. There are conflicting reports regarding the influence of CYP2D6, CYP3A5, and ABCB1 polymorphisms on the plasma concentration of donepezil. This study investigated the influence of these polymorphisms and sex on the plasma concentrations of donepezil and its active metabolite, 6-O-desmethyl donepezil (6ODD), in 47 patients with Alzheimer disease.
METHODS: Plasma donepezil and 6ODD concentrations were measured using liquid chromatography tandem mass spectrometry. Sex, the concomitant use of psychotropics, and CYP2D6, CYP3A5, and ABCB1 polymorphisms were analyzed as possible influencers.
RESULTS: The mean plasma concentrations of donepezil and 6ODD were well correlated (R2 = 0.418). The mean plasma concentration ratio of donepezil to 6ODD (metabolic ratio) was significantly lower in intermediate metabolizers of CYP2D6 than in extensive metabolizers. The metabolic ratio in patients receiving psychotropics was significantly lower than in those not receiving psychotropics. Among intermediate metabolizers, patients positive for CYP3A5 *3/*3 showed a significant increase in plasma mean 6ODD concentrations when compared with those who did not express this gene (CYP3A5 *1/*1 or *1/*3).
CONCLUSIONS: Results indicate that the mean plasma concentration ratio of donepezil to 6ODD is associated with CYP2D6 polymorphism and the concomitant use of psychotropics in patients with Alzheimer disease. In intermediate metabolizers, CYP3A5 may play a significant role in the metabolism of donepezil.}, }
@article {pmid33062155, year = {2020}, author = {Kargbo, RB}, title = {Selective DYRK1A Inhibitor for the Treatment of Neurodegenerative Diseases: Alzheimer, Parkinson, Huntington, and Down Syndrome.}, journal = {ACS medicinal chemistry letters}, volume = {11}, number = {10}, pages = {1795-1796}, pmid = {33062155}, issn = {1948-5875}, }
@article {pmid33061903, year = {2020}, author = {d'Errico, P and Meyer-Luehmann, M}, title = {Mechanisms of Pathogenic Tau and Aβ Protein Spreading in Alzheimer's Disease.}, journal = {Frontiers in aging neuroscience}, volume = {12}, number = {}, pages = {265}, pmid = {33061903}, issn = {1663-4365}, abstract = {Alzheimer's disease (AD) is pathologically defined by extracellular accumulation of amyloid-β (Aβ) peptides generated by the cleavage of amyloid precursor protein (APP), strings of hyperphosphorylated Tau proteins accumulating inside neurons known as neurofibrillary tangles (NFTs) and neuronal loss. The association between the two hallmarks and cognitive decline has been known since the beginning of the 20th century when the first description of the disease was carried out by Alois Alzheimer. Today, more than 40 million people worldwide are affected by AD that represents the most common cause of dementia and there is still no effective treatment available to cure the disease. In general, the aggregation of Aβ is considered an essential trigger in AD pathogenesis that gives rise to NFTs, neuronal dysfunction and dementia. During the process leading to AD, tau and Aβ first misfold and form aggregates in one brain region, from where they spread to interconnected areas of the brain thereby inducing its gradual morphological and functional deterioration. In this mini-review article, we present an overview of the current literature on the spreading mechanisms of Aβ and tau pathology in AD since a more profound understanding is necessary to design therapeutic approaches aimed at preventing or halting disease progression.}, }
@article {pmid33061334, year = {2020}, author = {Maresova, P and Hruska, J and Klimova, B and Barakovic, S and Krejcar, O}, title = {Activities of Daily Living and Associated Costs in the Most Widespread Neurodegenerative Diseases: A Systematic Review.}, journal = {Clinical interventions in aging}, volume = {15}, number = {}, pages = {1841-1862}, pmid = {33061334}, issn = {1178-1998}, mesh = {*Activities of Daily Living ; Aged ; Aged, 80 and over ; Female ; Health Care Costs ; Humans ; Male ; Middle Aged ; Neurodegenerative Diseases/*economics ; Quality of Life ; }, abstract = {Nowadays, the population is rapidly ageing because of increasing life expectancy and decreasing birth rates. Thus, the purpose of this systematic review is to prepare a comprehensive overview which identifies the activities of daily living (ADLs) that are gradually reduced among patients with dementia, as well as explore the therapies applied in relation to dementia and how they effectively improve the quality of life (QoL) of patients and caregivers. Furthermore, we aim to summarise the ADL activities influenced by therapies and examine the treatment costs and care for patients so that recommendations for research and development (R&D) can be made to improve both the QoL of people with dementia and cost-saving measures. The research focuses on four selected neurodegenerative diseases: Alzheimer, Parkinson, vascular dementia, and amyotrophic lateral sclerosis. Therefore, the peer-reviewed English written articles from 2014 to 2019 were searched between September 1 and December 13, 2019. Twenty-seven papers were included in the analysis. The results show that essential assistance occurs in connection with activities: eating, drinking, dressing, bathing, personal hygiene, use of the toilet, and transport. By contrast, shopping or cleaning is not addressed as much. A lower ability to take care of oneself is connected with poor patient health and higher social care costs because the patient requires care from external sources, such as home aid or nurse visits. The challenge that remains is to shift new knowledge from scientific disciplines and connect it with the needs of patients to remove legitimate barriers and increase the acceptance of new solutions by popularisation. Additionally, regarding the burden on caregivers, it would be appropriate to promote this area of education and employment so that family members can use formal caregivers, ensuring them free time and much-needed rest.}, }
@article {pmid33045895, year = {2020}, author = {Tuan, TA and Pham, TB and Kim, JY and Tavares, JMRS}, title = {Alzheimer's diagnosis using deep learning in segmenting and classifying 3D brain MR images.}, journal = {The International journal of neuroscience}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/00207454.2020.1835900}, pmid = {33045895}, issn = {1563-5279}, abstract = {BACKGROUND AND OBJECTIVES: Dementia is one of the brain diseases with serious symptoms such as memory loss, and thinking problems. According to the World Alzheimer Report 2016, in the world, there are 47 million people having dementia and it can be 131 million by 2050. There is no standard method to diagnose dementia, and consequently unable to access the treatment effectively. Hence, the computational diagnosis of the disease from brain Magnetic Resonance Image (MRI) scans plays an important role in supporting the early diagnosis. Alzheimer's Disease (AD), a common type of Dementia, includes problems related to disorientation, mood swings, not managing self-care, and behavioral issues. In this article, we present a new computational method to diagnosis Alzheimer's disease from 3D brain MR images.
METHODS: An efficient approach to diagnosis Alzheimer's disease from brain MRI scans is proposed comprising two phases: I) segmentation and II) classification, both based on deep learning. After the brain tissues are segmented by a model that combines Gaussian Mixture Model (GMM) and Convolutional Neural Network (CNN), a new model combining Extreme Gradient Boosting (XGBoost) and Support Vector Machine (SVM) is used to classify Alzheimer's disease based on the segmented tissues.
RESULTS: We present two evaluations for segmentation and classification. For comparison, the new method was evaluated using the AD-86 and AD-126 datasets leading to Dice 0.96 for segmentation in both datasets and accuracies 0.88, and 0.80 for classification, respectively.
CONCLUSION: Deep learning gives prominent results for segmentation and feature extraction in medical image processing. The combination of XGboost and SVM improves the results obtained.}, }
@article {pmid33045804, year = {2021}, author = {Kim, D and Yoon, HE and Park, HS and Shin, SJ and Choi, BS and Kim, BS and Ban, TH}, title = {Development of donepezil-induced hypokalemia following treatment of cognitive impairment.}, journal = {Yeungnam University journal of medicine}, volume = {38}, number = {1}, pages = {65-69}, pmid = {33045804}, issn = {2384-0293}, abstract = {Donepezil is a cholinesterase inhibitor used extensively to treat Alzheimer disease. The increased cholinergic activity is associated with adverse effects, therefore gastrointestinal symptoms, including nausea, vomiting, and diarrhea, are common. Hypokalemia is a rare adverse event that occurs in less than 1% of donepezil-treated patients. Although hypokalemia of mild and moderate grade does not present serious signs and symptoms, severe hypokalemia often results in prolonged hospitalization and mortality. Herein, we report a case of hypokalemia developed after the initiation of donepezil therapy for cognitive impairment.}, }
@article {pmid33044487, year = {2021}, author = {Insel, PS and Hansson, O and Mattsson-Carlgren, N}, title = {Association Between Apolipoprotein E ε2 vs ε4, Age, and β-Amyloid in Adults Without Cognitive Impairment.}, journal = {JAMA neurology}, volume = {78}, number = {2}, pages = {229-235}, doi = {10.1001/jamaneurol.2020.3780}, pmid = {33044487}, issn = {2168-6157}, abstract = {Importance: Although the most common recent approach in Alzheimer disease drug discovery is to directly target the β-amyloid (Aβ) pathway, the high prevalence of apolipoprotein E ε4 (APOE ε4) in Alzheimer disease and the ease of identifying ε4 carriers make the APOE genotype and its corresponding protein (apoE) an appealing therapeutic target to slow Aβ accumulation.
Objective: To determine whether the ε2 allele is protective against Aβ accumulation in the presence of the ε4 allele and evaluate how age and the APOE genotype are associated with emerging Aβ accumulation and cognitive dysfunction.
This cross-sectional study used screening data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease Study (A4 Study) collected from April 2014 to December 2017 and analyzed from November 2019 to July 2020. Of the 6943 participants who were a part of the multicenter clinical trial screening visit, 4432 were adults without cognitive impairment aged 65 to 85 years who completed a fluorine 18-labeled (18F)-florbetapir positron emission tomography scan, had APOE genotype information, and had a Clinical Dementia Rating of 0. Participants who were taking a prescription Alzheimer medication or had a current serious or unstable illness that could interfere with the study were excluded.
Main Outcomes and Measures: Aβ pathology, measured by 18F-florbetapir positron emission tomography and cognition, measured by the Preclinical Alzheimer Cognitive Composite.
Results: A total of 4432 participants were included (mean [SD] age, 71.3 [4.7] years; 2634 women [59.4%]), with a mean (SD) of 16.6 (2.8) years of education and 1512 (34.1%) with a positive Aβ level. APOE ε2 was associated with a reduction in both the overall (standardized uptake value ratio [SUVR], ε24, 1.11 [95% CI, 1.08-1.14]; ε34, 1.18 [95% CI, 1.17-1.19]) and the age-dependent level of Aβ in the presence of ε4, with Aβ levels in the APOE ε24 group (n = 115; ε24, 0.005 SUVR increase per year of age) increasing at less than half the rate with respect to increasing age compared with the APOE ε34 group (n = 1295; 0.012 SUVR increase per year of age; P = .04). The association between Aβ and decreasing Preclinical Alzheimer Cognitive Composite scores did not differ by APOE genotype, and the reduced performance on the Preclinical Alzheimer Cognitive Composite in APOE ε4 carriers compared with noncarriers was completely mediated by Aβ (unadjusted difference in composite scores between ε4 carriers and noncarriers = -0.084, P = .005; after adjusting for 18F-florbetapir = -0.006, P = .85; after adjusting for 18F-florbetapir and cardiovascular scores = -0.009, P = .78).
Conclusions and Relevance: These findings suggest that the protective outcome of carrying an ε2 allele in the presence of an ε4 allele against Aβ accumulation is important for potential treatments that attempt to biochemically mimic the function of the ε2 allele in order to facilitate Aβ clearance in ε4 carriers. Such a treatment strategy is appealing, as ε4 carriers make up approximately two-thirds of patients with Alzheimer disease dementia. This strategy could represent an early treatment option, as many ε4 carriers begin to accumulate Aβ in early middle age.}, }
@article {pmid33030113, year = {2021}, author = {Adeowo, FY and Ejalonibu, MA and Elrashedy, AA and Lawal, MM and Kumalo, HM}, title = {Multi-target approach for Alzheimer's disease treatment: computational biomolecular modeling of cholinesterase enzymes with a novel 4-N-phenylaminoquinoline derivative reveal promising potentials.}, journal = {Journal of biomolecular structure & dynamics}, volume = {39}, number = {11}, pages = {3825-3841}, doi = {10.1080/07391102.2020.1826129}, pmid = {33030113}, issn = {1538-0254}, mesh = {Acetylcholinesterase/metabolism ; *Alzheimer Disease/drug therapy ; *Butyrylcholinesterase/metabolism ; Cholinesterase Inhibitors/pharmacology ; Humans ; Molecular Docking Simulation ; Structure-Activity Relationship ; }, abstract = {The identification of dual inhibitors targeting the active sites of the cholinesterase enzymes, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), have lately surfaced as a multi-approach towards Alzheimer treatment. More recently, a novel series of 4-N-phenylaminoquinolines was synthesized and evaluated against AChE and BuChE in which one of the compounds displayed appreciable inhibition compared to the standard compound, galantamine. To provide a clearer picture of the inhibition mechanism of this potent compound at the molecular level, computational biomolecular modeling was carried out. The investigation was initiated with the exploration of the chemical properties of the identified compound 11 b and reference drug, galantamine. Density functional theory (DFT) calculations reveal some conceptual parameters that provide information on the stability and reactivity of the compounds as potential inhibitors. To unveil the binding mechanism, energetics and enzyme-ligand interactions, molecular dynamics (MD) simulations of six different systems were executed over a period. Calculated binding free energy values are in the same order with experimental IC50 data. Identification of the main residues driving optimum binding of the active compound 11 b to the binding region of both AChE and BuChE showed Trp81 and Trp110 as the most important, respectively. It was proposed that the studied compound could serve as a dual inhibitor for AChE and BuChE, therefore, would potentially be a promising moiety in a multi-target approach for the treatment of Alzheimer's disorder.Communicated by Ramaswamy H. Sarma.}, }
@article {pmid33027797, year = {2020}, author = {Lin, G and Ji, K and Li, S and Ma, W and Pan, X}, title = {The Genetics Analysis of Molecular Pathogenesis for Alzheimer's Disease.}, journal = {European neurology}, volume = {83}, number = {5}, pages = {458-467}, doi = {10.1159/000509799}, pmid = {33027797}, issn = {1421-9913}, mesh = {Aged ; Alzheimer Disease/*genetics ; Computational Biology ; Gene Expression Profiling ; Humans ; Protein Interaction Maps/genetics ; Signal Transduction/genetics ; *Transcriptome ; }, abstract = {INTRODUCTION: The molecular pathogenesis of Alzheimer's disease (AD) is still not clear, and the relationship between gene expression profile for different brain regions has not been studied.
OBJECTIVE: Bioinformatic analysis at the genetic level has become the best way for the pathogenesis research of AD, which can analyze the abovementioned relationship.
METHODS: In this study, the datasets of AD were obtained from the Gene Expression Omnibus (GEO), and Qlucore Omics Explorer (QOE) software was used to screen differentially expressed genes of GSE36980 and GSE9770 and verify gene expression of GSE63060. The Gene Ontology (GO) function enrichment analysis of these selected genes was conducted by Database for Annotation, Visualization, and Integrated Discovery (DAVID), and then the gene/protein interaction network was established by STRING to find the related proteins. R language was used for drafting maps and plots.
RESULTS: There were 20 differentially expressed genes related to AD selected from GSE36980 (p = 6.2e-6, q = 2.9422e-4) and GSE9770 (p = 3.3e-4, q = 0.016606). Their expression levels of the AD group were lower than those in the control group and varied among different brain regions. Cellular morphogenesis and establishment or maintenance of cell polarity were enriched, and LRRTM1 and RASAL1 were identified by the integration network. Moreover, the analysis of GSE63060 verified the expression level of LRRTM1 and RASAL1 in Alzheimer's patients, which was much lower than that in normal people aged >65 years.
CONCLUSIONS: The pathogenesis of AD at molecular levels may link to cell membrane structures and signal transduction; hence, a list of 20 genes, including LRRTM1 and RASAL1,potentially are important for the discovery of treatment target or molecular marker of AD.}, }
@article {pmid33024562, year = {2020}, author = {Zuo, S and Yu, J and Pan, H and Lu, L}, title = {Novel insights on targeting ferroptosis in cancer therapy.}, journal = {Biomarker research}, volume = {8}, number = {}, pages = {50}, pmid = {33024562}, issn = {2050-7771}, abstract = {Ferroptosis belongs to a novel form of regulated cell death. It is characterized by iron dependence, destruction of intracellular redox balance and non-apoptosis. And cellular structure and molecules level changes also occur abnormally during ferroptosis. It has been proved that ferroptosis exist widespreadly in many diseases, such as heart disease, brain damage or alzheimer disease. At the same time, the role of ferroptosis in cancer cannot be underestimated. More and more indications have told that ferroptosis is becoming a powerful weapon against cancer. In addition, therapies rely on ferroptosis have been applied to the clinic. Therefore, it is necessary to understand this newly discovered form of cell death and its connection with cancer. This review summarizes the mechanism of ferroptosis, ferroptosis inducers based on different targets and inspection methods. At last, we analyzed the relationship between ferroptosis and malignancies, in order to provide a novel theory basis for cancer treatment.}, }
@article {pmid33023416, year = {2020}, author = {Visioli, F and Rodríguez-Pérez, M and Gómez-Torres, Ó and Pintado-Losa, C and Burgos-Ramos, E}, title = {Hydroxytyrosol improves mitochondrial energetics of a cellular model of Alzheimer's disease.}, journal = {Nutritional neuroscience}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/1028415X.2020.1829344}, pmid = {33023416}, issn = {1476-8305}, abstract = {Mitochondrial energetic deficit is one of the hallmarks of neurodegenerative disorders, e.g. Alzheimer´s disease (AD). Adherence to a Mediterranean diet is associated with lower incidence of cognitive decline and AD and extra virgin olive oil's (poly)phenols such as oleuropein and hydroxytyrosol (HT) are being actively studied in this respect. In this study, we assessed the effects of HT on mitochondrial energetic dysfunction in the 7PA2 cells cellular model, i.e. one of the best cellular models of Aβ toxicity with a well-characterized mitochondrial dysfunction typically observed in AD. We report an increase of new mitochondria at 8 h post HT-treatment, which was followed by higher mitochondrial fusion. Further, ATP concentrations were significantly increased after 24 h of treatment with HT as compared with controls. Our data suggest that HT may revert the energetic deficit of a cellular model of AD by potentiating mitochondrial activity. Because HT is being proposed as dietary supplement or component of functional foods, future studies in appropriate animal models and - eventually - humans are warranted to further investigate its potential neuroprotective actions in AD.}, }
@article {pmid33023109, year = {2020}, author = {Roda, AR and Esquerda-Canals, G and Martí-Clúa, J and Villegas, S}, title = {Cognitive Impairment in the 3xTg-AD Mouse Model of Alzheimer's Disease is Affected by Aβ-ImmunoTherapy and Cognitive Stimulation.}, journal = {Pharmaceutics}, volume = {12}, number = {10}, pages = {}, pmid = {33023109}, issn = {1999-4923}, support = {SAF2017-89613R//Ministerio de Ciencia, Innovación y Universidades/ ; }, abstract = {Clinical symptoms of Alzheimer's Disease (AD) include behavioral alterations and cognitive impairment. These functional phenotypes early occur in triple-transgenic (3xTg-AD) mice. Specifically, behavioral alterations are first detected when mice are at around 2.5 months old and cognitive impairment in between 3- and 5-month-old mice. In this work, the effect of chronic Aβ-immunotherapy on behavioral and cognitive abilities was tested by monthly administering the antibody fragment scFv-h3D6 to 3xTg-AD female mice from 5 to 9 months of age. An untreated group was used as a reference, as well as to attain some information on the effect of training during the longitudinal study. Behavioral and psychological symptoms of dementia (BPSD)-like symptoms were already evident in 5-month-old mice, in the form of neophobia and anxious-like behavior. The exploratory activity decreased over the longitudinal study, not only for 3xTgAD mice but also for the corresponding non-transgenic mice (NTg). Learning abilities of 3xTg-AD mice were not seriously compromised but an impairment in long-term spatial memory was evident at 5 months of age. Interestingly, scFv-h3D6-treatment affected the cognitive impairment displayed by 5-month-old 3xTg-AD mice. It is worth noting that training also reduced cognitive impairment of 3xTg-AD mice over the longitudinal study, suggesting that to properly quantify the isolated therapeutic potential of any drug on cognition using this model it is convenient to perform a prompt, age-matched study rather than a longitudinal study. In addition, a combination of both training and Aβ-immunotherapy could constitute a possible approach to treat Alzheimer's disease.}, }
@article {pmid33021148, year = {2020}, author = {Potshangbam, AM and Nandeibam, A and Amom, T and Potshangbam, N and Rahaman, H and Rathore, RS and Singh, LR and Khan, A}, title = {An in silico approach to identify potential medicinal plants for treating Alzheimer disease: a case study with acetylcholinesterase.}, journal = {Journal of biomolecular structure & dynamics}, volume = {}, number = {}, pages = {1-13}, doi = {10.1080/07391102.2020.1828170}, pmid = {33021148}, issn = {1538-0254}, abstract = {Alzheimer's disease (AD) is a progressive neurological disorder affecting an estimated 10 million people worldwide. There is no cure for AD, and only a handful of drugs are known to provide some relief of the symptoms. The prescription drug donepezil has been widely used to treat to slow the progression and onset of the disease; however, the unpleasant side effects have paved the way to find alternative medicines. Many herbs are known to improve brain function, but evidence of medicinal plants that can treat AD is limited due to the lack of concrete rational evidences. Moreover, the traditional method of randomly screening plant extract against AD targets takes time and resources. In this study, a receptor-based in silico method has been implemented which serves to accelerate the process of identification of medicinal plants useful for treatment of AD. A database of natural compounds was compiled to identify hits against acetylcholinesterase (AChE). Receptor-based pharmacophore screening was performed, and selected hits were subjected to docking and molecular dynamics simulations. Molecular Mechanics/Generalized Born surface area (MM/GBSA) calculations were carried out to identify the best scoring hits further. In vitro assays were done for the plant extracts containing the top-scoring hits against AChE. Three plant extracts showed favorable inhibitory activity.Communicated by Ramaswamy H. Sarma.}, }
@article {pmid33019221, year = {2020}, author = {Hsieh, WT and Lefort-Besnard, J and Yang, HC and Kuo, LW and Lee, CC}, title = {Behavior Score-Embedded Brain Encoder Network for Improved Classification of Alzheimer Disease Using Resting State fMRI.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2020}, number = {}, pages = {5486-5489}, doi = {10.1109/EMBC44109.2020.9175312}, pmid = {33019221}, issn = {2694-0604}, mesh = {*Alzheimer Disease/diagnostic imaging ; Brain/diagnostic imaging ; *Cognitive Dysfunction/diagnostic imaging ; Humans ; Magnetic Resonance Imaging ; Tomography, X-Ray Computed ; }, abstract = {The ability to accurately detect onset of dementia is important in the treatment of the disease. Clinically, the diagnosis of Alzheimer Disease (AD) and Mild Cognitive Impairment (MCI) patients are based on an integrated assessment of psychological tests and brain imaging such as positron emission tomography (PET) and anatomical magnetic resonance imaging (MRI). In this work using two different datasets, we propose a behavior score-embedded encoder network (BSEN) that integrates regularly adminstrated psychological tests information into the encoding procedure of representing subject's resting-state fMRI data for automatic classification tasks. BSEN is based on a 3D convolutional autoencoder structure with contrastive loss jointly optimized using behavior scores from Mini-Mental State Examination (MMSE) and Clinical Dementia Rating (CDR). Our proposed classification framework of using BSEN achieved an overall recognition accuracy of 59.44% (3-class classification: AD, MCI and Healthy Control), and we further extracted the most discriminative regions between healthy control (HC) and AD patients.}, }
@article {pmid33010896, year = {2020}, author = {Cleveland, ML}, title = {Preserving Cognition, Preventing Dementia.}, journal = {Clinics in geriatric medicine}, volume = {36}, number = {4}, pages = {585-599}, doi = {10.1016/j.cger.2020.06.003}, pmid = {33010896}, issn = {1879-8853}, abstract = {Dementia incidence continues to rise in the United States and around the world. Although age is the single biggest risk factor for the development of dementia, it is not considered normal sequelae of aging. Although there has been little to no progress made in the past couple of decades in the treatment or cure of Alzheimer disease, there has been significant progress made in prevention. Single factors, such as hearing loss or cardiovascular risk factors, may increase the risk for cognitive decline. The opportunity to mitigate these risk factors provides an exciting new healthy aging approach to dementia prevention.}, }
@article {pmid33008542, year = {2020}, author = {Biskup, E and Martinkova, J and Ferretti, MT}, title = {Gender medicine: Towards a gender-specific treatment of neuropsychiatric disorders.}, journal = {Handbook of clinical neurology}, volume = {175}, number = {}, pages = {437-448}, doi = {10.1016/B978-0-444-64123-6.00029-1}, pmid = {33008542}, issn = {0072-9752}, mesh = {Humans ; *Precision Medicine ; Sex Factors ; }, abstract = {Sex and gender are increasingly recognized as major influencing factors in disorders across all medical specialties. Even though there is ample evidence of sex and gender differences in neuropsychiatric disorders, a sex and gender-differentiated approach has not yet been sufficiently applied to diagnostics and management. Therefore, there is an urgent need to establish general recommendations and guidelines toward precision and sex/gender medicine, with regard to dosage, tolerability, interactions and side effects, sensitivity of diagnostic tests, and distinct treatment strategies. This chapter illustrates the current knowledge about sex and gender aspects in neuropsychiatric disorders, providing a base not only to assist the clinician in the handling of specific pathologic entities, but also to sensitize medical practitioners to consider sex and gender in clinical decision-making. As such, the chapter is a call to action to physicians and researchers to produce more sex- and gender-stratified evidence, leading to an acceleration of guideline development. Such novel guidelines will provide a base for medical education, of both medical students and specialists, as well as a reference point for practitioners, toward precision medicine.}, }
@article {pmid33005040, year = {2020}, author = {Dalakas, MC and Alexopoulos, H and Spaeth, PJ}, title = {Complement in neurological disorders and emerging complement-targeted therapeutics.}, journal = {Nature reviews. Neurology}, volume = {16}, number = {11}, pages = {601-617}, pmid = {33005040}, issn = {1759-4766}, abstract = {The complement system consists of a network of plasma and membrane proteins that modulate tissue homeostasis and contribute to immune surveillance by interacting with the innate and adaptive immune systems. Dysregulation, impairment or inadvertent activation of complement components contribute to the pathogenesis of some autoimmune neurological disorders and could even contribute to neurodegenerative diseases. In this Review, we summarize current knowledge about the main functions of the complement pathways and the involvement of complement in neurological disorders. We describe the complex network of complement proteins that target muscle, the neuromuscular junction, peripheral nerves, the spinal cord or the brain and discuss the autoimmune mechanisms of complement-mediated myopathies, myasthenia, peripheral neuropathies, neuromyelitis and other CNS disorders. We also consider the emerging role of complement in some neurodegenerative diseases, such as Alzheimer disease, amyotrophic lateral sclerosis and even schizophrenia. Finally, we provide an overview of the latest complement-targeted immunotherapies including monoclonal antibodies, fusion proteins and peptidomimetics that have been approved, that are undergoing phase I-III clinical trials or that show promise for the treatment of neurological conditions that respond poorly to existing immunotherapies.}, }
@article {pmid33001019, year = {2020}, author = {Goswami, S and Kareem, O and Goyal, RK and Mumtaz, SM and Tonk, RK and Gupta, R and Pottoo, FH}, title = {Role of Forkhead Transcription Factors of the O Class (FoxO) in Development and Progression of Alzheimer's Disease.}, journal = {CNS & neurological disorders drug targets}, volume = {19}, number = {9}, pages = {709-721}, doi = {10.2174/1871527319666201001105553}, pmid = {33001019}, issn = {1996-3181}, abstract = {In the Central Nervous System (CNS), a specific loss of focal neurons leads to mental and neurological disorders like dementia, Alzheimer's Disease (AD), Huntington's disease, Parkinson's disease, etc. AD is a neurological degenerative disorder, which is progressive and irreversible in nature and is the widely recognized reason for dementia in the geriatric populace. It affects 10% of people above the age of 65 and is the fourth driving reason for death in the United States. Numerous evidence suggests that the neuronal compartment is not the only genesis of AD, but transcription factors also hold significant importance in the occurrence and advancement of the disease. It is the need of the time to find the novel molecular targets and new techniques for treating or slowing down the progression of neurological disorders, especially AD. In this article, we summarised a conceivable association between transcriptional factors and their defensive measures against neurodegeneration and AD. The mammalian forkhead transcription factors of the class O (FoxO) illustrate one of the potential objectives for the development of new methodologies against AD and other neurocognitive disorders. The presence of FoxO is easily noticeable in the "cognitive centers" of the brain, specifically in the amygdala, hippocampus, and the nucleus accumbens. FoxO proteins are the prominent and necessary factors in memory formation and cognitive functions. FoxO also assumes a pertinent role in the protection of multiple cells in the brain by controlling the involving mechanism of autophagy and apoptosis and also modulates the process of phosphorylation of the targeted protein, thus FoxO must be a putative target in the mitigation of AD. This review features the role of FoxO as an important biomarker and potential new targets for the treatment of AD.}, }
@article {pmid33000582, year = {2020}, author = {Wang, X and Li, Z and Li, C and Wang, Y and Yu, S and Ren, L}, title = {Electroacupuncture with Bushen Jiannao improves cognitive deficits in senescence-accelerated mouse prone 8 mice by inhibiting neuroinflammation.}, journal = {Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan}, volume = {40}, number = {5}, pages = {812-819}, doi = {10.19852/j.cnki.jtcm.2020.05.011}, pmid = {33000582}, issn = {2589-451X}, mesh = {Acupuncture Points ; Alzheimer Disease/genetics/immunology/psychology/*therapy ; Animals ; Cognition ; Disease Models, Animal ; *Electroacupuncture ; Hippocampus/immunology ; Humans ; Interleukin-17/genetics/immunology ; Interleukin-6/genetics/immunology ; Learning ; Male ; Memory ; Mice ; Tumor Necrosis Factor-alpha/genetics/immunology ; }, abstract = {OBJECTIVE: To investigate effect of electroacupuncture (EA) with Bushen Jiannao on learning and memory ability in senescence-accelerated mouse prone 8 (SAMP8) mice and the related mechanisms.
METHODS: 8-month-old senescence-accelerated-resistant (SAMR1) and SAMP8 mice were treated with EA at Baihui (GV 20), Shenshu (BL 23), and Taixi (KI 3) acupoint once a week for 8 weeks. The Morris water maze, enzyme linked immunosorbent assay, immunohistochemistry, and Western blot were used to assess Alzheimer's disease (AD)-associated cognitive and neuroinflammatory phenotypes.
RESULTS: Our data showed that EA treatment decreased activation of microglia and astrocytes, decreased levels of inflammatory factors including tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-17, and improved spatial memory deficits in SAMP8 mice. EA therapy with Bushen Jiannao exhibited anti-inflammatory properties and improved cognitive function.
CONCLUSION: The present study indicates that EA treatment based on the interaction between kidney and brain can improve learning and memory ability by inhibiting activation of astrocytes and microglia and decreasing expression of pro-inflammatory cytokines, TNF-α and IL-17. EA treatment based on the interaction between kidney and brain may be an effective treatment for AD.}, }
@article {pmid32993279, year = {2020}, author = {Goudarzi, G and Hamidabadi, HG and Bojnordi, MN and Hedayatpour, A and Niapour, A and Zahiri, M and Absalan, F and Darabi, S}, title = {Role of cerebrospinal fluid in differentiation of human dental pulp stem cells into neuron-like cells.}, journal = {Anatomy & cell biology}, volume = {53}, number = {3}, pages = {292-300}, pmid = {32993279}, issn = {2093-3665}, abstract = {Human dental pulp stem cells (hDPSCs) could be differentiated into neuron like-cells under particular microenvironments. It has been reported that a wide range of factors, presented in cerebrospinal fluid (CSF), playing part in neuronal differentiation during embryonic stages, we herein introduce a novel culture media complex to differentiate hDPSCs into neuron-like cells. The hDPSCs were initially isolated and characterized. The CSF was prepared from the Cisterna magna of 19-day-old Wistar rat embryos, embryonic cerebrospinal fluid (E-CSF). The hDPSCs were treated by 5% E-CSF for 2 days, then neurospheres were cultured in DMEM/F12 supplemented with 10-6 μm retinoic acid (RA), glial-derived neurotrophic factor and brain-derived neurotrophic factor for 6 days. The cells which were cultured in basic culture medium were considered as control group. Morphology of differentiated cells as well as process elongation were examined by an inverted microscope. In addition, the neural differentiation markers (Nestin and MAP2) were studied employing immunocytochemistry. Neuronal-like processes appeared 8 days after treatment. Neural progenitor marker (Nestin) and a mature neural marker (MAP2) were expressed in treated group. Moreover Nissl bodies were found in the cytoplasm of treated group. Taking these together, we have designed a simple protocol for generating neuron-like cells using CSF from the hDPSCs, applicable for cell therapy in several neurodegenerative disorders including Alzheimer's disease.}, }
@article {pmid32987701, year = {2020}, author = {Marí, M and de Gregorio, E and de Dios, C and Roca-Agujetas, V and Cucarull, B and Tutusaus, A and Morales, A and Colell, A}, title = {Mitochondrial Glutathione: Recent Insights and Role in Disease.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {9}, number = {10}, pages = {}, pmid = {32987701}, issn = {2076-3921}, support = {PI19/01410//Instituto de Salud Carlos III/ ; RTI2018-095672-B-I00//Ministerio de Ciencia e Innovación/ ; RTI2018-095572-B-I00//Ministerio de Ciencia e Innovación/ ; 2017_SGR_177//Agència de Gestió d'Ajuts Universitaris i de Recerca/ ; PI19/01410//European Regional Development Fund/ ; }, abstract = {Mitochondria are the main source of reactive oxygen species (ROS), most of them deriving from the mitochondrial respiratory chain. Among the numerous enzymatic and non-enzymatic antioxidant systems present in mitochondria, mitochondrial glutathione (mGSH) emerges as the main line of defense for maintaining the appropriate mitochondrial redox environment. mGSH's ability to act directly or as a co-factor in reactions catalyzed by other mitochondrial enzymes makes its presence essential to avoid or to repair oxidative modifications that can lead to mitochondrial dysfunction and subsequently to cell death. Since mitochondrial redox disorders play a central part in many diseases, harboring optimal levels of mGSH is vitally important. In this review, we will highlight the participation of mGSH as a contributor to disease progression in pathologies as diverse as Alzheimer's disease, alcoholic and non-alcoholic steatohepatitis, or diabetic nephropathy. Furthermore, the involvement of mitochondrial ROS in the signaling of new prescribed drugs and in other pathologies (or in other unmet medical needs, such as gender differences or coronavirus disease of 2019 (COVID-19) treatment) is still being revealed; guaranteeing that research on mGSH will be an interesting topic for years to come.}, }
@article {pmid32975732, year = {2020}, author = {Abdel-Haq, H}, title = {The Potential of Liquid Biopsy of the Brain Using Blood Extracellular Vesicles: The First Step Toward Effective Neuroprotection Against Neurodegenerative Diseases.}, journal = {Molecular diagnosis & therapy}, volume = {24}, number = {6}, pages = {703-713}, pmid = {32975732}, issn = {1179-2000}, mesh = {Animals ; Biomarkers/blood ; Brain/*metabolism ; Extracellular Vesicles/*metabolism ; Humans ; *Liquid Biopsy ; Neurodegenerative Diseases/*blood/*pathology ; *Neuroprotection ; }, abstract = {Early diagnosis and biomarker-based ante-mortem tests are essential in efforts against the development of neurodegenerative diseases and can be considered primary neuroprotective measures. Blood is the ideal biofluid for a routine ante-mortem screening test. However, biomarker discovery in the blood is particularly difficult because of interference from factors both intrinsic and extrinsic to blood with the detection of hallmark neurodegenerative biomarkers, such as the pathological prion protein, amyloid-β, and others. Blood extracellular vesicles (EVs), such as exosomes, are cell-derived vesicles released into the blood from all parts of the body (including the brain and spinal cord). They are an enriched source of neural-derived EVs containing neurodegenerative biomarkers that mirror (in the blood) the condition present in the brain. The feasibility of using, and the reliability of, neural-derived blood EVs (NDBEVs) as a method of diagnosing Alzheimer disease and other neurodegenerative diseases has been assessed in strong proof-of-concept studies. Results from these studies strongly suggest that NDBEVs might represent the right strategy for specific, reliable, and early diagnosis of neurodegenerative diseases. Based on these results, NDBEVs might enable the creation of an ante-mortem blood test (liquid biopsy of the brain) for neurodegenerative diseases. This would enormously accelerate the therapy of neurodegenerative diseases. This review highlights the powerful potential of liquid biopsy of the brain using NDBEVs for early diagnosis and treatment of neurodegenerative diseases, and the challenges and limitations related to the identification of clinically applicable EV (exosomal) biomarkers using blood are discussed.}, }
@article {pmid32973486, year = {2020}, author = {Rong, X and Xiang, L and Li, Y and Yang, H and Chen, W and Li, L and Liang, D and Zhou, X}, title = {Chronic Periodontitis and Alzheimer Disease: A Putative Link of Serum Proteins Identification by 2D-DIGE Proteomics.}, journal = {Frontiers in aging neuroscience}, volume = {12}, number = {}, pages = {248}, pmid = {32973486}, issn = {1663-4365}, abstract = {Increasing evidence indicates Chronic Periodontitis (CP) is a comorbidity of Alzheimer's disease (AD), which is the most common form of age-related dementia, and for the latter, effective diagnostic and treatment strategies are lacking. Although inflammation is present in both diseases, the exact mechanisms and cross-links between CP and AD are poorly understood; and a direct association between the two has not been reported. This study aimed to identify a direct serum proteins link between AD and CP. Two-dimensional differential in-gel electrophoresis was employed to analyze serum samples from 12 CP patients and 12 age-matched controls. Furthermore, to determine the molecular link between CP and AD, neuroblastoma SK-N-SH APPwt cells were treated with 1 μg/ml of lipopolysaccharide from Porphyromonas gingivalis (P.g-LPS). Ten differentially expressed proteins were identified in CP patients. Among them, nine proteins were up-regulated, and one protein was down-regulated. Of the 10 differentially expressed proteins, five proteins were reportedly involved in the pathology of AD: Cofilin-2, Cathepsin B, Clusterin, Triosephosphate isomerase, and inter-alpha-trypsin inhibitor heavy chain H4 (ITI-H4). Western blotting indicated significantly higher expression of Cofilin-2, Cathepsin B, and Clusterin and lower expression of ITI-H4 in the CP group than in the Control group. The serum concentration of Cathepsin B has a good correlation with MMSE scores. Moreover, the protein level of Cathepsin B (but not that of ADAM10 and BACE1) increased significantly along with a prominent increase in Aβ1-40 and Aβ1-42 in the cell lysates of P.g-LPS-treated SK-N-SH APPwt cells. Cathepsin B inhibition resulted in a sharp decrease in Aβ1-40 and Aβ1-42 in the cell lysates. Furthermore, TNF-α was one of the most important inflammatory cytokines for the P.g-LPS-induced Cathepsin B upregulation in SK-N-SH APPwt cells. These results show that CP and AD share an association, while Cathepsin B could be a key link between the two diseases. The discovery of the identical serum proteins provides a potential mechanism underlying the increased risk of AD in CP patients, which could be critical for elucidating the pathophysiology of AD.}, }
@article {pmid32967533, year = {2020}, author = {Sun, K and Jing, X and Guo, J and Yao, X and Guo, F}, title = {Mitophagy in degenerative joint diseases.}, journal = {Autophagy}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/15548627.2020.1822097}, pmid = {32967533}, issn = {1554-8635}, abstract = {Mitochondrial dysfunction is involved in aging and multiple degenerative diseases, including intervertebral disc degeneration (IVDD) and osteoarthritis (OA). Thus, the maintenance of mitochondria homeostasis and function is important. Mitophagy, a process that selectively clears damaged or dysfunctional mitochondria through autophagic machinery, functions to maintain mitochondrial quality control and homeostasis. IVDD and OA are similar joint diseases involving the degradation of cartilaginous tissues that are mainly caused by oxidative stress, cell apoptosis and extracellular matrix (ECM) degradation. Over the past decade, accumulating evidence indicates the essential role of mitophagy in the pathogenesis of IVDD and OA. Importantly, strategies by the regulation of mitophagy exert beneficial effects in the pre-clinical experiments. Given the importance and novelty of mitophagy, we provide an overview of mitophagy pathways and discuss the roles of mitophagy in IVDD and OA. We also highlight the potential of targeting mitophagy for the treatment of degenerative joint diseases.Abbreviations: AD: Alzheimer disease; AF: annulus fibrosus; ADORA2A/A2AR: adenosine A2a receptor; AMBRA1: autophagy and beclin 1 regulator 1; BMSCs: bone marrow mesenchymal stem cells; BNIP3: BCL2 interacting protein 3; BNIP3L/NIX: BCL2/adenovirus E1B interacting protein 3-like; CDH6: cadherin 6; CEP: cartilaginous endplates; circRNA: circular RNA; DNM1L/DRP1: dynamin 1-like; ECM: extracellular matrix; HIF1A: hypoxia inducible factor 1: alpha subunit; IL1B: interleukin 1 beta; IMM: inner mitochondrial membranes; IVDD: intervertebral disc degeneration; MAPK8/JNK: mitogen-activated protein kinase 8; MFN1: mitofusin 1; MFN2: mitofusin 2; MIA: monosodium iodoacetate; RHOT/MIRO: ras homolog family member T; MMP: mitochondrial transmembrane potential; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; NFE2L2: nuclear factor: erythroid 2 like 2; NP: nucleus pulposus; OA: osteoarthritis; OPA1: OPA1: mitochondrial dynamin like GTPase; OPTN: optineurin; PRKN: parkin RBR E3 ubiquitin protein ligase; PD: Parkinson disease; PGAM5: PGAM family member 5; PPARGC1A/PGC-1A: peroxisome proliferator activated receptor: gamma: coactivator 1 alpha; PHF23: PHD finger protein 23; PINK1: PTEN induced putative kinase 1; ROS: reactive oxygen species; SfMSCs: synovial fluid MSCs; SIRT1: sirtuin 1; SIRT2: sirtuin 2; SIRT3: sirtuin 3; SQSTM1/p62: sequestosome 1; TNF: tumor necrosis factor; Ub: ubiquitin; UBL: ubiquitin-like; VDAC: voltage-dependent anion channel.}, }
@article {pmid32964822, year = {2020}, author = {Al Mamun, A and Rahman, MM and Zaman, S and Munira, MS and Uddin, MS and Rauf, A and Banu, N and Ashraf, GM}, title = {Molecular Insight into the Crosstalk of UPS Components and Alzheimer's Disease.}, journal = {Current protein & peptide science}, volume = {21}, number = {12}, pages = {1193-1201}, doi = {10.2174/1389203721666200923153406}, pmid = {32964822}, issn = {1875-5550}, mesh = {Alzheimer Disease/*genetics/metabolism/pathology ; Amyloid beta-Peptides/*genetics/metabolism ; Amyloid beta-Protein Precursor/genetics/metabolism ; Brain/metabolism/pathology ; Gene Expression Regulation ; Humans ; Neurofibrillary Tangles/genetics/metabolism/pathology ; Proteasome Endopeptidase Complex/*metabolism ; Protein Aggregates/genetics ; Proteolysis ; Signal Transduction ; Ubiquitin C/*genetics/metabolism ; Ubiquitin Thiolesterase/*genetics/metabolism ; Ubiquitin-Conjugating Enzymes/genetics/metabolism ; Ubiquitin-Protein Ligases/*genetics/metabolism ; }, abstract = {The ubiquitin (Ub)-proteasome system (UPS) targets various cellular proteins for degradation. It has been found that defects in the UPS play a crucial role in the pathogenesis of Alzheimer's disease (AD), as the existence of Ub immunoreactivity in AD-linked neuronal inclusions, including neurofibrillary tangles, is observed in all types of AD cases. Current investigations have shown that components of the UPS can be connected with the early stage of AD, which is characterized by synaptic dysfunction, and to the late phases of the disease, marked by neurodegeneration. Although the significance of UPS in the pathogenesis of AD has been emphasized, targeted treatment at the main components of these pathways has a great perspective in advancing new therapeutic interventions for AD. In this review, we emphasize the relationship between UPS and AD pathology. We also represent the recent therapeutic advancements targeting UPS components in AD.}, }
@article {pmid32959702, year = {2021}, author = {Ibrahim, MA and Haleem, M and AbdelWahab, SA and Abdel-Aziz, AM}, title = {Sildenafil ameliorates Alzheimer disease via the modulation of vascular endothelial growth factor and vascular cell adhesion molecule-1 in rats.}, journal = {Human & experimental toxicology}, volume = {40}, number = {4}, pages = {596-607}, doi = {10.1177/0960327120960775}, pmid = {32959702}, issn = {1477-0903}, abstract = {Alzheimer disease (AD) is a chronic neurodegenerative disease with multi-pathways pathogenesis. Sildenafil is a selective phosphodiesterase-5 inhibitor with a potential benefit in the treatment of AD. This study investigated the possible mechanisms underlying the effect of sildenafil in AD with emphasis on vascular endothelial growth factor (VEGF), and vascular cell adhesion molecule-1 (VCAM-1). Twenty-four adult male rats were classified into four groups; control group: received vehicles, sildenafil-control: received sildenafil (15 mg/kg/day, p.o.), AD group received Aluminum (25 mg/kg/day, p.o.), AD-treated group: received sildenafil (15 mg/kg/day, p.o.) for 6 weeks. AD was assessed by memory performance test and confirmed by histopathological examination and immunostaining of, neurogenesis marker nestin and α-synuclein. The levels of VEGF-A, VCAM-1, oxidative stress markers and TNF-α in brain tissue were evaluated. AD rats showed histopathological evidences of AD; along with increased latency time in the memory test. There was a decrease in VEGF-A, and an increase in VCAM-1, TNF-α, and oxidative stress markers. Immunohistochemical study showed a significant increase in α-synuclein and a significant decrease in nestin expressions in brain tissues. Sildenafil administration ameliorated the histopathological changes and decreased latency time. Such effect was associated with a decrease in VCAM-1, TNF-α and oxidative stress as well as an increase in VEGF-A. Sildenafil caused a significant increase in nestin and a decrease in α-synuclein immunostaining. These findings suggested a protective effect of sildenafil via modulation of VEGF-A, and VCAM-1.}, }
@article {pmid32959271, year = {2020}, author = {Wu, B and Cai, H and Tang, S and Xu, Y and Shi, Q and Wei, L and Meng, L and Zhang, N and Wang, X and Xiao, D and Zou, Y and Yang, X and Li, X and Lu, C}, title = {Methionine-Mediated Protein Phosphatase 2A Catalytic Subunit (PP2Ac) Methylation Ameliorates the Tauopathy Induced by Manganese in Cell and Animal Models.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {17}, number = {4}, pages = {1878-1896}, pmid = {32959271}, issn = {1878-7479}, abstract = {The molecular mechanism of Alzheimer-like cognitive impairment induced by manganese (Mn) exposure has not yet been fully clarified, and there are currently no effective interventions to treat neurodegenerative lesions related to manganism. Protein phosphatase 2 A (PP2A) is a major tau phosphatase and was recently identified as a potential therapeutic target molecule for neurodegenerative diseases; its activity is directed by the methylation status of the catalytic C subunit. Methionine is an essential amino acid, and its downstream metabolite S-adenosylmethionine (SAM) participates in transmethylation pathways as a methyl donor. In this study, the neurotoxic mechanism of Mn and the protective effect of methionine were evaluated in Mn-exposed cell and rat models. We show that Mn-induced neurotoxicity is characterized by PP2Ac demethylation accompanied by abnormally decreased LCMT-1 and increased PME-1, which are associated with tau hyperphosphorylation and spatial learning and memory deficits, and that the poor availability of SAM in the hippocampus is likely to determine the loss of PP2Ac methylation. Importantly, maintenance of local SAM levels through continuous supplementation with exogenous methionine, or through specific inhibition of PP2Ac demethylation by ABL127 administration in vitro, can effectively prevent tau hyperphosphorylation to reduce cellular oxidative stress, apoptosis, damage to cell viability, and rat memory deficits in cell or animal Mn exposure models. In conclusion, our data suggest that SAM and PP2Ac methylation may be novel targets for the treatment of Mn poisoning and neurotoxic mechanism-related tauopathies.}, }
@article {pmid32957874, year = {2020}, author = {Mishra, J and Kumar, B and Pandey, M and Pottoo, FH and Fayaz, F and Khan, FA and Sahoo, PK}, title = {Carbon Nano Tubes: Novel drug delivery system in amelioration of Alzheimer's disease.}, journal = {Combinatorial chemistry & high throughput screening}, volume = {}, number = {}, pages = {}, doi = {10.2174/1386207323999200918112538}, pmid = {32957874}, issn = {1875-5402}, abstract = {BACKGROUND: Alzheimer's disease is an irreversible, progressive brain disorder manifested with symptoms like loss of memory (known as dementia), personality changes, loss of cognition, impaired movement, confusion, deteriorated planning and thought process. Neurodegeneration in Alzheimer's disease is the result of deposition of protein beta-amyloid that forms plaques and another protein called tau, forming tangles that prevent proper functioning of nerve cells in the brain.
METHODS: The goal of the review was to comprehensively study the utilization of nanotechnology and the role that carbon nanotubes can play as a drug delivery system for amelioration of Alzheimer's disease.
RESULTS: Nanotechnology is one of the most researched domains of modern science. It contributes significantly to therapeutics by facilitating drug therapy to reach the target sites, which are otherwise difficult to reach with conventional drug delivery systems. Carbon nanotubes are the allotropes of carbon in which several carbon atoms bind with each other to form a cylindrical or a tube-like structure. The carbon nanotubes possess several unique qualities, which confers them with a high potential of being utilized as an efficient drug delivery system. They offer high drug loading, can readily cross the toughest biological barriers like BBB. Carbon nanotubes also facilitate the passage of drugs to the brain via the olfactory route, which further helps in restoring normal autophagy, thus preventing the elimination of autophagic chemicals. They can carry a vast range of cargos, including drugs, antigens, genetic materials, and biological macromolecules.
CONCLUSION: Carbon nanotubes are highly promising drug delivery system for anti-Alzheimer's drugs. They have potential of overcoming the various biological barriers like BBB. However, more extensive research is required so as to set up a firm base for development of advanced commercial products based on carbon nanotubes for treatment of Alzheimer's disease.}, }
@article {pmid32957414, year = {2020}, author = {Kainuma, M and Funakoshi, K and Ouma, S and Yamashita, KI and Ohara, T and Yoshiiwa, A and Murata, M and Tsuboi, Y}, title = {The efficacy and safety of hachimijiogan for mild Alzheimer disease in an exploratory, open standard treatment controlled, randomized allocation, multicenter trial: A study protocol.}, journal = {Medicine}, volume = {99}, number = {38}, pages = {e22370}, doi = {10.1097/MD.0000000000022370}, pmid = {32957414}, issn = {1536-5964}, mesh = {Aged ; Alzheimer Disease/*drug therapy ; Cognition/drug effects ; Drugs, Chinese Herbal/*therapeutic use ; Female ; Humans ; Male ; Medicine, Kampo/methods ; Multicenter Studies as Topic ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Dementia among the Japanese aged 65 years or over population is estimated to approach about 700 million cases by 2025, and a corresponding rapid increase in Alzheimer disease (AD) can also be expected. The ballooning number of dementia patients, including AD, is creating major medical and social challenges. At present, only 3 drugs are recognized for the treatment of mild AD, and these are only used to alleviate symptoms. Although new therapies are needed to treat mild AD, insufficient development of disease-modifying drugs is being done.
METHODS/DESIGN: The aim of this exploratory, open standard, treatment-controlled, randomized allocation, multicenter trial is to determine the efficacy of the traditional Japanese Kampo medicine hachimijiogan (HJG) on the cognitive dysfunction of mild AD.Eighty-six patients with AD diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 and as mild AD according to the Mini Mental State Examination (MMSE ≥21) will be included. All will already have been taking the same dose of Donepezil, Galantamine, or Rivastigmine for more than 3 months. The patients will be randomly assigned to receive additional treatment with HJG or to continue mild AD treatment without additional HJG. The primary endpoint is the change from baseline of the Alzheimer's Disease Assessment Scale-cognitive component- Japanese version (ADAS-Jcog). ADAS-Jcog is a useful index for detecting change over time that investigates memory and visuospatial cognition injury from the early stage. The secondary endpoints are the changes from baseline of the Instrumental Activity of Daily Life, Apathy scale, and Nueropsychiatric Inventory scores. In this protocol, we will examine the Geriatric depression scale and do Metabolome analysis as exploratory endpoints. The recruitment period will be from August 2019 to July 2021.
DISCUSSION: This is the first trial of Kampo medicine designed to examine the efficacy of HJG for the cognitive dysfunction of patients with mild AD.
TRIAL REGISTRATION: This trial was registered on the Japan Registry of Clinical trials on 2 August 2, 2019 (jRCTs 071190018).}, }
@article {pmid32947427, year = {2020}, author = {Lorettu, L and Carpita, B and Nivoli, A and Milia, P and De Iorio, G and Cremone, IM and DellʼOsso, L}, title = {Lithium Use During Pregnancy in a Patient With Bipolar Disorder and Multiple Sclerosis.}, journal = {Clinical neuropharmacology}, volume = {43}, number = {5}, pages = {158-161}, doi = {10.1097/WNF.0000000000000407}, pmid = {32947427}, issn = {1537-162X}, mesh = {Adult ; Antimanic Agents/*adverse effects/*therapeutic use ; Bipolar Disorder/complications/*drug therapy ; Female ; Humans ; Infant, Newborn ; Lithium Compounds/*adverse effects/*therapeutic use ; Multiple Sclerosis/complications/*drug therapy ; Pregnancy ; Pregnancy Complications/*drug therapy ; Thyroid Hormones/therapeutic use ; Treatment Outcome ; }, abstract = {Although lithium is widely used as a first-line treatment for mood disorders, its mood-stabilizing effects remain not fully understood. A growing body of data are stressing that lithium seems to show broader properties, including neuroprotective effects. Lithium's ability to inhibit glycogen synthase kinase 3β, an enzyme that participates in the phosphorylation of τ, a microtubule-associated protein, stimulated interest in its possible therapeutic role in Alzheimer disease and other neurodegenerative disorders. Preliminary data also support exploration of lithium's potential therapeutic role in multiple sclerosis, an autoimmune disorder that is associated with co-occurring mood disorders. Lithium is associated with teratogenic risks to the developing fetus; however, recently revised downward estimates of its teratogenic risk of causing fetal cardiac malformation suggest that its potential therapeutic benefit to both mothers with bipolar disorder and their offspring should be considered in at least some cases. A 43-year-old woman previously diagnosed with bipolar disorder and MS was treated with lithium and thyroid hormone supplementation as her sole medications during her pregnancy. The patient remained euthymic throughout her pregnancy and over the course of her 5-year follow-up evaluations on this medication regimen. In addition to her stable mood, there has been no symptomatic progression or relapse of her MS, and her daughter continues to develop normally.The case supports consideration of balancing lithium's mood-stabilizing benefit with its known teratogenic risk during pregnancy. The case also supports exploration of possible additional benefit in the context of MS co-occurring with bipolar disorder.}, }
@article {pmid32941929, year = {2020}, author = {Vaz, M and Silvestre, S}, title = {Alzheimer's disease: Recent treatment strategies.}, journal = {European journal of pharmacology}, volume = {887}, number = {}, pages = {173554}, doi = {10.1016/j.ejphar.2020.173554}, pmid = {32941929}, issn = {1879-0712}, mesh = {Alzheimer Disease/*drug therapy/metabolism ; Amyloid beta-Peptides/drug effects/metabolism ; Animals ; Antibodies, Monoclonal/therapeutic use ; Humans ; Immunotherapy ; Tauopathies/drug therapy ; tau Proteins/drug effects/metabolism ; }, abstract = {Alzheimer Disease (AD) is a neurodegenerative disease characterized by two neuropathological hallmarks: extracellular deposition of amyloid plaques and intracellular neurofibrillary tangles. Current treatment for AD (donepezil, galantamine, rivastigmine and memantine) is only symptomatic and has modest benefits. Thus, the development of drugs with the potential to change the progression of the disease has been a priority. Therapies targeting amyloid β have been the focus for almost 30 years. However, highly promising drugs recently failed to show clinical benefits in phase III trials. Even the positive findings presented by Biogen on Aducanumab are not entirely clear and further data is necessary to confirm its validity. Therefore, researchers are turning their efforts around to tau-targeting therapies, since tau protein appears to be better correlated with the severity of cognitive decline than amyloid β. Currently, most anti-tau agents in clinical trials are immunotherapies and they are in the early stages of clinical research. Four monoclonal antibodies anti-tau (Gosuranemab, Tilavonemab, Semorinemab and Zagotenemab) and one anti-tau vaccine (AADvac1) have reached phase II, so far. In this review, we discuss the potential disease-modifying agents tested in clinical trials and update the information of drugs that are still under clinical evaluation.}, }
@article {pmid32939050, year = {2020}, author = {Ballard, C and Aarsland, D and Cummings, J and O'Brien, J and Mills, R and Molinuevo, JL and Fladby, T and Williams, G and Doherty, P and Corbett, A and Sultana, J}, title = {Drug repositioning and repurposing for Alzheimer disease.}, journal = {Nature reviews. Neurology}, volume = {16}, number = {12}, pages = {661-673}, pmid = {32939050}, issn = {1759-4766}, support = {P20 AG068053/AG/NIA NIH HHS/United States ; U01 NS093334/NS/NINDS NIH HHS/United States ; P20 GM109025/GM/NIGMS NIH HHS/United States ; R01 AG053798/AG/NIA NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; }, abstract = {Drug repositioning and repurposing can enhance traditional drug development efforts and could accelerate the identification of new treatments for individuals with Alzheimer disease (AD) dementia and mild cognitive impairment. Transcriptional profiling offers a new and highly efficient approach to the identification of novel candidates for repositioning and repurposing. In the future, novel AD transcriptional signatures from cells isolated at early stages of disease, or from human neurons or microglia that carry mutations that increase the risk of AD, might be used as probes to identify additional candidate drugs. Phase II trials assessing repurposed agents must consider the best target population for a specific candidate therapy as well as the mechanism of action of the treatment. In this Review, we highlight promising compounds to prioritize for clinical trials in individuals with AD, and discuss the value of Delphi consensus methodology and evidence-based reviews to inform this prioritization process. We also describe emerging work, focusing on the potential value of transcript signatures as a cost-effective approach to the identification of novel candidates for repositioning.}, }
@article {pmid32932702, year = {2020}, author = {Semenov, VE and Zueva, IV and Mukhamedyarov, MA and Lushchekina, SV and Petukhova, EO and Gubaidullina, LM and Krylova, ES and Saifina, LF and Lenina, OA and Petrov, KA}, title = {Novel Acetylcholinesterase Inhibitors Based on Uracil Moiety for Possible Treatment of Alzheimer Disease.}, journal = {Molecules (Basel, Switzerland)}, volume = {25}, number = {18}, pages = {}, pmid = {32932702}, issn = {1420-3049}, support = {19-15-00344//Russian Science Support Foundation/ ; 19-03-00043//Russian Foundation for Basic Research/ ; АААА-А18-118040390114-8//Ministry of Education and Science of the Russian Federation/ ; }, mesh = {Acetylcholinesterase/*chemistry ; Alzheimer Disease/*drug therapy ; Ammonium Compounds/chemistry ; Animals ; Anions ; Behavior, Animal ; Binding Sites ; Blood-Brain Barrier/drug effects ; Butyrylcholinesterase/*chemistry ; Catalytic Domain ; Cholinesterase Inhibitors/*pharmacology ; Disease Models, Animal ; Drug Design ; Drug Evaluation, Preclinical ; Humans ; Inhibitory Concentration 50 ; Maze Learning ; Memory Disorders/*drug therapy ; Mice ; Molecular Docking Simulation ; Scopolamine ; Uracil/analogs & derivatives/*chemistry ; }, abstract = {In this study, novel derivatives based on 6-methyluracil and condensed uracil were synthesized, namely, 2,4-quinazoline-2,4-dione with ω-(ortho-nitrilebenzylethylamino) alkyl chains at the N atoms of the pyrimidine ring. In this series of synthesized compounds, the polymethylene chains were varied from having tetra- to hexamethylene chains, and secondary NH, tertiary ethylamino, and quaternary ammonium groups were introduced into the chains. The molecular modeling of the compounds indicated that they could function as dual binding site acetylcholinesterase inhibitors, binding to both the peripheral anionic site and active site. The data from in vitro experiments show that the most active compounds exhibit affinity toward acetylcholinesterase within a nanomolar range, with selectivity for acetylcholinesterase over butyrylcholinesterase reaching four orders of magnitude. In vivo biological assays demonstrated the potency of these compounds in the treatment of memory impairment using an animal model of Alzheimer disease.}, }
@article {pmid32932142, year = {2020}, author = {Elzoghby, AO and Abdelmoneem, MA and Hassanin, IA and Abd Elwakil, MM and Elnaggar, MA and Mokhtar, S and Fang, JY and Elkhodairy, KA}, title = {Lactoferrin, a multi-functional glycoprotein: Active therapeutic, drug nanocarrier & targeting ligand.}, journal = {Biomaterials}, volume = {263}, number = {}, pages = {120355}, doi = {10.1016/j.biomaterials.2020.120355}, pmid = {32932142}, issn = {1878-5905}, mesh = {Drug Carriers ; Drug Delivery Systems ; *Lactoferrin ; Ligands ; *Nanoparticles ; }, abstract = {Recent progress in protein-based nanomedicine, inspired by the success of Abraxane® albumin-paclitaxel nanoparticles, have resulted in novel therapeutics used for treatment of challenging diseases like cancer and viral infections. However, absence of specific drug targeting, poor pharmacokinetics, premature drug release, and off-target toxicity are still formidable challenges in the clinic. Therefore, alternative protein-based nanomedicines were developed to overcome those challenges. In this regard, lactoferrin (Lf), a glycoprotein of transferrin family, offers a promising biodegradable well tolerated material that could be exploited both as an active therapeutic and drug nanocarrier. This review highlights the major pharmacological actions of Lf including anti-cancer, antiviral, and immunomodulatory actions. Delivery technologies of Lf to improve its pries and enhance its efficacy were also reviewed. Moreover, different nano-engineering strategies used for fabrication of drug-loaded Lf nanocarriers were discussed. In addition, the use of Lf for functionalization of drug nanocarriers with emphasis on tumor-targeted drug delivery was illustrated. Besides its wide application in oncology nano-therapeutics, we discussed the recent advances of Lf-based nanocarriers as efficient platforms for delivery of anti-parkinsonian, anti-Alzheimer, anti-viral drugs, immunomodulatory and bone engineering applications.}, }
@article {pmid32927795, year = {2020}, author = {Roda, AR and Montoliu-Gaya, L and Serra-Mir, G and Villegas, S}, title = {Both Amyloid-β Peptide and Tau Protein Are Affected by an Anti-Amyloid-β Antibody Fragment in Elderly 3xTg-AD Mice.}, journal = {International journal of molecular sciences}, volume = {21}, number = {18}, pages = {}, pmid = {32927795}, issn = {1422-0067}, support = {SAF2017-89613-R//Ministerio de Ciencia e Innovación/ ; }, mesh = {Alzheimer Disease/*drug therapy/metabolism ; Amyloid beta-Peptides/metabolism ; Animals ; Drug Evaluation, Preclinical ; Female ; Hippocampus/metabolism ; Mice, Transgenic ; tau Proteins/metabolism ; }, abstract = {Alzheimer's disease (AD) is the most common dementia worldwide. According to the amyloid hypothesis, the early accumulation of the Aβ-peptide triggers tau phosphorylation, synaptic dysfunction, and eventually neuronal death leading to cognitive impairment, as well as behavioral and psychological symptoms of dementia. ScFv-h3D6 is a single-chain variable fragment that has already shown its ability to diminish the amyloid burden in 5-month-old 3xTg-AD mice. However, tau pathology is not evident at this early stage of the disease in this mouse model. In this study, the effects of scFv-h3D6 on Aβ and tau pathologies have been assessed in 22-month-old 3xTg-AD mice. Briefly, 3xTg-AD female mice were treated for 2 weeks with scFv-h3D6 and compared with 3xTg-AD and non-transgenic (NTg) mice treated with PBS. The treatment with scFv-h3D6 was unequivocally effective in reducing the area of Aβ staining. Furthermore, a tendency for a reduction in tau levels was also observed after treatment that points to the interplay between Aβ and tau pathologies. The pro-inflammatory state observed in the 3xTg-AD mice did not progress after scFv-h3D6 treatment. In addition, the treatment did not alter the levels of apolipoprotein E or apolipoprotein J. Thus, a 2-week treatment with scFv-h3D6 was able to reduce AD-like pathology in elderly 3xTg-AD female mice.}, }
@article {pmid32925798, year = {2020}, author = {Wang, M and Peng, H and Peng, Z and Huang, K and Li, T and Li, L and Wu, X and Shi, H}, title = {Efficacy and safety of ginkgo preparation in patients with vascular dementia: A protocol for systematic review and meta-analysis.}, journal = {Medicine}, volume = {99}, number = {37}, pages = {e22209}, doi = {10.1097/MD.0000000000022209}, pmid = {32925798}, issn = {1536-5964}, mesh = {Activities of Daily Living ; Dementia, Vascular/*drug therapy/epidemiology ; Depression/epidemiology ; Health Status ; Humans ; Mental Status and Dementia Tests ; Plant Extracts/adverse effects/*therapeutic use ; Randomized Controlled Trials as Topic ; Research Design ; }, abstract = {BACKGROUND: Vascular dementia has become the second most common type of dementia after Alzheimer disease. At present, there is no uniform standard for VaD treatment guidelines among countries. The efficacy of ginkgo biloba in the treatment of vascular dementia is still controversial. The purpose of this study is to evaluate the effectiveness and safety of ginkgo biloba in the treatment of vascular dementia through meta-analysis.
METHODS: Six English databases (PubMed, Web of science, Medline, EBASE, Springer Cochrane Library, and WHO International Clinical Trials Registry Platform) and 4 Chinese databases (Wan fang Database, Chinese Scientific Journal Database, China National Knowledge Infrastructure Database(CNKI) and Chinese Biomedical Literature Database) will be searched normatively according to the rule of each database from the inception to August 1, 2020. Two reviewers will independently conduct article selection, data collection, and risk of bias evaluation. Any disagreement will be resolved by discussion with the third reviewer. Either the fixed-effects or random-effects model will be used for data synthesis based on the heterogeneity test. The change in the scores on mini-mental state examination, activity of daily living scale and Montreal cognitive assement will be used as the main outcome measure, Hamilton depression scale, Hastgawa dementia scale, blessed dementia scale, clinical dmentia rating scale as the secondary outcome. Treatment emergent symptom scale, general physical examination (temperature, pulse, respiration, blood pressure), Routine examination of blood, urine and stool, electrocardiogram, liver and kidney function examination as the security indexs. RevMan5.3.5 will be used for meta-analysis.
RESULTS: This study will provide high-quality evidence to assess the effectiveness and safety of ginkgo preparation for vascular dementia.
CONCLUSION: This systematic review will explore whether ginkgo preparation is an effective and safe intervention for vascular dementia.
ETHICS AND DISSEMINATION: Ethical approval are not required for this study. The systematic review will be published in a peer-reviewed journal, presented at conferences, and will be shared on social media platforms. This review will be disseminated in a peer-reviewed journal or conference presentation.
PROSPERO REGISTRATION NUMBER: PROSPERO CRD42020167851.}, }
@article {pmid32925791, year = {2020}, author = {Wang, H and Yu, H and Song, K and Xiong, F and Zhang, H}, title = {Traditional Chinese medicine for mild cognitive impairment: A protocol for systematic review and network meta-analysis.}, journal = {Medicine}, volume = {99}, number = {37}, pages = {e22187}, doi = {10.1097/MD.0000000000022187}, pmid = {32925791}, issn = {1536-5964}, mesh = {Activities of Daily Living ; Cognitive Dysfunction/*therapy ; Humans ; Medicine, Chinese Traditional/adverse effects/*methods ; Network Meta-Analysis ; Randomized Controlled Trials as Topic ; Research Design ; }, abstract = {BACKGROUND: Mild cognitive impairment (MCI) is an intermediate stage between normal aging and Alzheimer disease, which is the most common form of dementia in the world. In clinical practice, traditional Chinese medicine (TCM) interventions have been administered for MCI, However, there is still uncertain about what strategy of TCM interventions treatment should be preferred in clinical practice. This study aims to evaluate the efficacy and acceptability of different TCM therapies through systematic review and network meta-analysis.
METHODS: According to the strategy, the authors will retrieve a total of 7 electronic databases by August 2020, including PubMed, the Cochrane Library, EMbase, China National Knowledge Infrastructure, China Biological Medicine, Chongqing VIP, and Wan-fang databases. After a series of screening, 2 researchers will use Aggregate Data Drug Information System and Stata software to analyze the data extracted from the randomized controlled trials of TCM therapies for MCI. The primary outcome of this study is the improvement of cognitive function and the secondary outcome is the activities of daily living, clinical efficacy, and adverse events, and the quality of the evidence will be evaluated using the Grading of Recommendations Assessment, Development and Evaluation instrument.
RESULTS: This study will provide a reliable evidence for the selection of TCM therapies in the treatment of MCI.
CONCLUSION: This study will generate evidence for different TCM therapies for MCI and provide a decision-making reference for clinical research.
ETHICS AND DISSEMINATION: This study does not require ethical approval. The results will be disseminated through a peer-reviewed publication.
OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/JV9KG.}, }
@article {pmid32921425, year = {2021}, author = {Vecchierini, MF and Kilic-Huck, U and Quera-Salva, MA and , }, title = {Melatonin (MEL) and its use in neurological diseases and insomnia: Recommendations of the French Medical and Research Sleep Society (SFRMS).}, journal = {Revue neurologique}, volume = {177}, number = {3}, pages = {245-259}, doi = {10.1016/j.neurol.2020.06.009}, pmid = {32921425}, issn = {0035-3787}, mesh = {Central Nervous System Diseases ; Circadian Rhythm ; Humans ; Melatonin/*therapeutic use ; Quality of Life ; Sleep ; *Sleep Initiation and Maintenance Disorders/drug therapy ; }, abstract = {The French Medicine and Research Sleep Society had organized a consensus conference about sleep/wake circadian rhythms and their disorders. During this conference a subgroup of 11 sleep doctors/researchers looked specifically at the use of MEL in different pathologies. This article gives a summary of the main results of MEL therapy in some neurological diseases and insomnia approved by this consensus group. Exogenous MEL, which crosses the blood-brain barrier, has been used as a treatment in its two available forms: an immediate release form that principally shows a chronobiotic action and a long release form that mimics the physiological MEL secretion rhythm and is used to replace reduced physiological secretion. MEL secretion decreases frequently with age, mostly in elderly insomniacs and dementia patients. Results of level A studies show that MEL therapy, used as an add-on treatment, has beneficial effects in mild cognitive impairment (MCI) and Alzheimer patients with sleep disorders in improving sleep quality and in regulating the sleep/wake rhythm. MEL has to be prescribed as early as possible and for a long period, at a dose of 2 to 5 or 10 mg. It may have a beneficial effect on cognitive function in MCI but shows no effect in moderate to severe Alzheimer's disease. It should be emphasized that there are no serious side effects with MEL treatment. In these diseases, light therapy used 12 hours before melatonin treatment has a positive synergic effect. In REM sleep behavior disorder, immediate release MEL should be prescribed first as its side effect profile is much better than clonazepam shortly before bedtime. MEL has a good efficacy on clinical symptoms and PSG REM sleep without atonia episodes and is well tolerated. In Parkinson disease with sleep disorders and without REM sleep behavior disorder, MEL seems to improve subjective sleep quality but no conclusions can be drawn. There is insufficient scientific proof for using MEL as a prophylactic treatment in primary headache, migraine and cluster headache. In epileptic patients, MEL can be safely used to regulate the sleep/wake rhythm and to improve insomnia but more randomized controlled studies are necessary. In primary or no-comorbid insomnia, only a 2 mg dose of slow release MEL, 1 to 2 hours before bedtime, over a period of 3 to 12 weeks, is recommended. It decreases sleep onset latency, improves quality of sleep, morning alertness and quality of life without serious side effects and without withdrawal symptoms.}, }
@article {pmid32920292, year = {2020}, author = {Elibol, B and Beker, M and Terzioglu-Usak, S and Dalli, T and Kilic, U}, title = {Thymoquinone administration ameliorates Alzheimer's disease-like phenotype by promoting cell survival in the hippocampus of amyloid beta1-42 infused rat model.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {79}, number = {}, pages = {153324}, doi = {10.1016/j.phymed.2020.153324}, pmid = {32920292}, issn = {1618-095X}, mesh = {Acetylcholinesterase/metabolism ; Alzheimer Disease/*drug therapy/genetics/pathology ; Amyloid beta-Peptides/pharmacology ; Animals ; Benzoquinones/*pharmacology ; Cell Survival/drug effects ; Disease Models, Animal ; Female ; Gene Expression Regulation/drug effects ; Hippocampus/*drug effects/metabolism/pathology ; MAP Kinase Signaling System/drug effects ; Maze Learning/drug effects ; Memory/drug effects ; Neurons/drug effects ; Neuroprotective Agents/*pharmacology ; Peptide Fragments/pharmacology ; Phosphorylation/drug effects ; Rats, Sprague-Dawley ; }, abstract = {BACKGROUND: Thymoquinone (TQ), a biologically active ingredient of Nigella sativa, has anti-inflammatory, anti-oxidative and neuroprotective properties. Therefore, it could be a good candidate in the recovery of Alzheimer`s disease (AD) pathology rather than current symptomatic reliefs.
PURPOSE: In the present study, we examined the molecular healing effects of TQ in amyloid beta 1-42 (Aβ1-42) peptide-infused AD rat hippocampus.
STUDY DESIGN: A micro-osmotic pump containing aggregated Aβ1-42 was cannulated into the hippocampus of adult female rats. After two weeks infusion, the dose of TQ (10 mg/kg or 20 mg/kg) was determined according to the HPLC results of cerebrospinal fluid and TQ was given to rats intragastrically for 15 days.
METHODS: The memory performance of rats was determined by Morris water maze test. Afterwards, the acetylcholinesterase (AChE) level were measured by ELISA. Histopathological examinations of hippocampal tissue were performed for cell survival by Nissl staining, for detection of amyloid plaque deposits by Congo red staining and for determination of degenerating neurons by Fluoro Jade C staining. MicroRNA/mRNA levels and protein expressions of AD-related genes and proteins were analyzed by Real-Time Polymerase Chain Reaction and Western Blotting, respectively.
RESULTS: Administration of TQ enhanced the memory performance of Aβ1-42 infused rats and it also ameliorated the neuronal loss in the cornu ammonis (CA1), but not in the dentate gyrus (DG). In addition, TQ treatment decreased the fibril deposition whose accumulation was significantly higher in the Aβ1-42-infused animals compared to that of the control group. The expression profiles of mir29c and Bax which significantly upregulated in the Aβ1-42-infused animals were attenuated by TQ. Furthermore, administration of TQ decreased the expressions of Aβ, phosphorylated-tau, and BACE-1 proteins. There was no significant therapeutic effect of TQ on the AKT/GSK3β or MAPK signaling pathways which were affected due to Aβ1-42 infusion.
CONCLUSION: TQ has the capacity to recover the neuropathology by removing Aβ plaques and by restoring neuron viability. All might have established the molecular basement of the consolidation in the memory observed by means of TQ treatment.}, }
@article {pmid32917871, year = {2020}, author = {Flores, J and Noël, A and Foveau, B and Beauchet, O and LeBlanc, AC}, title = {Pre-symptomatic Caspase-1 inhibitor delays cognitive decline in a mouse model of Alzheimer disease and aging.}, journal = {Nature communications}, volume = {11}, number = {1}, pages = {4571}, pmid = {32917871}, issn = {2041-1723}, support = {153097//CIHR/Canada ; }, mesh = {Aging/*metabolism ; Alzheimer Disease/drug therapy/*metabolism ; Amyloid beta-Peptides/metabolism ; Animals ; Behavior, Animal ; Cognitive Dysfunction/drug therapy/*metabolism ; Cytokines/metabolism ; Dipeptides/blood/pharmacology ; Disease Models, Animal ; Encephalitis/metabolism/pathology ; Female ; Humans ; Inflammation/metabolism ; Male ; Memory Disorders/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Serpins/blood/*metabolism/pharmacology ; Spatial Memory/physiology ; Viral Proteins/blood/*metabolism/pharmacology ; para-Aminobenzoates/blood/pharmacology ; }, abstract = {Early therapeutic interventions are essential to prevent Alzheimer Disease (AD). The association of several inflammation-related genetic markers with AD and the early activation of pro-inflammatory pathways in AD suggest inflammation as a plausible therapeutic target. Inflammatory Caspase-1 has a significant impact on AD-like pathophysiology and Caspase-1 inhibitor, VX-765, reverses cognitive deficits in AD mouse models. Here, a one-month pre-symptomatic treatment of Swedish/Indiana mutant amyloid precursor protein (APPSw/Ind) J20 and wild-type mice with VX-765 delays both APPSw/Ind- and age-induced episodic and spatial memory deficits. VX-765 delays inflammation without considerably affecting soluble and aggregated amyloid beta peptide (Aβ) levels. Episodic memory scores correlate negatively with microglial activation. These results suggest that Caspase-1-mediated inflammation occurs early in the disease and raise hope that VX-765, a previously Food and Drug Administration-approved drug for human CNS clinical trials, may be a useful drug to prevent the onset of cognitive deficits and brain inflammation in AD.}, }
@article {pmid32914577, year = {2020}, author = {Guo, J and Wang, Z and Liu, R and Huang, Y and Zhang, N and Zhang, R}, title = {Memantine, Donepezil, or Combination Therapy-What is the best therapy for Alzheimer's Disease? A Network Meta-Analysis.}, journal = {Brain and behavior}, volume = {10}, number = {11}, pages = {e01831}, pmid = {32914577}, issn = {2162-3279}, support = {81674066//National Natural Science Foundation of China/ ; cstc2017jcyjAX0397//Natural Science Foundation of Chongqing/ ; }, mesh = {*Alzheimer Disease/drug therapy ; China ; Donepezil ; Humans ; *Memantine/therapeutic use ; Network Meta-Analysis ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a degenerative brain disease that progresses over time, heavily burdening patients, families, and aging societies worldwide. Memantine and donepezil are frequently used in its treatment, both as monotherapy and in combination. This multiple treatment comparison meta-analysis assessed the efficacy of these regimens and placebo in the management of AD.
METHODS: We searched PubMed, Embase, the Cochrane Library, and Wanfang Med Online and China National Knowledge Infrastructure for English and Chinese publications from the first records to 17 April 2020. Two investigators scanned articles for placebo-controlled trials of memantine and donepezil alone and in combination. We extracted data on the following outcomes: cognition, global assessment, daily activities, neuropsychiatric symptoms, adverse events, and the acceptability and cost of these treatment regimens.
RESULTS: Of 936 records screened, we included 54 trials in this analysis. The combination therapy was more effective in improving cognition (mean difference (MD)-5.01, 95% credible interval (95% Crl) -10.73 to 0.86 in the Alzheimer's Disease Assessment Scale-Cognitive Subscale; MD 9.61, 95% Crl 2.29 to 16.97 in the Severe Impairment Battery), global assessment (MD -2.88, 95% Crl -6.04 to 0.40), daily activities (MD 13.06, 95% Crl -34.04 to 58.92), and neuropsychiatric symptoms (MD -6.84, 95% Crl -10.62 to -2.82) compared with placebo. Memantine was more acceptable than placebo (MD 0.93, 95% Crl 0.69 to 1.22).
CONCLUSIONS: Memantine plus donepezil showed superior outcomes for cognition, global assessment, daily activities, and neuropsychiatric symptoms, but lower acceptability than monotherapy and placebo. Combination therapy may be more cost-effective, because memantine slows the progression of AD.}, }
@article {pmid32914393, year = {2021}, author = {Stazi, M and Wirths, O}, title = {Chronic Memantine Treatment Ameliorates Behavioral Deficits, Neuron Loss, and Impaired Neurogenesis in a Model of Alzheimer's Disease.}, journal = {Molecular neurobiology}, volume = {58}, number = {1}, pages = {204-216}, pmid = {32914393}, issn = {1559-1182}, mesh = {Administration, Oral ; Alzheimer Disease/complications/*drug therapy/*pathology/physiopathology ; Animals ; Anxiety/complications/physiopathology ; *Behavior, Animal/drug effects ; CA1 Region, Hippocampal/pathology ; Disease Models, Animal ; Memantine/administration & dosage/pharmacology/*therapeutic use ; Mice, Transgenic ; Motor Activity/drug effects ; *Neurogenesis/drug effects ; Neurons/drug effects/*pathology ; Open Field Test ; Spatial Memory/drug effects ; }, abstract = {Memantine, a non-competitive NMDA receptor antagonist possessing neuroprotective properties, belongs to the small group of drugs which have been approved for the treatment of Alzheimer's disease (AD). While several preclinical studies employing different transgenic AD mouse models have described beneficial effects with regard to rescued behavioral deficits or reduced amyloid plaque pathology, it is largely unknown whether memantine might have beneficial effects on neurodegeneration. In the current study, we assessed whether memantine treatment has an impact on hippocampal neuron loss and associated behavioral deficits in the Tg4-42 mouse model of AD. We demonstrate that a chronic oral memantine treatment for 4 months diminishes hippocampal CA1 neuron loss and rescues learning and memory performance in different behavioral paradigms, such as Morris water maze or a novel object recognition task. Cognitive benefits of chronic memantine treatment were accompanied by an amelioration of impaired adult hippocampal neurogenesis. Taken together, our results demonstrate that memantine successfully counteracts pathological alterations in a preclinical mouse model of AD.}, }
@article {pmid32913022, year = {2020}, author = {Cirrito, JR and Wallace, CE and Yan, P and Davis, TA and Gardiner, WD and Doherty, BM and King, D and Yuede, CM and Lee, JM and Sheline, YI}, title = {Effect of escitalopram on Aβ levels and plaque load in an Alzheimer mouse model.}, journal = {Neurology}, volume = {95}, number = {19}, pages = {e2666-e2674}, pmid = {32913022}, issn = {1526-632X}, support = {P01 NS074969/NS/NINDS NIH HHS/United States ; R01 NS094692/NS/NINDS NIH HHS/United States ; R21 AG055333/AG/NIA NIH HHS/United States ; R01 AG041502/AG/NIA NIH HHS/United States ; }, mesh = {Alzheimer Disease/genetics/metabolism/*pathology ; Amyloid beta-Peptides/*drug effects/metabolism ; Amyloid beta-Protein Precursor/genetics ; Animals ; Brain/*drug effects/metabolism/pathology ; Citalopram/*pharmacology ; Disease Models, Animal ; Extracellular Fluid ; Intravital Microscopy ; Mice ; Microdialysis ; Microscopy, Fluorescence, Multiphoton ; Peptide Fragments/*drug effects/metabolism ; Plaque, Amyloid/metabolism/*pathology ; Presenilin-1/genetics ; Serotonin Uptake Inhibitors/*pharmacology ; }, abstract = {BACKGROUND: Several neurotransmitter receptors activate signaling pathways that alter processing of the amyloid precursor protein (APP) into β-amyloid (Aβ). Serotonin signaling through a subset of serotonin receptors suppresses Aβ generation. We proposed that escitalopram, the most specific selective serotonin reuptake inhibitor (SSRI) that inhibits the serotonin transporter SERT, would suppress Aβ levels in mice.
OBJECTIVES: We hypothesized that acute treatment with escitalopram would reduce Aβ generation, which would be reflected chronically with a significant reduction in Aβ plaque load.
METHODS: We performed in vivo microdialysis and in vivo 2-photon imaging to assess changes in brain interstitial fluid (ISF) Aβ and Aβ plaque size over time, respectively, in the APP/presenilin 1 mouse model of Alzheimer disease treated with vehicle or escitalopram. We also chronically treated mice with escitalopram to determine the effect on plaques histologically.
RESULTS: Escitalopram acutely reduced ISF Aβ by 25% by increasing α-secretase cleavage of APP. Chronic administration of escitalopram significantly reduced plaque load by 28% and 34% at 2.5 and 5 mg/d, respectively. Escitalopram at 5 mg/kg did not remove existing plaques, but completely arrested individual plaque growth over time.
CONCLUSIONS: Escitalopram significantly reduced Aβ in mice, similar to previous findings in humans treated with acute dosing of an SSRI.}, }
@article {pmid32913021, year = {2020}, author = {Sheline, YI and Snider, BJ and Beer, JC and Seok, D and Fagan, AM and Suckow, RF and Lee, JM and Waligorska, T and Korecka, M and Aselcioglu, I and Morris, JC and Shaw, LM and Cirrito, JR}, title = {Effect of escitalopram dose and treatment duration on CSF Aβ levels in healthy older adults: A controlled clinical trial.}, journal = {Neurology}, volume = {95}, number = {19}, pages = {e2658-e2665}, pmid = {32913021}, issn = {1526-632X}, support = {P30 AG066444/AG/NIA NIH HHS/United States ; P01 NS074969/NS/NINDS NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; R01 AG041502/AG/NIA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; P50 AG005681/AG/NIA NIH HHS/United States ; }, mesh = {Aged ; Aged, 80 and over ; Amyloid beta-Peptides/*cerebrospinal fluid/drug effects ; Citalopram/*administration & dosage/pharmacology ; Cohort Studies ; Dose-Response Relationship, Drug ; *Duration of Therapy ; Female ; Healthy Volunteers ; Humans ; Male ; Middle Aged ; Peptide Fragments/*cerebrospinal fluid/drug effects ; Prospective Studies ; Serotonin Uptake Inhibitors/*administration & dosage/pharmacology ; }, abstract = {OBJECTIVE: To determine whether treatment with escitalopram compared with placebo would lower CSF β-amyloid 42 (Aβ42) levels.
RATIONALE: Serotonin signaling suppresses Aβ42 in animal models of Alzheimer disease (AD) and young healthy humans. In a prospective study in older adults, we examined dose and treatment duration effects of escitalopram.
METHODS: Using lumbar punctures to sample CSF levels before and after a course of escitalopram treatment, cognitively normal older adults (n = 114) were assigned to placebo, 20 mg escitalopram × 2 weeks, 20 mg escitalopram × 8 weeks, or 30 mg escitalopram × 8 weeks; CSF sampled pretreatment and posttreatment and within-subject percent change in Aβ42 was used as the primary outcome in subsequent analyses.
RESULTS: An overall 9.4% greater reduction in CSF Aβ42 was found in escitalopram-treated compared with placebo-treated groups (p < 0.001, 95% confidence interval [CI] 4.9%-14.2%, d = 0.81). Positive baseline Aβ status (CSF Aβ42 levels <250 pg/mL) was associated with smaller Aβ42 reduction (p = 0.006, 95% CI -16.7% to 0.5%, d = -0.52) compared with negative baseline amyloid status (CSF Aβ42 levels >250 pg/mL).
CONCLUSIONS: Short-term longitudinal doses of escitalopram decreased CSF Aβ42 in cognitively normal older adults, the target group for AD prevention.
CLINICALTRIALSGOV IDENTIFIER: NCT02161458.
CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for cognitively normal older adults, escitalopram decreases CSF Aβ42.}, }
@article {pmid32903462, year = {2020}, author = {Chai, X and Zhang, W and Li, L and Wu, Y and Zhu, X and Zhao, S}, title = {Profile of MIF in Developing Hippocampus: Association With Cell Proliferation and Neurite Outgrowth.}, journal = {Frontiers in molecular neuroscience}, volume = {13}, number = {}, pages = {147}, pmid = {32903462}, issn = {1662-5099}, abstract = {Proinflammatory cytokine macrophage migration inhibitory factor (MIF) is a multifunctional cytokine and has been found involved in many neurological diseases such as Alzheimer disease (AD), epilepsy, and multiple sclerosis. Previous studies have shown that MIF is expressed in neocortex, hippocampus, hypothalamus, cerebellum, and spinal cord in adult mice. It is expressed by astrocytes and activates microglias in neuroinflammation. Further studies have shown that MIF is detected in moss fibers of dentate granule cells and in apical dendrites of pyramidal neurons in adult hippocampus. Only NeuroD-positive immature granule neurons but not NeuN-positive mature neurons express MIF. These findings led us eager to know the exact role of MIF in the development of hippocampus. Therefore, we systematically checked the spatial and temporal expression pattern of MIF and characterized MIF-positive cells in hippocampus from mice aged from postnatal day 0 (P0) to 3 months. Our results showed that the lowest level of MIF protein occurred at P7 and mif mRNA increased from P0, reached a peak at P7, and stably expressed until P30 before declining dramatically at 3 months. MIF was localized in fibers of GFAP- and BLBP-positive radial glial precursor cells in dentate gyrus (DG). DCX-expressing newly generated neurons were MIF-negative. Inhibition of MIF by MIF antagonist S, R-3-(4-hydroxyphenyl)-4, 5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1) reduced BrdU-positive cells. Interestingly, MIF was expressed by NeuN-positive GABAergic interneurons including parvalbumin-and Reelin-expressing cells in the DG. Neither NeuN-positive granule cells nor NeuN-positive pyramidal neurons expressed MIF. In transgenic mice, POMC-EGFP-positive immature dentate granule cells and Thy1-EGFP-positive mature granule cells were MIF-negative. Treatment of neuronal cultures with ISO-1 inhibited neurite outgrowth. Therefore, we conclude that MIF might be important for feature maintenance of neural stem cells and neurite outgrowth during hippocampal development.}, }
@article {pmid32887883, year = {2020}, author = {Zhao, L and Li, Z and Vong, JSL and Chen, X and Lai, HM and Yan, LYC and Huang, J and Sy, SKH and Tian, X and Huang, Y and Chan, HYE and So, HC and Ng, WL and Tang, Y and Lin, WJ and Mok, VCT and Ko, H}, title = {Pharmacologically reversible zonation-dependent endothelial cell transcriptomic changes with neurodegenerative disease associations in the aged brain.}, journal = {Nature communications}, volume = {11}, number = {1}, pages = {4413}, pmid = {32887883}, issn = {2041-1723}, mesh = {Aging/*pathology ; Alzheimer Disease/physiopathology ; Animals ; *Blood-Brain Barrier/drug effects/physiopathology ; Brain/*physiopathology ; Capillaries/metabolism ; Cells, Cultured ; Endothelial Cells/*metabolism ; Exenatide/*pharmacology ; Humans ; Mice ; Microglia/drug effects ; Neurodegenerative Diseases/physiopathology ; Transcriptome/drug effects ; }, abstract = {The molecular signatures of cells in the brain have been revealed in unprecedented detail, yet the ageing-associated genome-wide expression changes that may contribute to neurovascular dysfunction in neurodegenerative diseases remain elusive. Here, we report zonation-dependent transcriptomic changes in aged mouse brain endothelial cells (ECs), which prominently implicate altered immune/cytokine signaling in ECs of all vascular segments, and functional changes impacting the blood-brain barrier (BBB) and glucose/energy metabolism especially in capillary ECs (capECs). An overrepresentation of Alzheimer disease (AD) GWAS genes is evident among the human orthologs of the differentially expressed genes of aged capECs, while comparative analysis revealed a subset of concordantly downregulated, functionally important genes in human AD brains. Treatment with exenatide, a glucagon-like peptide-1 receptor agonist, strongly reverses aged mouse brain EC transcriptomic changes and BBB leakage, with associated attenuation of microglial priming. We thus revealed transcriptomic alterations underlying brain EC ageing that are complex yet pharmacologically reversible.}, }
@article {pmid32884267, year = {2020}, author = {Binda, A and Murano, C and Rivolta, I}, title = {Innovative Therapies and Nanomedicine Applications for the Treatment of Alzheimer's Disease: A State-of-the-Art (2017-2020).}, journal = {International journal of nanomedicine}, volume = {15}, number = {}, pages = {6113-6135}, pmid = {32884267}, issn = {1178-2013}, mesh = {Alzheimer Disease/*drug therapy/physiopathology ; Animals ; Blood-Brain Barrier/*drug effects/physiology ; Drug Carriers/therapeutic use ; Drug Delivery Systems/methods ; Humans ; Nanomedicine/*methods ; Nanoparticles/administration & dosage/therapeutic use ; Precision Medicine ; Stem Cell Transplantation ; Theranostic Nanomedicine/methods ; Therapies, Investigational ; }, abstract = {The field of nanomedicine is constantly expanding. Since the first work dated in 1999, almost 28 thousand articles have been published, and more and more are published every year: just think that only in the last five years 20,855 have come out (source PUBMED) including original research and reviews. The goal of this review is to present the current knowledge about nanomedicine in Alzheimer's disease, a widespread neurodegenerative disorder in the over 60 population that deeply affects memory and cognition. Thus, after a brief introduction on the pathology and on the state-of-the-art research for NPs passing the BBB, special attention is placed to new targets that can enter the interest of nanoparticle designers and to new promising therapies. The authors performed a literature review limited to the last three years (2017-2020) of available studies with the intention to present only novel formulations or approaches where at least in vitro studies have been performed. This choice was made because, while limiting the sector to nanotechnology applied to Alzheimer, an organic census of all the relevant news is difficult to obtain.}, }
@article {pmid32881117, year = {2021}, author = {Perera, G and Mueller, C and Stewart, R}, title = {Factors associated with slow progression of cognitive impairment following first dementia diagnosis.}, journal = {International journal of geriatric psychiatry}, volume = {36}, number = {2}, pages = {271-285}, doi = {10.1002/gps.5420}, pmid = {32881117}, issn = {1099-1166}, support = {MC_PC_17214/MRC_/Medical Research Council/United Kingdom ; /DH_/Department of Health/United Kingdom ; }, mesh = {Aged ; *Alzheimer Disease/diagnosis ; Cholinesterase Inhibitors ; *Cognitive Dysfunction/diagnosis/etiology ; *Dementia ; Disease Progression ; Humans ; London ; Male ; }, abstract = {OBJECTIVES: To investigate the extent to which slow progression of dementia after diagnosis might be predicted from routine longitudinal healthcare data, in order to clarify characteristics of people who experience this outcome.
METHODS: A retrospective observational study was conducted using data from the South London and Maudsley NHS Foundation Trust Biomedical Research Centre Case Register. This study included all patients receiving a first dementia diagnosis between 2006 and 2017, restricted to those with a baseline Mini-Mental State Examination (MMSE) score within 6 months of initial diagnosis of dementia and at least one MMSE score after 3 years post-diagnosis. Slow progression was defined as a change in MMSE score of -1, 0 or an increase at the follow-up point. This group was compared to the remainder with an MMSE decline of -2 or more.
RESULTS: Overall, 682 patients with slow progression were compared to 1045 with faster progression. In the confounder-adjusted multivariate logistic regression model, slow progression was more likely in younger patients (age 65-74 years; odds ratio: 1.18; 95% confidence intervals: 1.04-1.37), males (1.24; 1.01-1.53), those with moderate or severe dementia according to MMSE, patients with mixed-type dementia (2.06; 1.11-3.82) compared to Alzheimer's disease and less likely in those receiving acetylcholinesterase inhibitor (AChEI) treatment (0.57; 0.46-0.71).
CONCLUSION: Slow dementia progression after diagnosis was common in patients with mixed Alzheimer's and vascular dementia, younger age, males and non-receipt of AChEIs, possibly suggesting non-Alzheimer pathologies and clarifying such predictors is important, as there is currently very limited information on which to base prognosis estimates in post-diagnosis counselling.}, }
@article {pmid32872063, year = {2020}, author = {Lee, J and Jin, C and Cho, SY and Park, SU and Jung, WS and Moon, SK and Park, JM and Ko, CN and Cho, KH and Kwon, S}, title = {Herbal medicine treatment for Alzheimer disease: A protocol for a systematic review and meta-analysis.}, journal = {Medicine}, volume = {99}, number = {33}, pages = {e21745}, doi = {10.1097/MD.0000000000021745}, pmid = {32872063}, issn = {1536-5964}, mesh = {Alzheimer Disease/*drug therapy ; Herbal Medicine ; Humans ; Meta-Analysis as Topic ; *Phytotherapy ; Plant Extracts/*therapeutic use ; Systematic Reviews as Topic ; }, abstract = {BACKGROUND: Alzheimer disease (AD) is a leading progressive neurodegenerative disease worldwide, but treating it is challenging in clinical practice. This review is aimed at evaluating the efficacy and safety of herbal medicine for treating AD.
METHODS AND ANALYSIS: We will search for randomized controlled trials related to the effect and safety of herbal medicine for AD in the following databases: PubMed, Cochrane Central Register of Controlled Trials, Excerpta Medica Database, China National Knowledge Infrastructure database, Oriental Medicine Advanced Searching Integrated system, Korean Traditional Knowledge Portal, and Citation Information by National Institute for Informatics. The risk of bias will be evaluated using the Cochrane risk-of-bias assessment tool. After screening the studies, a meta-analysis will be performed. The primary outcome will be the Mini-Mental State Examination score. Secondary outcomes will consist of other scales for cognitive function and other aspects, such as behavioral and psychological symptoms and plasma levels of amyloid-β.
RESULTS: This study will provide the current status of evidence for herbal medicine to treat AD.
CONCLUSION: The results of this review will determine the efficacy and safety of herbal medicine for AD.
ETHICS AND DISSEMINATION: Ethical approval is not required, as this study is based on a review of published research. This review will be published in a peer-reviewed journal and disseminated both electronically and in print.
TRIAL REGISTRATION NUMBER: Research Registry reviewregistry933.}, }
@article {pmid32868453, year = {2020}, author = {Maulik, M and Vasan, L and Bose, A and Dutta Chowdhury, S and Sengupta, N and Das Sarma, J}, title = {Amyloid-β regulates gap junction protein connexin 43 trafficking in cultured primary astrocytes.}, journal = {The Journal of biological chemistry}, volume = {295}, number = {44}, pages = {15097-15111}, pmid = {32868453}, issn = {1083-351X}, support = {/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Alzheimer Disease/metabolism ; Amyloid beta-Peptides/*physiology ; Animals ; Astrocytes/drug effects/*metabolism ; Cells, Cultured ; Connexin 43/*metabolism ; Endocytosis/physiology ; Endoplasmic Reticulum/metabolism ; Gap Junctions/*metabolism ; Golgi Apparatus/metabolism ; Mice ; Phenylbutyrates/pharmacology ; Protein Transport ; }, abstract = {Altered expression and function of astroglial gap junction protein connexin 43 (Cx43) has increasingly been associated to neurotoxicity in Alzheimer disease (AD). Although earlier studies have examined the effect of increased β-amyloid (Aβ) on Cx43 expression and function leading to neuronal damage, underlying mechanisms by which Aβ modulates Cx43 in astrocytes remain elusive. Here, using mouse primary astrocyte cultures, we have examined the cellular processes by which Aβ can alter Cx43 gap junctions. We show that Aβ25-35 impairs functional gap junction coupling yet increases hemichannel activity. Interestingly, Aβ25-35 increased the intracellular pool of Cx43 with a parallel decrease in gap junction assembly at the surface. Intracellular Cx43 was found to be partly retained in the endoplasmic reticulum-associated cell compartments. However, forward trafficking of the newly synthesized Cx43 that already reached the Golgi was not affected in Aβ25-35-exposed astrocytes. Supporting this, treatment with 4-phenylbutyrate, a well-known chemical chaperone that improves trafficking of several transmembrane proteins, restored Aβ-induced impaired gap junction coupling between astrocytes. We further show that interruption of Cx43 endocytosis in Aβ25-35-exposed astrocytes resulted in their retention at the cell surface in the form of functional gap junctions indicating that Aβ25-35 causes rapid internalization of Cx43 gap junctions. Additionally, in silico molecular docking suggests that Aβ can bind favorably to Cx43. Our study thus provides novel insights into the cellular mechanisms by which Aβ modulates Cx43 function in astrocytes, the basic understanding of which is vital for the development of alternative therapeutic strategy targeting connexin channels in AD.}, }
@article {pmid32865575, year = {2020}, author = {Huang, WK and Liu, CH and Pang, ST and Liu, JR and Chang, JW and Liaw, CC and Hsu, CL and Lin, YC and See, LC}, title = {Type of Androgen Deprivation Therapy and Risk of Dementia Among Patients With Prostate Cancer in Taiwan.}, journal = {JAMA network open}, volume = {3}, number = {8}, pages = {e2015189}, pmid = {32865575}, issn = {2574-3805}, mesh = {Adult ; Aged ; Aged, 80 and over ; Androgen Antagonists/adverse effects/therapeutic use ; Cohort Studies ; *Dementia/epidemiology/etiology ; Humans ; Male ; Middle Aged ; Orchiectomy/adverse effects/statistics & numerical data ; *Prostatic Neoplasms/complications/drug therapy/epidemiology ; Risk Factors ; Taiwan ; }, abstract = {Importance: It remains unclear whether androgen deprivation therapy (ADT) is associated with subsequent dementia risk in patients with prostate cancer. There are limited data regarding dementia risk across ADT types.
Objective: To examine the association between all-cause dementia, including Alzheimer disease (AD), and different ADT types in patients with prostate cancer.
This cohort study used linked data from the Taiwan National Cancer Registry, the National Health Insurance Research Database, and the Taiwan National Death Registry. A cohort of 23 651 patients with newly diagnosed prostate cancer between January 1, 2008, and December 31, 2015, was identified and followed up from 1 year after diagnosis until December 31, 2017. Data analysis was performed between January 2019 and May 2020.
Exposures: Patients who received and did not receive ADT, including gonadotropin-releasing hormone (GnRH) agonists, orchiectomy, or antiandrogen monotherapy.
Main Outcomes and Measures: The primary outcomes were all-cause dementia or AD. Stabilized inverse probability of treatment weighting was used to balance baseline covariates. The association between dementia and various ADT types was examined using the Cox proportional hazards model. Furthermore, a multivariate Cox proportional model with age as the time scale was conducted for complementary comparison.
Results: In the cohort of 23 651 male patients (median [interquartile range] age, 73 [66-79] years), 6904 (29.2%) did not receive ADT, 11 817 (50.0%) received GnRH agonists, 876 (3.7%) received orchiectomy, and 4054 (17.1%) received antiandrogen monotherapy. Overall, 1525 patients were diagnosed with incident dementia (1.72 per 100 person-years) during a median (interquartile range) follow-up of 3.46 (1.92-5.51) years. Compared with those who did not receive ADT, those using antiandrogen monotherapy showed an increased risk of dementia (weighted hazard ratio [HR], 1.34; 95% CI, 1.16-1.55) and AD (weighted HR, 1.52; 95% CI, 1.13-2.04). The risk of dementia was similar between GnRH agonist use or orchiectomy and no ADT use (GnRH agonist: weighted HR, 1.13; 95% CI, 1.00-1.28; orchiectomy: 1.00; 95% CI, 0.74-1.37). Several sensitivity analyses revealed consistent findings for both outcomes.
Conclusions and Relevance: In this study, the use of antiandrogen monotherapy was associated with increased risk of dementia or AD, while GnRH agonist use and orchiectomy had no significant difference compared with patients who did not receive ADT. Further prospective studies are warranted to confirm these findings.}, }
@article {pmid32864980, year = {2020}, author = {Gupta, S and Nair, A and Jhawat, V and Mustaq, N and Sharma, A and Dhanawat, M and Khan, SA}, title = {Unwinding Complexities of Diabetic Alzheimer by Potent Novel Molecules.}, journal = {American journal of Alzheimer's disease and other dementias}, volume = {35}, number = {}, pages = {1533317520937542}, doi = {10.1177/1533317520937542}, pmid = {32864980}, issn = {1938-2731}, mesh = {*Alzheimer Disease/drug therapy ; Cross-Sectional Studies ; Diabetes Mellitus, Type 2/drug therapy ; Humans ; Hypoglycemic Agents ; }, abstract = {Diabetes mellitus is one of the aggressive disorders in global society. No pharmacotherapy is available for permanent diabetes cure, although management is possible with drugs and physical activities. One of the recent complications noticed in type 2 diabetes mellitus includes diabetes-induced Alzheimer. It has been proposed that the possible diabetes-induced Alzheimer could be of type 3 diabetes. A variety of cross-sectional studies have proved that type 2 diabetes mellitus is one of the factors responsible for the pathophysiology of Alzheimer. New drug molecules developed by pharmaceutical companies with adequate neuroprotective effect have demonstrated their efficacy in treatment of Alzheimer in various preclinical diabetic studies. Patients of type 2 diabetes mellitus may show the benefit with existing drugs but may not cause complete cure. Extensive studies are being carried out to find new drug molecules that show their potential as antidiabetic drug and could treat type 2 diabetes-induced Alzheimer as well. This review provides an overview about the recent advancement in pharmacotherapy of diabetes-induced Alzheimer. The pathomechanistic links between diabetes and Alzheimer as well as neurochemical changes in diabetes-induced Alzheimer are also briefed.}, }
@article {pmid32863801, year = {2020}, author = {Li, G and Sun, X and Wan, X and Wang, D}, title = {Lactoferrin-Loaded PEG/PLA Block Copolymer Targeted With Anti-Transferrin Receptor Antibodies for Alzheimer Disease.}, journal = {Dose-response : a publication of International Hormesis Society}, volume = {18}, number = {3}, pages = {1559325820917836}, pmid = {32863801}, issn = {1559-3258}, abstract = {Last few years, struggles have been reported to develop the nanovesicles for drug delivery via the brain-blood barrier (BBB). Novel drugs, for instance, iAβ5, are efficient to inhibit the aggregates connected to the treatment of Alzheimer disease and are being evaluated, but most of the reports reflect some drawbacks of the drugs to reach the brain in preferred concentrations owing to the less BBB penetrability of the surface dimensions. In this report, we designed and developed a new approach to enhance the transport of drug via BBB, constructed with lactoferrin (Lf)-coated polyethylene glycol-polylactide nanoparticles (Lf-PPN) with superficial monoclonal antibody-functionalized antitransferrin receptor and anti-Aβ to deliver the iAβ5 hooked on the brain. The porcine brain capillary endothelial cells were utilized as BBB typically to examine the framework efficacy and toxicity. The cellular uptake of the immuno-nanoparticles with measured conveyance of the iAβ5 peptide was significantly enhanced and associated with Lf-PPN without monoclonal antibody functionalizations.}, }
@article {pmid32854771, year = {2020}, author = {Wei, W and Wang, Y and Liu, Y and Dai, CL and Tung, YC and Liu, F and Iqbal, K}, title = {Prenatal to early postnatal neurotrophic treatment prevents Alzheimer-like behavior and pathology in mice.}, journal = {Alzheimer's research & therapy}, volume = {12}, number = {1}, pages = {102}, pmid = {32854771}, issn = {1758-9193}, mesh = {*Alzheimer Disease/drug therapy ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor ; Animals ; Brain/metabolism ; *Cognitive Dysfunction ; Disease Models, Animal ; Female ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Plaque, Amyloid ; Pregnancy ; tau Proteins/metabolism ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder of middle-aged to old individuals. The pathophysiological process of AD is believed to begin many years before the emergence of clinical symptoms. The important influence of congenital genetic aberrations on the development of AD provides a novel opportunity to initiate prenatal to early postnatal pharmacological treatment to address the role of this critical period of brain development in the disease.
METHODS: We investigated for the first time the effect of oral treatment during prenatal to early postnatal development with a neurotrophic compound, P021 (Ac-DGGLAG-NH2), on neurobehavior and AD-like pathology in 3xTg-AD, a transgenic mouse model of AD. The transgenic and control wild-type female mice were treated from prenatal day 8 to postnatal day 21 with a custom-made diet containing P021 or a vehicle diet, followed by a standard diet. AD-type cognitive function and pathological features were studied during adulthood and old age.
RESULTS: The P021 treatment rescued cognitive deficits at 4 months, reduced abnormal hyperphosphorylation and accumulation of tau at known major AD neurofibrillary pathology-associated sites, and decreased Aβ plaque load at 22 months in 3xTg-AD mice. Prenatal to early postnatal treatment with P021 also ameliorated certain markers of postsynaptic deficits, including PSD-95 levels and CREB activity, and decreased one measure of neuroinflammation, GFAP level in the brain at 4 and 22 months in 3xTg mice.
CONCLUSIONS: These findings suggest that neurotrophic impairment during early development can be one of the etiopathogenic factors of AD and that the neurotrophic peptide mimetic is a potential early prevention strategy for this disease.}, }
@article {pmid32853472, year = {2021}, author = {Suresh, J and Khor, IW and Kaur, P and Heng, HL and Torta, F and Dawe, GS and Tai, ES and Tolwinski, NS}, title = {Shared signaling pathways in Alzheimer's and metabolic disease may point to new treatment approaches.}, journal = {The FEBS journal}, volume = {288}, number = {12}, pages = {3855-3873}, doi = {10.1111/febs.15540}, pmid = {32853472}, issn = {1742-4658}, mesh = {Alzheimer Disease/drug therapy/genetics/*metabolism/pathology ; Amyloid beta-Peptides/genetics/metabolism ; Cerebral Cortex/drug effects/*metabolism/pathology ; Diabetes Mellitus, Type 2/drug therapy/genetics/*metabolism/pathology ; Dipeptidyl-Peptidase IV Inhibitors/therapeutic use ; Gene Expression Regulation ; Glucose/*metabolism ; Glycogen Synthase Kinase 3 beta/genetics/metabolism ; Humans ; Insulin/metabolism ; Insulin Resistance ; Metformin/therapeutic use ; Neuroprotective Agents/*therapeutic use ; Optogenetics/methods ; Oxidative Stress/drug effects ; Signal Transduction/drug effects/*genetics ; Sulfonylurea Compounds/therapeutic use ; tau Proteins/genetics/metabolism ; }, abstract = {'A peculiar severe disease process of the cerebral cortex' are the exact words used by A. Alzheimer in 1906 to describe a patient's increasingly severe condition of memory loss, changes in personality, and sleep disturbance. A century later, this 'peculiar' disease has become widely known as Alzheimer's disease (AD), the world's most common neurodegenerative disease, affecting more than 35 million people globally. At the same time, its pathology remains unclear and no successful treatment exists. Several theories for AD etiology have emerged throughout the past century. In this review, we focus on the metabolic mechanisms that are similar between AD and metabolic diseases, based on the results from genome-wide association studies. We discuss signaling pathways involved in both types of disease and look into new optogenetic methods to study the in vivo mechanisms of AD.}, }
@article {pmid32852770, year = {2020}, author = {Dehlin, M and Kapetanovic, M and Svärd, A and Bengtsson Boström, K and Wändell, P and Sigurdardottir, V and Forsblad d'Elia, H and Jacobsson, L}, title = {[Consequences of Gout and Hyperuricemia].}, journal = {Lakartidningen}, volume = {117}, number = {}, pages = {}, pmid = {32852770}, issn = {1652-7518}, mesh = {*Cardiovascular Diseases/complications ; *Gout/complications ; Gout Suppressants ; Humans ; *Hyperuricemia/complications ; Uric Acid ; }, abstract = {Hyperuricemia (HU) and gout are strongly associated with CVD, associations that are most likely due to shared etiologies rather than causality. HU is for example causally related to the metabolic syndrome and in particular to obesity. Gout and HU can both be caused by and lead to decreased kidney function. On the other hand, there are observational data suggesting that HU may protect against neurodegenerative diseases such as Alzheimer and Parkinson's disease. Ongoing RCTs with urate and urate lowering therapy (ULT) will help to resolve some of these controversies. Nevertheless, gout is a "curable disease" by ULT, a treatment which in adequate doses may also have positive effect on several associated co-morbidities.}, }
@article {pmid32848579, year = {2020}, author = {Izrael, M and Slutsky, SG and Revel, M}, title = {Rising Stars: Astrocytes as a Therapeutic Target for ALS Disease.}, journal = {Frontiers in neuroscience}, volume = {14}, number = {}, pages = {824}, pmid = {32848579}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a multifactorial disease, characterized by a progressive loss of motor neurons that eventually leads to paralysis and death. The current ALS-approved drugs modestly change the clinical course of the disease. The mechanism by which motor neurons progressively degenerate remains unclear but entails a non-cell autonomous process. Astrocytes impaired biological functionality were implicated in multiple neurodegenerative diseases, including ALS, frontotemporal dementia (FTD), Parkinson's disease (PD), and Alzheimer disease (AD). In ALS disease patients, A1 reactive astrocytes were found to play a key role in the pathology of ALS disease and death of motor neurons, via loss or gain of function or acquired toxicity. The contribution of astrocytes to the maintenance of motor neurons by diverse mechanisms makes them a promising therapeutic candidate for the treatment of ALS. Therapeutic approaches targeting at modulating the function of endogenous astrocytes or replacing lost functionality by transplantation of healthy astrocytes, may contribute to the development of therapies which might slow down or even halt the progression ALS diseases. The proposed mechanisms by which astrocytes can potentially ameliorate ALS progression and the status of ALS clinical studies involving astrocytes are discussed.}, }
@article {pmid32840331, year = {2020}, author = {Wong, W}, title = {Economic burden of Alzheimer disease and managed care considerations.}, journal = {The American journal of managed care}, volume = {26}, number = {8 Suppl}, pages = {S177-S183}, doi = {10.37765/ajmc.2020.88482}, pmid = {32840331}, issn = {1936-2692}, abstract = {Alzheimer disease is the most common cause of dementia and the fifth leading cause of death in adults older than 65 years. The estimated total healthcare costs for the treatment of Alzheimer disease in 2020 is estimated at $305 billion, with the cost expected to increase to more than $1 trillion as the population ages. Most of the direct costs of care for Alzheimer disease are attributed to skilled nursing care, home healthcare, and hospice care. Indirect costs of care, including quality of life and informal caregiving, are likely underestimated and are associated with significant negative societal and personal burden. Managed care organizations are in a unique position to develop utilization strategies that would positively impact early diagnosis and treatment to lead to better outcomes and lower costs for patients, caregivers, and the healthcare system. Additionally, the recent inclusion of Alzheimer disease diagnoses into risk corridor calculations by the Centers for Medicare & Medicaid Services may encourage Medicare Advantage organizations to invest in programs that aid in its early detection and diagnosis.}, }
@article {pmid32840330, year = {2020}, author = {Marasco, RA}, title = {Current and evolving treatment strategies for the Alzheimer disease continuum.}, journal = {The American journal of managed care}, volume = {26}, number = {8 Suppl}, pages = {S167-S176}, doi = {10.37765/ajmc.2020.88481}, pmid = {32840330}, issn = {1936-2692}, abstract = {The burden of Alzheimer disease (AD) on the US healthcare system is substantial and increasing. AD progresses along a continuum from preclinical disease characterized by normal cognition and abnormal brain biomarkers to mild cognitive impairment and then clinically apparent dementia. Diagnosis early in the AD continuum has benefits for patients and caregivers and appears cost-effective, but often, the clinical diagnosis of AD may be delayed. Currently available biomarkers include β-amyloid positron emission tomography and cerebrospinal fluid tests. Collectively, they are expensive, may lead to adverse effects, are not widely available, and are not suited for primary care. Currently available treatment options, cholinesterase inhibitors and memantine, do not alter disease progression, but can help with some symptoms. Benefits of currently available treatments on cognition are difficult to quantify and are offset by a burden of adverse effects that often go unrecognized. More accurate diagnostic biomarkers and disease-modifying drug therapies are critical unmet needs of patients with AD despite decades of clinical research. Because many phase 3 clinical trials that enrolled patients with symptomatic AD have failed, researchers believe that disease-modifying treatment is more likely to demonstrate benefit when utilized early in the disease continuum. Within the past few years, significant achievements that will advance clinical trials in early AD include the Research Framework to define and stage the AD continuum, FDA guidance on study design in early AD, and development of scales to measure cognition that are suitable for early AD. In October 2019, the AD community was re-invigorated by unexpected news that a Biologics License Application will be submitted for aducanumab to treat AD. This article explores the current state of biomarker-driven drug development across the AD continuum and reviews investigational drugs in phase 2/3 clinical development for AD.}, }
@article {pmid32832321, year = {2020}, author = {Xuan, WT and Wang, H and Zhou, P and Ye, T and Gao, HW and Ye, S and Wang, JH and Chen, ML and Song, H and Wang, Y and Cai, B}, title = {Berberine ameliorates rats model of combined Alzheimer's disease and type 2 diabetes mellitus via the suppression of endoplasmic reticulum stress.}, journal = {3 Biotech}, volume = {10}, number = {8}, pages = {359}, pmid = {32832321}, issn = {2190-572X}, abstract = {This study is aimed to investigate the protective effect against type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) of Berberine (BBR), and the underlying mechanism of action is explored. We established a rat model of combined AD and T2DM and used it to investigate the effect of BBR (150 mg/kg) on the course of these pathologies. The Morris water maze, biochemical analysis, hematoxylin-eosin staining, immunohistochemical study, immunofluorescent staining, TUNEL assay, RT-qPCR and western blot were used to reveal the effect of BBR on blood glucose, lipid changes, hippocampal injuries and cognitive impairment. The results showed that BBR could alleviate memory deficits, restore the disordered arrangement of nerve cells, the damage of neurons, improve TUNEL-positive cells and decrease the elevated levels of fasting blood glucose, triglyceride, total cholesterol and glycosylated serum protein levels in Alzheimer diabetic rats. Moreover, BBR treatment reduces the transcription of mRNAs and expression of proteins related to endoplasmic reticulum (ER) stress. These findings conclude that BBR can protect neurons by inhibiting the pathway of ER stress and thereby play an essential role in the preventive and therapeutic of AD and T2DM.}, }
@article {pmid32819251, year = {2020}, author = {Pandey, M and Choudhury, H and Verma, RK and Chawla, V and Bhattamisra, SK and Gorain, B and Raja, MAG and Amjad, MW}, title = {Nanoparticles Based Intranasal Delivery of Drug to Treat Alzheimer's Disease: A Recent Update.}, journal = {CNS & neurological disorders drug targets}, volume = {19}, number = {9}, pages = {648-662}, doi = {10.2174/1871527319999200819095620}, pmid = {32819251}, issn = {1996-3181}, abstract = {Alzheimer Association Report (2019) stated that the 6th primary cause of death in the USA is Alzheimer's Disease (AD), which leads to behaviour and cognitive impairment. Nearly 5.8 million peoples of all ages in the USA have suffered from this disease, including 5.6 million elderly populations. The statistics of the progression of this disease is similar to the global scenario. Still, the treatment of AD is limited to a few conventional oral drugs, which often fail to deliver an adequate amount of the drug in the brain. The reduction in the therapeutic efficacy of an anti-AD drug is due to poor solubility, existence to the blood-brain barrier and low permeability. In this context, nasal drug delivery emerges as a promising route for the delivery of large and small molecular drugs for the treatment of AD. This promising pathway delivers the drug directly into the brain via an olfactory route, which leads to the low systemic side effect, enhanced bioavailability, and higher therapeutic efficacy. However, few setbacks, such as mucociliary clearance and poor drug mucosal permeation, limit its translation from the laboratory to the clinic. The above stated limitation could be overcome by the adaption of nanoparticle as a drug delivery carrier, which may lead to prolong delivery of drugs with better permeability and high efficacy. This review highlights the latest work on the development of promising Nanoparticles (NPs) via the intranasal route for the treatment of AD. Additionally, the current update in this article will draw the attention of the researcher working on these fields and facing challenges in practical applicability.}, }
@article {pmid32811395, year = {2021}, author = {Singh, M and Singh, SP and Yadav, D and Agarwal, M and Agarwal, S and Agarwal, V and Swargiary, G and Srivastava, S and Tyagi, S and Kaur, R and Mani, S}, title = {Targeted Delivery for Neurodegenerative Disorders Using Gene Therapy Vectors: Gene Next Therapeutic Goals.}, journal = {Current gene therapy}, volume = {21}, number = {1}, pages = {23-42}, doi = {10.2174/1566523220999200817164907}, pmid = {32811395}, issn = {1875-5631}, abstract = {The technique of gene therapy, ever since its advent nearly fifty years ago, has been utilized by scientists as a potential treatment option for various disorders. This review discusses some of the major neurodegenerative diseases (NDDs) like Alzheimer's disease (AD), Parkinson's Disease (PD), Motor neuron diseases (MND), Spinal Muscular Atrophy (SMA), Huntington's Disease (HD), Multiple Sclerosis (MS), etc. and their underlying genetic mechanisms along with the role that gene therapy can play in combating them. The pathogenesis and the molecular mechanisms specifying the altered gene expression of each of these NDDs have also been discussed in elaboration. The use of gene therapy vectors can prove to be an effective tool in the field of curative modern medicine for the generations to come. Therefore, consistent efforts and progressive research towards its implementation can provide us with powerful treatment options for disease conditions that have so far been considered as incurable.}, }
@article {pmid32781866, year = {2021}, author = {Övey, İS and Nazıroğlu, M}, title = {Effects of homocysteine and memantine on oxidative stress related TRP cation channels in in-vitro model of Alzheimer's disease.}, journal = {Journal of receptor and signal transduction research}, volume = {41}, number = {3}, pages = {273-283}, doi = {10.1080/10799893.2020.1806321}, pmid = {32781866}, issn = {1532-4281}, abstract = {Memantine (MEM) has been used to treat patients with Alzheimer' disease though inhibition of reactive oxygen species (ROS), Ca2+ entry and glutamate receptor. The Ca2+ permeable TRPA1, TRPM2 and TRPV1 channels are activated in the hippocampus by ROS, and antioxidant MEM as a potent TRPA1, TRPM2 and TRPV1 channel antagonist may reduce Aβ-induced oxidative stress and apoptosis in the neurons. In the current study, we investigated the neuroprotective properties of MEM in Aβ-induced hippocampal neuron cultures. Freshly isolated hippocampal neurons of mice were divided into eight groups as control, Aβ, Hcy, MEM, Aβ + Hcy, Aβ + Hcy + MEM, Aβ + MEM and Hcy + MEM. The neurons were exposed to incubated with Aβ (20 µM for 24 h), Hcy (250 µM for 30 min) and MEM (10 µM for 24 h). TRPA1, TRPM2 and TRPV1 of the eight groups were further stimulated by cinnamaldehyde, cumene hydyroperoxide and capsaicin, respectively although they were further inhibited by AP-18, N-(p-Amylcinnamoyl) anthranilic acid (ACA) and capsazepine (CPZ). The [Ca2+] concentration, apoptosis, caspase 3, caspase 9 activations, mitochondrial membrane depolarization and intracellular ROS production values in the neurons were higher in Aβ and Hcy groups than in control although they were lower in the MEM group than in Aβ and Hcy groups. The values were further decreased by MEM + AP-18, MEM + CPZ and MEM + ACA treatments as compared to MEM only. Aβ and Hcy-induced decrease of cell viability level was increased by MEM treatment although Aβ and Hcy-induced increase of caspase 3, caspase 9, PARP1, TRPA1, TRPM2 and TRPV1 expression levels were decreased by MEM treatments. In conclusion, TRPA1, TRPM2 and TRPV1 channels are involved in Aβ and Hcy-induced neuronal death, and modulation of the activity of these channels by MEM treatment may account for their neuroprotective activity against apoptosis, excessive ROS production, and Ca2+ entry.}, }
@article {pmid32778535, year = {2020}, author = {Swaminathan, SK and Zhou, AL and Ahlschwede, KM and Curran, GL and Lowe, VJ and Li, L and Kandimalla, KK}, title = {High-Density Lipoprotein Mimetic Peptide 4F Efficiently Crosses the Blood-Brain Barrier and Modulates Amyloid-β Distribution between Brain and Plasma.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {375}, number = {2}, pages = {308-316}, pmid = {32778535}, issn = {1521-0103}, support = {R21 AG056025/AG/NIA NIH HHS/United States ; RF1 AG058081/AG/NIA NIH HHS/United States ; }, mesh = {Amyloid beta-Peptides/blood/*metabolism ; Animals ; Blood-Brain Barrier/*metabolism ; Mice ; Peptide Fragments/blood/*metabolism ; Peptides/*metabolism/*pharmacology ; Protein Transport/drug effects ; }, abstract = {Treatments to elevate high-density lipoprotein (HDL) levels in plasma have decreased cerebrovascular amyloid -β (Aβ) deposition and mitigated cognitive decline in Alzheimer disease (AD) transgenic mice. Since the major protein component of HDL particles, apolipoprotein A-I (ApoA-I), has very low permeability at the blood-brain barrier (BBB), we investigated 4F, an 18-amino-acid ApoA-I/HDL mimetic peptide, as a therapeutic alternative. Specifically, we examined the BBB permeability of 4F and its effects on [125I]Aβ trafficking from brain to blood and from blood to brain. After systemic injection in mice, the BBB permeability of [125I]4F, estimated as the permeability-surface area (PS) product, ranged between 2 and 5 × 10-6 ml/g per second in various brain regions. The PS products of [125I]4F were ∼1000-fold higher compared with those determined for [125I]ApoA-I. Moreover, systemic infusion with 4F increased the brain efflux of intracerebrally injected [125I]Aβ42. Conversely, 4F infusion decreased the brain influx of systemically injected [125I]Aβ42. Interestingly, 4F did not significantly alter the brain influx of [125I]Aβ40. To corroborate the in vivo findings, we evaluated the effects of 4F on [125I]Aβ42 transcytosis across polarized human BBB endothelial cell (hCMEC/D3) monolayers. Treatment with 4F increased the abluminal-to-luminal flux and decreased the luminal-to-abluminal flux of [125I]Aβ42 across the hCMEC/D3 monolayers. Additionally, 4F decreased the endothelial accumulation of fluorescein-labeled Aβ42 in the hCMEC/D3 monolayers. These findings provide a mechanistic interpretation for the reductions in brain Aβ burden reported in AD mice after oral 4F administration, which represents a novel strategy for treating AD and cerebral amyloid angiopathy. SIGNIFICANCE STATEMENT: The brain permeability of the ApoA-I mimetic peptide 4F was estimated to be ∼1000-fold greater than ApoA-I after systemic injection of radiolabeled peptide/protein in mice. Further, 4F treatment increased the brain efflux of amyloid -β and also decreased its brain influx, as evaluated in mice and in blood-brain barrier cell monolayers. Thus, 4F represents a potential therapeutic strategy to mitigate brain amyloid accumulation in cerebral amyloid angiopathy and Alzheimer disease.}, }
@article {pmid32777579, year = {2020}, author = {Haghighijoo, Z and Akrami, S and Saeedi, M and Zonouzi, A and Iraji, A and Larijani, B and Fakherzadeh, H and Sharifi, F and Arzaghi, SM and Mahdavi, M and Edraki, N}, title = {N-Cyclohexylimidazo[1,2-a]pyridine derivatives as multi-target-directed ligands for treatment of Alzheimer's disease.}, journal = {Bioorganic chemistry}, volume = {103}, number = {}, pages = {104146}, doi = {10.1016/j.bioorg.2020.104146}, pmid = {32777579}, issn = {1090-2120}, mesh = {Alzheimer Disease/*drug therapy ; Antioxidants/pharmacology/*therapeutic use ; Humans ; Ligands ; Molecular Docking Simulation/*methods ; Molecular Structure ; Pyridines/pharmacology/therapeutic use ; Structure-Activity Relationship ; }, abstract = {Alzheimer's disease (AD) is the most common form of dementia. While drugs that target several pathways underlying AD have been proposed, effective treatments remain to be discovered. BACE1, an enzyme associated with AD progression, is a promising target for developing anti-Alzheimer drugs. To find novel multifunctional anti-Alzheimer agents, we designed and synthesized a series of new substituted benzyl-1H-1,2,3-triazol-4-yl-N-cyclohexylimidazo[1,2-a]pyridin-3-amine. The in vitro screening results revealed that most of the compounds exhibited moderate to potent BACE1 and BuChE inhibitory and antioxidant activities. Compounds 7f and 7g, bearing dichloro (2,3-Cl2 and 3,4-Cl2) moieties on the benzyl pendant were selected as the most active compounds in our BACE1 inhibitory assay with respective IC50 values of about 12 and 8.9 μM. In addition, compounds 7g and 7h (4-bromo derivative) showed the highest BuChE inhibitory activity with IC50 of 3.2 and 2.5 µM, respectively. Compound 7g also possessed antioxidant activity with an IC50 value of 10.2 μM and metal chelation potential. Moreover, docking studies were performed to investigate the possible mechanism of inhibition. Taken together, we demonstrate that N-cyclohexylimidazo[1,2-a]pyridine containing triazole motif derivatives deserve further investigation for anti-Alzheimer drug development.}, }
@article {pmid32777010, year = {2020}, author = {Grill, JD and Raman, R and Ernstrom, K and Sultzer, DL and Burns, JM and Donohue, MC and Johnson, KA and Aisen, PS and Sperling, RA and Karlawish, J and , }, title = {Short-term Psychological Outcomes of Disclosing Amyloid Imaging Results to Research Participants Who Do Not Have Cognitive Impairment.}, journal = {JAMA neurology}, volume = {77}, number = {12}, pages = {1504-1513}, doi = {10.1001/jamaneurol.2020.2734}, pmid = {32777010}, issn = {2168-6157}, support = {P30 AG010124/AG/NIA NIH HHS/United States ; R01 AG063689/AG/NIA NIH HHS/United States ; K24 AG035007/AG/NIA NIH HHS/United States ; U24 AG057437/AG/NIA NIH HHS/United States ; P01 AG036694/AG/NIA NIH HHS/United States ; P50 AG016573/AG/NIA NIH HHS/United States ; UL1 TR001414/TR/NCATS NIH HHS/United States ; U19 AG010483/AG/NIA NIH HHS/United States ; }, mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/prevention & control ; *Amyloid/metabolism ; Antibodies, Monoclonal, Humanized/therapeutic use ; Biomarkers/analysis ; *Brain/diagnostic imaging/metabolism/pathology ; Cognitive Dysfunction ; Female ; Humans ; Male ; Positron-Emission Tomography ; Research Subjects/*psychology ; *Truth Disclosure ; }, abstract = {Importance: The goal of preclinical Alzheimer disease (AD) clinical trials is to move diagnosis and treatment to presymptomatic stages, which will require biomarker testing and disclosure.
Objective: To assess the short-term psychological outcomes of disclosing amyloid positron emission tomography results to older adults who did not have cognitive impairment.
This observational study included participants who were screening for a multisite randomized clinical trial that began on February 28, 2014, and is anticipated to be completed in 2022. Participants aged 65 to 85 years who had no known cognitive impairments underwent an amyloid positron emission tomography scan and learned their result from an investigator who used a protocol-specified process that included prescan education and psychological assessments. This report compares participants with elevated amyloid levels with at least 1 available outcome measure with participants who did not have elevated amyloid levels who enrolled in an observational cohort study and received further evaluations. Data were collected from April 2014 to December 2017 and analyzed from March 2019 to October 2019.
Exposures: A personal biomarker result described as either an elevated or not elevated amyloid level.
Main Outcomes and Measures: To assess the immediate and short-term psychological outcome of disclosure, the following validated measures were used: the Geriatric Depression Scale, the state items from the State-Trait Anxiety Inventory, and the Columbia Suicide Severity Rating Scale, as well as the Concerns About AD Scale and the Future Time Perspective Scale to assess changes in participants' perceived risk for AD and perceived remaining life span, respectively.
Results: A total of 1167 participants with elevated amyloid levels and 538 participants with not elevated amyloid levels were included. Participants had a mean (SD) age of 71.5 (4.7) years, 1025 (60.1%) were women, and most were white (1611 [94.5%]) and non-Latino (1638 [96.1%]). Compared with participants who learned that they had a not elevated amyloid result, individuals who learned of an elevated amyloid result were no more likely to experience short-term increases in depression (mean [SD] change in the Geriatric Depression Scale score, 0.02 [1.3] vs 0.04 [1.3]; P = .90), anxiety (mean [SD] change in State-Trait Anxiety Inventory score, -0.02 [3.2] vs -0.15 [3.0]; P = .65), or suicidality (mean [SD] change in the Columbia Suicide Severity Rating Scale score, 0.0 [0.4] vs -0.01 [0.5]; P = .67). Participants with elevated amyloid levels had increased Concern About AD scores (raw change in scores: elevated amyloid group, 0.8 [3.9]; not elevated amyloid group, -0.4 [3.8]; P < .001). Participants with not elevated amyloid levels experienced a slight increase in Future Time Perspective score(mean [SD] score, 1.15 [7.4] points; P < .001); there was no change in time perspective among those receiving an elevated amyloid result (mean [SD] score, 0.33 [7.8] points).
Conclusions and Relevance: In this observational preclinical AD study, participants who learned they had elevated amyloid levels did not experience short-term negative psychological sequelae compared with persons who learned they did not have elevated amyloid levels.}, }
@article {pmid32759365, year = {2020}, author = {Peng, HB and Noh, K and Pan, SR and Saldivia, V and Serson, S and Toscan, A and de Lannoy, IAM and Pang, KS}, title = {Human Amyloid-β40 Kinetics after Intravenous and Intracerebroventricular Injections and Calcitriol Treatment in Rats In Vivo.}, journal = {Drug metabolism and disposition: the biological fate of chemicals}, volume = {48}, number = {10}, pages = {944-955}, doi = {10.1124/dmd.120.090886}, pmid = {32759365}, issn = {1521-009X}, abstract = {Amyloid-β peptides of 40 and 42 amino acid lengths, which are synthesized in neurons and degraded in the brain and liver, have the potential to aggregate and form neuritic plaques in Alzheimer disease. The kinetics of human amyloid-β (hAβ) 40 were examined in the rat pursuant to intravenous and intracerebroventricular administration after pretreatment with calcitriol, the active vitamin D receptor ligand (6.4 nmol·kg-1 in 0.3 ml corn oil every other day for four intraperitoneal doses) to induce P-glycoprotein (P-gp) and enhance hAβ40 brain efflux. The interference of hAβ40 by media matrix that suppressed absorbance readings in the ELISA assay was circumvented with use of different calibration curves prepared in Standard Dilution Buffer, undiluted, 10-10,000 or 5-fold diluted plasma, or artificial cerebrospinal fluid. Simultaneous fitting of hAβ40 plasma and cerebrospinal fluid (CSF) data after intravenous and intracerebroventricular administration were described by catenary-mammillary models comprising of a central and two peripheral compartments, the brain, and one to four CSF compartments. The model with only one CSF compartment (model I) best fitted the intravenous data that showed a faster plasma decay t1/2 and slower equilibration between plasma and brain/CSF. Calcitriol induction increased the brain efflux rate constant, k41 (1.8-fold), at the blood-brain barrier when compared with the control group, as confirmed by the 2-fold (P < 0.05) increase in brain P-gp relative protein expression. SIGNIFICANCE STATEMENT: An accurate description of the kinetic behavior of human amyloid-β (hAβ) 40 is needed in defining the toxic peptide as a biomarker of Alzheimer disease. Modeling of hAβ40 data after intravenous and intracerebroventricular administration to the rat revealed an initially faster plasma half-life that reflected faster peripheral distribution but slower equilibration between plasma and brain/cerebrospinal fluid even with calcitriol pretreatment that increased P-glycoprotein protein expression and enhanced efflux clearance from brain.}, }
@article {pmid32758340, year = {2020}, author = {Fu, Y and Yang, Y and Shi, J and Bishayee, K and Lin, L and Lin, Y and Zhang, Y and Ji, L and Li, C}, title = {Acori tatarinowii rhizoma extract ameliorates Alzheimer's pathological syndromes by repairing myelin injury and lowering Tau phosphorylation in mice.}, journal = {Die Pharmazie}, volume = {75}, number = {8}, pages = {395-400}, doi = {10.1691/ph.2020.0492}, pmid = {32758340}, issn = {0031-7144}, mesh = {Alzheimer Disease/*drug therapy/physiopathology ; Animals ; Behavior, Animal/*drug effects ; Disease Models, Animal ; Drugs, Chinese Herbal/*pharmacology ; Learning/drug effects ; Male ; Maze Learning ; Mice ; Mice, Transgenic ; Myelin Sheath/*drug effects/pathology ; Phosphorylation ; Rhizome ; tau Proteins/metabolism ; }, abstract = {It has been shown that Acori tatarinowii rhizoma (ATR) extract can improve cognitive functions in Alzheimer Diseas (AD) patients or animal models. In this study, we have examined the activity of ATR in 3×Tg-AD model mice with different comprehensive behavioral tests like the Morris water maze and Y-maze test assay for behavior. Moreover, we performed LFB staining for myelin determination in the AD model mouse. By analyzing different pathways, we determined key proteins that are beneficial for ameliorating AD syndrome in the mouse. Periluminally, ATR treatment improved the learning and memory ability that was determined by comprehensive behavioral tests. Moreover, treatment reduces the p-Tau accumulation in the 3×Tg-AD mouse and the level of p-Tau accumulation was at per with the wildtype control mouse and improves the myelin lining in 3×Tg-AD mouse. In conclusion, our results indicate that ATR-treatment can improve the learning ability of AD model mice and the hyperphosphorylation of Tau protein was decreased. ATR can protect myelin lining from damage in AD syndrome.}, }
@article {pmid32746727, year = {2020}, author = {Işık, M and Beydemir, Ş}, title = {The impact of some phenolic compounds on serum acetylcholinesterase: kinetic analysis of an enzyme/inhibitor interaction and molecular docking study.}, journal = {Journal of biomolecular structure & dynamics}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/07391102.2020.1801509}, pmid = {32746727}, issn = {1538-0254}, abstract = {In the treatment of Alzheimer's disease (AD), it is important to develop alternative cholinesterase inhibitors with antioxidant properties that will reduce acetylcholine deficiency and free radical formation. The aim of this study was to investigate the effect of hydroquinone, 4-hydroxybenzoic acid, 3,5-dihydroxybenzoic acid, caffeic acid, vanillic acid and chlorogenic acid against acetylcholinesterase (AChE), partially purified from serum. Binding of compounds with effective inhibitory potential to the AChE active site as competitive was illuminated by molecular docking. Hydroquinone, chlorogenic acid and 4-hydroxybenzoic acid have been found to have higher inhibitory potential than others against the AChE. IC50 and KI values of the phenolic compounds against AChE were found in the range of 0.26 ± 0.01-36.34 ± 2.72 mM and 0.72 ± 0.00-29.23 ± 2.62 mM, respectively. The effectiveness of the compounds has been associated with its structure. Consequently, the phenolic compounds, which have AChE inhibitory potential and antioxidant properties, can be considered as alternative drugs in the treatment of AD.Communicated by Ramaswamy H. Sarma.}, }
@article {pmid32744972, year = {2021}, author = {Firdaus, Z and Singh, TD}, title = {An Insight in Pathophysiological Mechanism of Alzheimer's Disease and its Management Using Plant Natural Products.}, journal = {Mini reviews in medicinal chemistry}, volume = {21}, number = {1}, pages = {35-57}, doi = {10.2174/1389557520666200730155928}, pmid = {32744972}, issn = {1875-5607}, mesh = {Alzheimer Disease/*drug therapy/physiopathology ; Antioxidants/chemistry/*therapeutic use ; Biological Products/chemistry/*therapeutic use ; Humans ; Molecular Structure ; Neuroprotective Agents/chemistry/*therapeutic use ; }, abstract = {Alzheimer's disease (AD) is an age-associated nervous system disorder and a leading cause of dementia worldwide. Clinically, it is described by cognitive impairment and pathophysiologically by deposition of amyloid plaques and neurofibrillary tangles in the brain and neurodegeneration. This article reviews the pathophysiology, course of neuronal degeneration, and the various possible hypothesis of AD progression. These hypotheses include amyloid cascade, tau hyperphosphorylation, cholinergic disruption, metal dysregulation, vascular dysfunction, oxidative stress, and neuroinflammation. There is an exponential increase in the occurrence of AD in the recent few years that indicate an urgent need to develop some effective treatment. Currently, only 2 classes of drugs are available for AD treatment, namely acetylcholinesterase inhibitor and NMDA receptor antagonist. Since AD is a complex neurological disorder and these drugs use a single target approach, alternatives are needed due to limited effectiveness and unpleasant side-effects of these drugs. Currently, plants have been used for drug development research especially because of their multiple sites of action and fewer side effects. Uses of some herbs and phytoconstituents for the management of neuronal disorders like AD have been documented in this article. Phytochemical screening of these plants shows the presence of many beneficial constituents like flavonoids, triterpenes, alkaloids, sterols, polyphenols, and tannins. These compounds show a wide array of pharmacological activities, such as anti-amyloidogenic, anticholinesterase, and antioxidants. This article summarizes the present understanding of AD progression and gathers biochemical evidence from various works on natural products that can be useful in the management of this disease.}, }
@article {pmid32743317, year = {2020}, author = {Naing, HL and Teo, SP}, title = {Impact of Hypertension on Cognitive Decline and Dementia.}, journal = {Annals of geriatric medicine and research}, volume = {24}, number = {1}, pages = {15-19}, pmid = {32743317}, issn = {2508-4909}, abstract = {Dementia reduces a person's ability to perform their activities of daily living and is the leading cause of morbidity worldwide. While most preventive measures are ineffective in reducing dementia risk, active treatment of hypertension in middle-aged and older adults without dementia may reduce the incidence of dementia. Hypertension is associated with vascular dementia but may also affect the manifestations of Alzheimer disease. Observational studies support the association between hypertension and white matter lesions, hippocampal atrophy, and cognitive decline. Both increased and decreased blood pressure were related to the development of white matter lesions. Cohort studies showed that hypertension treatment and treatment duration were associated with lower cognitive decline. This review describes findings from randomized controlled studies on the effects of antihypertensives on cognitive decline. Only the Systolic Hypertension in Europe (Syst-Eur) trial using calcium-channel blockers demonstrated a significant reduction in dementia incidence. Further studies are required to evaluate the long-term benefits of antihypertensive treatment in dementia.}, }
@article {pmid32742119, year = {2020}, author = {Ahmed, Z and Aziz, S and Hanif, M and Mohiuddin, SG and Ali Khan, SH and Ahmed, R and Sheikh Ghadzi, SM and Naoras Bitar, A}, title = {Phytochemical screening and enzymatic and antioxidant activities of Erythrina suberosa (Roxb) bark.}, journal = {Journal of pharmacy & bioallied sciences}, volume = {12}, number = {2}, pages = {192-200}, pmid = {32742119}, issn = {0976-4879}, abstract = {Background: This study aimed to evaluate the phytochemicals screening of Erythrina suberosa (Roxb) bark and to analyze the enzymatic activities of its various organic fractions.
Materials and Methods: Crude methanolic fraction of E. suberosa (Roxb) bark and its respective fractions were screened for the presence of different phytochemicals with different reagents. On the basis of increasing order of polarity, different organic solvents were used to obtain different fractions. Enzymatic studies were performed on crude methanolic extract of the plant. All the assays were performed under standard in vitro conditions.
Results: The phytochemical analysis shows the presence of alkaloids, phenols, triterpenoids, phytosterols, and flavonoids. Phenolic compounds and flavonoids are the major constituents of the plant. In anticholinesterase assay, the percent inhibition of standard drug (eserine) was 91.27 ± 1.17 and the half maximal inhibitory concentration (IC50) was 0.04 ± 0.0001. For α-glucosidase inhibition, the IC50 value for Dichloromethane fraction was 8.45 ± 0.13, for Methanol fraction it was 64.24 ± 0.15, and for aqueous fraction it was 42.62 ± 0.17 as compared with standard IC50 that is 37.42 (acarbose). Furthermore, results show that all fractions have potential against anti-urease enzyme, but DCM fraction of crude aqueous extract has significant IC50 value (45.26 ± 0.13) than other fractions.
Conclusion: Keeping in view all the results, it is evident that the plant can be used in future for formulating effective drugs against many ailments. Secondary metabolites and their derivatives possess different biological activities, for example, .g. flavonoids in cancer, asthma, and Alzheimer. Furthermore, the extracts of this plant can be used in their crude form, which is an addition to the complementary and alternative treatment strategies.}, }
@article {pmid32741817, year = {2020}, author = {Hasegawa, T and Kosoku, Y and Sano, Y and Yoshida, H and Kudoh, C and Tabira, T}, title = {Homocysteic Acid in Blood Can Detect Mild Cognitive Impairment: A Preliminary Study.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {77}, number = {2}, pages = {773-780}, doi = {10.3233/JAD-200234}, pmid = {32741817}, issn = {1875-8908}, abstract = {BACKGROUND: In the treatment of Alzheimer's disease (AD), it is thought to be most effective to intervene at the earliest and mildest stages. For diagnosis at the earliest and mildest stages, it is desirable to use a biomarker that can be detected by a minimally invasive, cost-effective technique. Recent research indicates the potential clinical usefulness of plasma amyloid-β (Aβ) biomarkers in predicting brain Aβ burden at an individual level. However, it is as yet unproven that accumulation of Aβ necessarily leads to the development of AD.
OBJECTIVE: Homocysteic acid (HCA) is useful as an early diagnostic marker for mild cognitive impairment (MCI), a pre-stage of AD.
METHODS: We measured the concentration of HCA, tumor necrosis factor alpha, cortisol, tau, and phosphorylated tau (p-tau) in patients' plasma of 22 AD, 23 MCI, and 9 negative control (NC) cases.
RESULTS: Plasma HCA was shown to be very high in areas under the receiver operating characteristic curves (AUC), distinguished between MCI and NC; when 0.116μM was chosen as the analyte concentration cut-off, the sensitivity was 95.7% and the specificity was 70%.
CONCLUSION: Our results suggest that plasma HCA may be a useful indicator as an early diagnostic marker for MCI. HCA seems to be upstream from neurodegeneration in the AD pathology because it is known that an overactive NMDA receptor promotes amyloid polymerization and tau phosphorylation in AD.}, }
@article {pmid32736994, year = {2021}, author = {Abdeljalil, AB and de Mauléon, A and Baziard, M and Vellas, B and Lapeyre-Mestre, M and Soto, M}, title = {Antidepressant Use and Progression of Mild to Moderate Alzheimer's Disease: Results from the European ICTUS Cohort.}, journal = {Journal of the American Medical Directors Association}, volume = {22}, number = {2}, pages = {433-439}, doi = {10.1016/j.jamda.2020.06.028}, pmid = {32736994}, issn = {1538-9375}, mesh = {Activities of Daily Living ; *Alzheimer Disease/drug therapy ; Antidepressive Agents/adverse effects ; Disease Progression ; Europe ; Humans ; Prospective Studies ; }, abstract = {OBJECTIVES: Neuropsychiatric symptoms (NPS) are a core and troubling feature among patients with Alzheimer disease (AD). Because of growing safety warnings against antipsychotics, the use of antidepressants (ATD) in AD has increased extensively. We investigated the potential long-term associations between ATD exposure and functional and cognitive progression in patients with mild to moderate AD.
DESIGN: Two-year prospective multicenter cohort ICTUS (Impact of Cholinergic Treatment USe) study with biannual assessments.
SETTING: Twenty-nine memory clinics from 12 European countries.
PARTICIPANTS: Community-dwelling patients with mild to moderate AD.
METHODS: Global cognitive function was measured using the Mini Mental State Examination (MMSE) and the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). Functional impairment was measured using the Activities of Daily Living (ADL). Assessments were performed biannually for 2 years. Antidepressant exposure was defined by an ATD prescription for a minimum period of 6 months. Linear mixed models were used to study the associations between ATD exposure and cognitive and functional progression.
RESULTS: Antidepressant exposure was not associated with cognitive decline [MMSE: β-coefficients of the linear mixed models (Coef) = 0.06, 95% confidence interval (CI) -0.65 to 0.76, P = .87; ADAS-Cog: Coef = -13.9, 95% CI -34.80 to 7.03, P = .19] or with functional decline (ADL: Coef = -0.05, 95% CI -0.21 to 0.09, P = .48) at 2-year follow-up. Antipsychotic exposure at baseline was associated with a greater functional decline in the ADL score (Coef = -0.39, 95% CI - 0.68 to 0.10, P < .01).
CONCLUSIONS AND IMPLICATIONS: Antidepressant exposure was not associated with a faster rate of cognitive or functional decline in patients with mild to moderate AD. Antidepressants might be appropriate alternatives to antipsychotics in the management of NPS in mild to moderate AD.}, }
@article {pmid32735939, year = {2020}, author = {Sugin, LJS and Murugesan, A and Bindu, M and Sunil, KN}, title = {Roflumilast: A potential drug for the treatment of cognitive impairment?.}, journal = {Neuroscience letters}, volume = {736}, number = {}, pages = {135281}, doi = {10.1016/j.neulet.2020.135281}, pmid = {32735939}, issn = {1872-7972}, mesh = {Aminopyridines/administration & dosage/*therapeutic use ; Animals ; Benzamides/administration & dosage/*therapeutic use ; Cognitive Dysfunction/*drug therapy ; Cyclopropanes/administration & dosage/therapeutic use ; Humans ; Memory/*drug effects ; Phosphodiesterase 4 Inhibitors/administration & dosage/*therapeutic use ; }, abstract = {Phosphodiesterase-4 regulates the intracellular level of cAMP. Roflumilast, a selective PDE-4 inhibitor was the first agent in this class to have reached the market for patients with chronic obstructive pulmonary disease worldwide. Numerous preclinical evidences indicate the role of PDE-4 inhibitors in reversal of ageing-related alterations induced in animal models by various pharmacological agents, overexpression of mutant forms of human amyloid precursor proteins and in aging, as well. Roflumilast was capable of decreasing PDE-4B and 4D subtypes with an increase in the expression of pCREB and BDNF in hippocampus of rats. The beneficial effects of roflumilast on cognition are believed to be mediated through the above-mentioned cellular effects. Recently, Jabaris et al had shown that roflumilast has improved the short and long-term memory in rodents. Several lines of evidence indicate that targeting PDE-4 inhibition might offer novel approaches in the treatment of age-associated memory impairment and in Alzheimer's disease. Likewise, in a recent report, roflumilast improved the memory functions in humans after administration of 100 μg of the drug, without the typical side effects of PDE-4 inhibitors, which might offer a novel therapeutic option for the treatment of cognitive impairment and Alzheimer disease. In the current article, the author reviews the most recent evidences demonstrating the beneficial effects of roflumilast on learning and memory in animal models and humans.}, }
@article {pmid32724479, year = {2020}, author = {Sun, Y and Wang, Y and Chen, ST and Chen, YJ and Shen, J and Yao, WB and Gao, XD and Chen, S}, title = {Modulation of the Astrocyte-Neuron Lactate Shuttle System contributes to Neuroprotective action of Fibroblast Growth Factor 21.}, journal = {Theranostics}, volume = {10}, number = {18}, pages = {8430-8445}, pmid = {32724479}, issn = {1838-7640}, mesh = {Alzheimer Disease/genetics/*pathology ; Amyloid beta-Protein Precursor/genetics ; Animals ; Astrocytes/metabolism ; Cell Line ; Coculture Techniques ; Disease Models, Animal ; Fibroblast Growth Factors/*metabolism ; Hippocampus/cytology ; Humans ; Lactic Acid/*metabolism ; Male ; Mice ; Mice, Transgenic ; Neurons/metabolism ; *Neuroprotection ; Presenilin-1/genetics ; Primary Cell Culture ; Rats ; }, abstract = {A viewpoint considering Alzheimer's disease (AD) as "type 3 diabetes" emphasizes the pivotal role of dysfunctional brain energy metabolism in AD. The hormone fibroblast growth factor 21 (FGF21) is a crucial regulator in energy metabolism; however, our understanding of the therapeutic potential and mechanisms underlying the effect of FGF21 on neurodegeneration of AD is far from complete. Methods: To further elucidate the effect of FGF21 on AD-related neurodegeneration, we used APP/PS1 transgenic mice to assess the effects of FGF21 on memory dysfunction, amyloid plaque pathology and pathological tau hyperphosphorylation. We also established an in vitro system to mimic astrocyte-neuron communication and an in vivo model of acute injury. Based on the in vivo and in vitro models, we analyzed the neuroprotective actions of FGF21 and pathways related to astrocyte-neuron communication and further focused on the astrocyte-neuron lactate shuttle system. Results: Here, we report that FGF21 can ameliorate Alzheimer-like neurodegeneration in APP/PS1 transgenic mice. We detected defects in the astrocyte-neuron lactate shuttle system in the in vivo and in vitro models of AD and identified FGF21 as a neuroprotective molecule that can rescue these deficits. Administration of FGF21 can alleviate memory dysfunction, amyloid plaque pathology and pathological tau hyperphosphorylation, and the function of FGF21 in neurodegeneration is mediated in part by monocarboxylate transporters (MCTs). In vivo evidence also suggests that FGF21 acts centrally in mice to exert its effects on neurodegeneration and energy metabolism via its regulation of MCTs. Conclusions: These results suggest that FGF21 alters metabolic parameters to mediate its neuroprotective functions. Modulation of the astrocyte-neuron lactate shuttle system can be one of the most efficient strategies for FGF21 in Alzheimer-like degeneration and contributes to improvements in brain metabolic defects and amyloid β-induced cytotoxicity. Our findings provide insights into the mechanisms underlying the effects of FGF21 on neurodegeneration and brain energy metabolism and suggest that FGF21 may have therapeutic value in the treatment of AD and other neurodegenerative diseases.}, }
@article {pmid32722122, year = {2020}, author = {Varano, F and Catarzi, D and Vigiani, E and Vincenzi, F and Pasquini, S and Varani, K and Colotta, V}, title = {Piperazine- and Piperidine-Containing Thiazolo[5,4-d]pyrimidine Derivatives as New Potent and Selective Adenosine A2A Receptor Inverse Agonists.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {13}, number = {8}, pages = {}, pmid = {32722122}, issn = {1424-8247}, support = {Fondi Ateneo Ricerca 2019//Università degli Studi di Firenze/ ; }, abstract = {The therapeutic use of A2A adenosine receptor (AR) antagonists for the treatment of neurodegenerative disorders, such as Parkinson and Alzheimer diseases, is a very promising approach. Moreover, the potential therapeutic role of A2A AR antagonists to avoid both immunoescaping of tumor cells and tumor development is well documented. Herein, we report on the synthesis and biological evaluation of a new set of piperazine- and piperidine- containing 7-amino-2-(furan-2-yl)thiazolo[5,4-d]pyrimidine derivatives designed as human A2A AR antagonists/inverse agonists. Binding and potency data indicated that a good number of potent and selective hA2A AR inverse agonists were found. Amongst them, the 2-(furan-2-yl)-N5-(2-(4-phenylpiperazin-1-yl)ethyl)thiazolo[5,4-d]pyrimidine-5,7-diamine 11 exhibited the highest A2A AR binding affinity (Ki = 8.62 nM) as well as inverse agonist potency (IC50 = 7.42 nM). In addition, bioinformatics prediction using the web tool SwissADME revealed that 8, 11, and 19 possessed good drug-likeness profiles.}, }
@article {pmid32712274, year = {2020}, author = {Lushchekina, SV and Masson, P}, title = {Slow-binding inhibitors of acetylcholinesterase of medical interest.}, journal = {Neuropharmacology}, volume = {177}, number = {}, pages = {108236}, doi = {10.1016/j.neuropharm.2020.108236}, pmid = {32712274}, issn = {1873-7064}, mesh = {Acetylcholinesterase/*metabolism ; Alkaloids/administration & dosage/metabolism ; Alzheimer Disease/drug therapy/enzymology ; Animals ; Cholinesterase Inhibitors/*administration & dosage/*metabolism ; Humans ; Myasthenia Gravis/drug therapy/enzymology ; Nervous System Diseases/*drug therapy/*enzymology ; Protein Binding ; Sesquiterpenes/administration & dosage/metabolism ; Tocopherols/administration & dosage/metabolism ; }, abstract = {Certain ligands slowly bind to acetylcholinesterase. As a result, there is a slow establishment of enzyme-inhibitor equilibrium characterized by a slow onset of inhibition prior reaching steady state. Three mechanisms account for slow-binding inhibition: a) slow binding rate constant kon, b) slow ligand induced-fit following a fast binding step, c) slow conformational selection of an enzyme form. The slow equilibrium may be followed by a chemical step. This later that can be irreversible has been observed with certain alkylating agents and substrate transition state analogs. Slow-binding inhibitors present long residence times on target. This results in prolonged pharmacological or toxicological action. Through several well-known molecules (e.g. huperzine) and new examples (tocopherol, trifluoroacetophenone and a 6-methyluracil alkylammonium derivative), we show that slow-binding inhibitors of acetylcholinesterase are promising drugs for treatment of neurological diseases such as Alzheimer disease and myasthenia gravis. Moreover, they may be of interest for neuroprotection (prophylaxis) against organophosphorus poisoning. This article is part of the special issue entitled 'Acetylcholinesterase Inhibitors: From Bench to Bedside to Battlefield'.}, }
@article {pmid32706773, year = {2020}, author = {Tanaka, N and Okuda, M and Nishigaki, T and Tsuchiya, N and Kobayashi, Y and Uemura, T and Kumo, S and Sugimoto, H and Miyata, S and Waku, T}, title = {Development of a brain-permeable peptide nanofiber that prevents aggregation of Alzheimer pathogenic proteins.}, journal = {PloS one}, volume = {15}, number = {7}, pages = {e0235979}, pmid = {32706773}, issn = {1932-6203}, mesh = {Administration, Intranasal ; Alzheimer Disease/etiology/pathology/*prevention & control ; Amyloid beta-Peptides/*administration & dosage ; Animals ; Brain/drug effects/*metabolism ; *Disease Models, Animal ; Female ; Memory Disorders/etiology/pathology/*prevention & control ; Mice ; Mice, Transgenic ; Nanofibers/*administration & dosage/chemistry ; Plaque, Amyloid/etiology/pathology/*prevention & control ; }, abstract = {Alzheimer's disease (AD) is proposed to be induced by abnormal aggregation of amyloidβ in the brain. Here, we designed a brain-permeable peptide nanofiber drug from a fragment of heat shock protein to suppress aggregation of the pathogenic proteins. To facilitate delivery of the nanofiber into the brain, a protein transduction domain from Drosophila Antennapedia was incorporated into the peptide sequence. The resulting nanofiber efficiently suppressed the cytotoxicity of amyloid βby trapping amyloid β onto its hydrophobic nanofiber surface. Moreover, the intravenously or intranasally injected nanofiber was delivered into the mouse brain, and improved the cognitive function of an Alzheimer transgenic mouse model. These results demonstrate the potential therapeutic utility of nanofibers for the treatment of AD.}, }
@article {pmid32705955, year = {2020}, author = {Mascarenhas, AMS and de Almeida, RBM and de Araujo Neto, MF and Mendes, GO and da Cruz, JN and Dos Santos, CBR and Botura, MB and Leite, FHA}, title = {Pharmacophore-based virtual screening and molecular docking to identify promising dual inhibitors of human acetylcholinesterase and butyrylcholinesterase.}, journal = {Journal of biomolecular structure & dynamics}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/07391102.2020.1796791}, pmid = {32705955}, issn = {1538-0254}, abstract = {The dual inhibition of human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBuChE) plays an important role in Alzheimer's disease treatment. Thus, this study aims identify promising dual inhibitors against hAChE and hBuChE by in silico approaches (pharmacophore-based virtual screening and molecular docking). Ten 3 D pharmacophore models for dual inhibitors using default genetic parameters were built by GALAHAD™ available on SYBYL-X 2.0. Validation steps were carried out according to Energy (<100.0 kcal/mol), Pareto = 0, Area under the ROC Curve (>0.70), Boltzmann-Enhanced Discrimination of ROC curve (BEDROC >0.50) and structure-activity relationship (SAR) for known inhibitors. The best dual pharmacophore model based on internal/external statistical parameters and SAR data (one hydrogen bond acceptor, two hydrogen bond donors and four hydrophobic centers) was employed in virtual screening at Sigma-Aldrich® subset (n = 214,446) of ZINC database by UNITY module of SYBYL-X 2.0. According to superposition values (QFIT), the best ranked compounds were prioritized for molecular docking and partition coefficient analysis (clog p < 5.0). 37 top-ranked compounds (QFIT > 64.22) from pharmacophore model showed affinity in hAChE (-10.2 < Affinity energy < -6.3 kcal/mol) and hBuChE (-10.9 < Affinity energy < -2.3 kcal/mol) binding sites. Next, liposolubity prediction and commercially available showed that ZINC43198636, ZINC43198637 and ZINC00390718 can be potential dual inhibitors against hAChE and hBuChE.Communicated by Ramaswamy H. Sarma.}, }
@article {pmid32698354, year = {2020}, author = {Joseph, CR}, title = {Novel MRI Techniques Identifying Vascular Leak and Paravascular Flow Reduction in Early Alzheimer Disease.}, journal = {Biomedicines}, volume = {8}, number = {7}, pages = {}, pmid = {32698354}, issn = {2227-9059}, abstract = {With beta amyloid and tau antibody treatment trial failures, avenues directed to other facets of the disease pathophysiology are being explored to treat in the preclinical or early clinical state. Clear evidence of blood-brain barrier (BBB) breakdown occurring early in the AD process has recently been established. Likewise, the glymphatic system regulating water and solute inflow and outflow in parallel with the vascular system is affected causing delayed clearance of fluid waste. Its dysfunction as a component of AD along with BBB leak are reasonable candidates to explore for future treatments. Ideally, human medication trials require a minimally invasive method of quantifying both improvements in BBB integrity and glymphatic fluid clearance correlated with clinical outcomes. We will review the known physiology and anatomy of the BBB system, and its relationship to the glymphatic system and the microglial surveillance system. Dysfunction of this tripart system occurring in preclinical Alzheimer disease (AD) will be reviewed along with existing MRI tools for identifying altered flow dynamics useful for monitoring improved functionality with future treatments. High-resolution dynamic contrast enhanced MRI imaging demonstrating BBB leak and the recently reported non-invasive 3D PASL MRI pilot study demonstrating significant delay in glymphatic clearance in AD subjects appear to be the best candidates.}, }
@article {pmid32679025, year = {2020}, author = {Ghai, R and Nagarajan, K and Arora, M and Grover, P and Ali, N and Kapoor, G}, title = {Current Strategies and Novel Drug Approaches for Alzheimer Disease.}, journal = {CNS & neurological disorders drug targets}, volume = {19}, number = {9}, pages = {676-690}, doi = {10.2174/1871527319666200717091513}, pmid = {32679025}, issn = {1996-3181}, abstract = {Alzheimer's Disease (AD) is a chronic, devastating dysfunction of neurons in the brain leading to dementia. It mainly arises due to neuronal injury in the cerebral cortex and hippocampus area of the brain and is clinically manifested as a progressive mental failure, disordered cognitive functions, personality changes, reduced verbal fluency and impairment of speech. The pathology behind AD is the formation of intraneuronal fibrillary tangles, deposition of amyloid plaque and decline in choline acetyltransferase and loss of cholinergic neurons. Tragically, the disease cannot be cured, but its progression can be halted. Various cholinesterase inhibitors available in the market like Tacrine, Donepezil, Galantamine, Rivastigmine, etc. are being used to manage the symptoms of Alzheimer's disease. The paper's objective is to throw light not only on the cellular/genetic basis of the disease, but also on the current trends and various strategies of treatment including the use of phytopharmaceuticals and nutraceuticals. Enormous literature survey was conducted and published articles of PubMed, Scifinder, Google Scholar, Clinical Trials.org and Alzheimer Association reports were studied intensively to consolidate the information on the strategies available to combat Alzheimer's disease. Currently, several strategies are being investigated for the treatment of Alzheimer's disease. Immunotherapies targeting amyloid-beta plaques, tau protein and neural pathways are undergoing clinical trials. Moreover, antisense oligonucleotide methodologies are being approached as therapies for its management. Phytopharmaceuticals and nutraceuticals are also gaining attention in overcoming the symptoms related to AD. The present review article concludes that novel and traditional therapies simultaneously promise future hope for AD treatment.}, }
@article {pmid32678552, year = {2020}, author = {Sokolova, SV and Sozarukova, MM and Khannanova, AN and Grishina, NK and Portnova, GV and Proskurnina, EV}, title = {[Antioxidant status in patients with paranoid schizophrenia and Alzheimer disease].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {120}, number = {6}, pages = {82-87}, doi = {10.17116/jnevro202012006182}, pmid = {32678552}, issn = {1997-7298}, mesh = {*Alzheimer Disease ; Antioxidants ; Antipsychotic Agents ; Clozapine ; Humans ; Risperidone ; *Schizophrenia, Paranoid ; }, abstract = {OBJECTIVE: To study the antioxidant profile of blood plasma in patients with paranoid schizophrenia and Alzheimer disease (AD).
MATERIAL AND METHODS: Thirty-three patients with paranoid schizophrenia and 18 patients with AD were included in the study. Patients with schizophrenia were stratified into two subgroups by response to therapy. The indicators of the antioxidant profile were determined using methods based on chemiluminometry and spectrofluorimetry.
RESULTS: Systemic oxidative stress due to insufficiency of low molecular weight plasma antioxidants is not determined neither in AD nor in treatment resistant schizophrenia. At the same time, a «thiol» oxidative stress, which indirectly indicates a deficiency of the glutathione system, is present in both groups. In patients with paranoid schizophrenia responsive to treatment, systemic oxidative stress is more pronounced and «thiol» oxidative stress is less significant. Among the antipsychotics studied, haloperidol, zuclopenthixol, risperidone and ziprasidone do not exhibit antioxidant properties, but periciazine, clozapine and especially chlorpromazine exhibit strong antioxidant properties, but they unlikely affect the antioxidant potential of blood plasma.
CONCLUSIONS: The glutathione part of the antioxidant system is mostly affected, but systemic oxidative stress is not significant in patients with treatment resistant paranoid schizophrenia and AD. Oxidative disorders are more pronounced in treatment responsive paranoid schizophrenia.}, }
@article {pmid32678276, year = {2020}, author = {Jin, N and Ziyatdinova, S and Gureviciene, I and Tanila, H}, title = {Response of spike-wave discharges in aged APP/PS1 Alzheimer model mice to antiepileptic, metabolic and cholinergic drugs.}, journal = {Scientific reports}, volume = {10}, number = {1}, pages = {11851}, pmid = {32678276}, issn = {2045-2322}, mesh = {3-Hydroxybutyric Acid/pharmacology ; Action Potentials/*drug effects ; Alzheimer Disease/*drug therapy/physiopathology ; Animals ; Anticonvulsants/*pharmacology ; Atropine/pharmacology ; Disease Models, Animal ; Donepezil/pharmacology ; Drug Administration Schedule ; Electroencephalography ; Epilepsy/*drug therapy/physiopathology ; Ethosuximide/pharmacology ; GABA Antagonists/pharmacology ; Humans ; Injections, Intraperitoneal ; Lactic Acid/pharmacology ; Levetiracetam/pharmacology ; Male ; Mice ; Mice, Transgenic ; Nootropic Agents/*pharmacology ; Organophosphorus Compounds/pharmacology ; Parasympatholytics/*pharmacology ; Plaque, Amyloid/*drug therapy/physiopathology ; Pyruvic Acid/pharmacology ; Video Recording ; }, abstract = {Epileptic nonconvulsive spike-wave discharges (SWDs) are commonly seen in amyloid plaque bearing transgenic mice but only rarely in their wild-type littermates. To shed light on their possible treatment options, we assessed the effect of drugs with variable and known mechanisms of action on the occurrence of SWDs in aged APPswe/PS1dE9 mice. The treatments included prototypic antiepileptic drugs (ethosuximide and levetiracetam), donepezil as the typical Alzheimer drug and atropine as an antagonistic effect, GABAB antagonist CGP-35348, and alternate energy substrates beta-hydroxybutyrate (BHB), pyruvate and lactate on the occurrence of SWDs in aged APPswe/PS1dE9 mice. All agents were administered by single intraperitoneal injections at doses earlier documented to be effective and response was assessed by recording 3 h of video-EEG. Atropine at 25 mg/kg significantly decreased SWD occurrence in all behavioral states, and also resulted in altered frequency composition of SWDs and general EEG slowing during sleep. Ethosuximide at 200 mg/kg and levetiracetam at 75 mg/kg effectively suppressed SWDs only during a period of mixed behavioral states, but levetiracetam also increased SWDs in sleep. BHB at 1 g/kg decreased SWDs in sleep, while both pyruvate and lactate at the same dose tended to increase SWD number and total duration. Unexpectantly, donepezil at 0.3 mg/kg CGP-35348 at 100 mg/kg had no effect on SWDs. These findings call for re-evaluation of some prevailing theories on neural circuit alternations that underlie SWD generation and show the utility of APP/PS1 mice for testing potential new treatments for nonconvulsive epileptic activity related to Alzheimer pathology.}, }
@article {pmid32667654, year = {2020}, author = {Koch, G and Motta, C and Bonnì, S and Pellicciari, MC and Picazio, S and Casula, EP and Maiella, M and Di Lorenzo, F and Ponzo, V and Ferrari, C and Scaricamazza, E and Caltagirone, C and Martorana, A}, title = {Effect of Rotigotine vs Placebo on Cognitive Functions Among Patients With Mild to Moderate Alzheimer Disease: A Randomized Clinical Trial.}, journal = {JAMA network open}, volume = {3}, number = {7}, pages = {e2010372}, pmid = {32667654}, issn = {2574-3805}, mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/diagnosis/*drug therapy ; Cognition/*drug effects ; Female ; Humans ; Male ; Mental Status and Dementia Tests ; Middle Aged ; Nootropic Agents/*therapeutic use ; Tetrahydronaphthalenes/*therapeutic use ; Thiophenes/*therapeutic use ; Treatment Outcome ; }, abstract = {Importance: Impairment of dopaminergic transmission may contribute to cognitive dysfunction in Alzheimer disease (AD).
Objective: To investigate whether therapy with dopaminergic agonists may affect cognitive functions in patients with AD.
This phase 2, monocentric, randomized, double-blind, placebo-controlled trial was conducted in Italy. Patients with mild to moderate AD were enrolled between September 1, 2017, and December 31, 2018. Data were analyzed from July 1 to September 1, 2019.
Interventions: A rotigotine 2 mg transdermal patch for 1 week followed by a 4 mg patch for 23 weeks (n = 47) or a placebo transdermal patch for 24 weeks (n = 47).
Main Outcomes and Measures: The primary end point was change from baseline on the Alzheimer Disease Assessment Scale-Cognitive Subscale. Secondary end points were changes in Frontal Assessment Battery, Alzheimer Disease Cooperative Study-Activities of Daily Living, and Neuropsychiatric Inventory scores. Prefrontal cortex activity was evaluated by transcranial magnetic stimulation combined with electroencephalography.
Results: Among 94 patients randomized (mean [SD] age, 73.9 [5.6] years; 58 [62%] women), 78 (83%) completed the study. Rotigotine, as compared with placebo, had no significant effect on the primary end point: estimated mean change in Alzheimer Disease Assessment Scale-Cognitive Subscale score was 2.92 (95% CI, 2.51-3.33) for the rotigotine group and 2.66 (95% CI, 2.31-3.01) for the placebo group. For the secondary outcomes, there were significant estimated mean changes between groups for Alzheimer Disease Cooperative Study-Activities of Daily Living score (-3.32 [95% CI, -4.02 to -2.62] for rotigotine and -7.24 [95% CI, -7.84 to -6.64] for placebo) and Frontal Assessment Battery score (0.48 [95% CI, 0.31 to 0.65] for rotigotine and -0.66 [95% CI, -0.80 to -0.52] for placebo). There was no longitudinal change in Neuropsychiatric Inventory scores (1.64 [95% CI, 1.06-2.22] for rotigotine and 1.26 [95% CI, 0.77-1.75] for placebo group). Neurophysiological analysis of electroencephalography results indicated that prefrontal cortical activity increased in rotigotine but not in the placebo group. Adverse events were more common in the rotigotine group, with 11 patients dropping out compared with 5 in the placebo group.
Conclusions and Relevance: In this randomized clinical trial, rotigotine treatment did not significantly affect global cognition in patients with mild to moderate AD; however, improvement was observed in cognitive functions highly associated with the frontal lobe and in activities of daily living. These findings suggest that treatment with the dopaminergic agonist rotigotine may reduce symptoms associated with frontal lobe cognitive dysfunction and thus may delay the impairment of activities of daily living.
Trial Registration: ClinicalTrials.gov Identifier: NCT03250741.}, }
@article {pmid32658034, year = {2020}, author = {Liao, Z and Cheng, L and Li, X and Zhang, M and Wang, S and Huo, R}, title = {Meta-analysis of Ginkgo biloba Preparation for the Treatment of Alzheimer's Disease.}, journal = {Clinical neuropharmacology}, volume = {43}, number = {4}, pages = {93-99}, doi = {10.1097/WNF.0000000000000394}, pmid = {32658034}, issn = {1537-162X}, mesh = {Alzheimer Disease/*diagnosis/*drug therapy/psychology ; Cognition/drug effects/physiology ; *Ginkgo biloba ; Humans ; Phytotherapy/*methods ; Plant Extracts/isolation & purification/pharmacology/*therapeutic use ; Randomized Controlled Trials as Topic/methods ; }, abstract = {OBJECTIVE: The objective of this study was to investigate the efficacy and safety of Ginkgo biloba preparation for the treatment of Alzheimer disease (AD).
METHODS: Both English (PubMed, Embase, Cochrane Library databases, and the Cochrane Controlled Trials Register) and Chinese (WanFang, Chinese Biomedical, CNKI, and VIP databases) databases were systematically and independently searched by 2 authors from their inception until July 3, 2019. All relevant studies included AD patients who were treated with Ginkgo biloba. The efficacy and safety of the medicine were used as the main measurement index.
RESULTS: Seven studies (N = 939) were identified and analyzed. When compared with placebo, Ginkgo biloba showed exact validity in cognitive function and global clinical assessment (cognitive function section: risk ratio = 1.98, 95% confidence interval = 1.52-2.59, Z = 5.12, P < 0.001; according to Clinical Global Impression Change: odds ratio = 3.119, 95% confidence interval = 2.206-4.410, Z = 6.44, P < 0.001). Adverse events were mild.
CONCLUSIONS: Ginkgo biloba preparation has reliable efficacy of cognitive function and global clinical assessment and safety in the treatment of AD.}, }
@article {pmid32651872, year = {2020}, author = {Rajabi, F and Gusbeth, C and Frey, W and Maisch, J and Nick, P}, title = {Nanosecond pulsed electrical fields enhance product recovery in plant cell fermentation.}, journal = {Protoplasma}, volume = {257}, number = {6}, pages = {1585-1594}, pmid = {32651872}, issn = {1615-6102}, support = {031B0065A//Bundesministerium für Bildung und Forschung/ ; }, mesh = {Fermentation ; Plant Cells/*chemistry ; Signal Transduction ; }, abstract = {The potential of pharmacologically active secondary plant metabolites is limited by the low yield from often rare plants, and the lack of economically feasible chemical synthesis of these complex compounds. Plant cell fermentation offers an alternative strategy to overcome these constraints. However, the efficiency of this approach is limited by intracellular sequestration of the products, such that continuous bioprocessing is not possible. As a precondition for such a, more attractive, continuous process, it is of great importance to stimulate the export of the product into the medium without impairing viability and, thus, the productivity of the cells. Using nicotine alkaloids of tobacco as a case study, an alternative strategy is explored, where nanosecond pulsed electric fields (nsPEFs) are applied for the efficient downstream recovery of the products. To maintain cell viability and allow for the further use of biomass, cells were exposed to strong (1-20 kV·cm-1), but very short (10-100 ns) electric pulses, which leads to a temporary permeabilisation of cell membranes. Using two transgenic cell lines, where two key genes involved in the metabolism of the anti-Alzheimer compound nornicotine were overexpressed, we could show that this nsPEF treatment improved the partitioning of some nicotine alkaloids to the culture medium without impairing viability, nor the synthesis of alkaloids. However, this release was only partial and did not work for nornicotine. Thus, nsPEFs produced a fractionation of alkaloids. We explain this electrofractionation by a working model considering the differential intracellular compartmentalization of nicotineic alkaloids.}, }
@article {pmid32650180, year = {2020}, author = {Kısa, D and Korkmaz, N and Taslimi, P and Tuzun, B and Tekin, Ş and Karadag, A and Şen, F}, title = {Bioactivity and molecular docking studies of some nickel complexes: New analogues for the treatment of Alzheimer, glaucoma and epileptic diseases.}, journal = {Bioorganic chemistry}, volume = {101}, number = {}, pages = {104066}, doi = {10.1016/j.bioorg.2020.104066}, pmid = {32650180}, issn = {1090-2120}, mesh = {Alzheimer Disease/*drug therapy ; Epilepsy/*drug therapy ; Glaucoma/*drug therapy ; Humans ; Molecular Docking Simulation/*methods ; Molecular Structure ; Nickel/pharmacology/*therapeutic use ; Structure-Activity Relationship ; }, abstract = {The interaction of the coordination compounds with biological molecules resulted in the investigation of the drug potential of these molecules. In this study, enzyme inhibition of DSA (1-3) coordination compounds that were previously investigated for their anticancer and antibacterial properties was investigated. Also, DSA (1-3) had Ki values of 635.30 + 152.62, 184.01 + 90.05, and 163.03 ± 60.01 µM against human carbonic anhydrase I, 352.23 ± 143.09, 46.2 ± 15.47, and 54.117 ± 18.80 µM against AChE, 310.64 ± 97.35, 35.54 ± 7.01, and 101.51 ± 15.314 µM against BChE, respectively. The biological activity values of these compounds against enzymes whose name are AChE, BChE, and hCAI were compared. Ellman and Verporte methods were used for the study of these enzymes. Cholinesterase inhibitors, also known as anti-cholinesterase and cholinesterase blocking drugs, are chemicals that prevent the breakdown of the neurotransmitter acetylcholine or butyrylcholine. They may be used as drugs for Alzheimer's and myasthenia gravis. It is a common method for comparing biological activity values of nickel complexes with molecular docking calculations. Nickel complexes were studied against enzymes that are human carbonic anhydrase isozyme I for ID 2CAB (hCA I), butyrylcholinesterase for ID 1P0I (BChE), and acetylcholinesterase for ID 1EEA (AChE), respectively.}, }
@article {pmid32648620, year = {2020}, author = {Liu, B and Cao, Y and Shi, F and Wang, L and Li, N and Cheng, X and Du, J and Tian, Q and Zhou, X}, title = {The overexpression of RBM3 alleviates TBI-induced behaviour impairment and AD-like tauopathy in mice.}, journal = {Journal of cellular and molecular medicine}, volume = {24}, number = {16}, pages = {9176-9188}, pmid = {32648620}, issn = {1582-4934}, abstract = {The therapeutic hypothermia is an effective tool for TBI-associated brain impairment, but its side effects limit in clinical routine use. Hypothermia up-regulates RNA-binding motif protein 3 (RBM3), which is verified to protect synaptic plasticity. Here, we found that cognitive and LTP deficits, loss of spines, AD-like tau pathologies are displayed one month after TBI in mice. In contrast, the deficits of LTP and cognitive, loss of spines and tau abnormal phosphorylation at several sites are obviously reversed in TBI mice combined with hypothermia pre-treatment (HT). But, the neuroprotective role of HT disappears in TBI mouse models under condition of blocking RBM3 expression with RBM3 shRNA. In other hand, overexpressing RBM3 by AAV-RBM3 plasmid can mimic HT-like neuroprotection against TBI-induced chronic brain injuries, such as improving LTP and cognitive, loss of spines and tau hyperphosphorylation in TBI mouse models. Taken together, hypothermia pre-treatment reverses TBI-induced chronic AD-like pathology and behaviour deficits in RBM3 expression dependent manner, RBM3 may be a potential target for neurodegeneration diseases including Alzheimer disease.}, }
@article {pmid32645433, year = {2020}, author = {Azib, L and Debbache-Benaida, N and Da Costa, G and Atmani-Kilani, D and Saidene, N and Bouguellid, G and Ourabah, A and Krisa, S and Richard, T and Atmani, D}, title = {Neuroprotective effects of Fraxinus angustifolia Vahl. bark extract against Alzheimer's disease.}, journal = {Journal of chemical neuroanatomy}, volume = {109}, number = {}, pages = {101848}, doi = {10.1016/j.jchemneu.2020.101848}, pmid = {32645433}, issn = {1873-6300}, mesh = {Alzheimer Disease/*drug therapy/metabolism ; Amyloid beta-Peptides/metabolism ; Animals ; Cognition/*drug effects ; Disease ; *Fraxinus ; Lipid Peroxidation/drug effects ; Memory/*drug effects ; Mice ; Neuroprotective Agents/pharmacology/*therapeutic use ; PC12 Cells ; Peptide Fragments/metabolism ; Plant Extracts/pharmacology/*therapeutic use ; Rats ; Spatial Memory/drug effects ; Synaptosomes/drug effects/metabolism ; }, abstract = {Alzheimer disease's (AD) is a neurodegenerative disease induced by amyloid-β (Aβ) aggregation and accumulation of neurotoxic metals in the brain. Fraxinus angustifolia Vahl. (Oleaceae) is a Mediterranean plant traditionally used to treat several human problems as nervous system problems. This study aimed to evaluate the neuroprotective effects of F. angustifolia Vahl. bark extract (FAB) in vitro and in vivo against Aβ-aggregation and aluminium induced-neurotoxicity in mice. FAB was characterized by colorimetric methods and its individual compounds were identified and quantified by LC-MS. First, the neuroprotective effect of FAB was evaluated against Aβ25-35-aggregation where it was directly incubated with Aβ25-35 and the kinetic of aggregation was measured by spectrophotometer at 200 nm. Then, the extract was tested against Aβ25-35-induced cytotoxicity on PC12 cells and the cells viability was determined by MTT test. On the other hand, FAB (0.01-0.5 mg/mL) was tested against aluminium-activated lipid peroxidation in mice synaptosomal membranes, and in vivo against aluminium-caused neurotoxicity in male N.M.R.I. (Naval Medical Research Institute) mice; this test consisted of daily co-administration of the extract with Al for 60 days. At the end of the treatment, behavioral and memory tests (locomotor activity, black and white and Morris water maze tests) and histological analysis were realized. The identification and quantification of FAB phenolics revealed the presence of different phenolic classes with high concentration of phenylethanoids and hydroxycoumarins. FAB showed a high Aβ25-35 anti-aggregative effect and a dose dependent protective effect on PC12 cells. The extract also demonstrated a significant inhibition of lipid peroxidation and was found to prevent the Al harmful effects where it significantly increased the locomotor activity, decreased the anxiety, improved memory and reduced histological alterations. In conclusion, FAB is rich of bioactive compounds that gave it the ability to inhibit Aβ-aggregation and Al-caused neurotoxicity in mice.}, }
@article {pmid32641955, year = {2019}, author = {Ghanbari-Maman, A and Ghasemian-Roudsari, F and Aliakbari, S and Gholami Pourbadie, H and Khodagholi, F and Shaerzadeh, F and Daftari, M}, title = {Calcium Channel Blockade Ameliorates Endoplasmic Reticulum Stress in the Hippocampus Induced by Amyloidopathy in the Entorhinal Cortex.}, journal = {Iranian journal of pharmaceutical research : IJPR}, volume = {18}, number = {3}, pages = {1466-1476}, pmid = {32641955}, issn = {1735-0328}, abstract = {Entorhinal cortex (EC) is one of the first cerebral regions affected in Alzheimer's disease (AD). The pathology propagates to neighboring cerebral regions through a prion-like mechanism. In AD, intracellular calcium dyshomeostasis is associated with endoplasmic reticulum (ER) stress. This study was designed to examine hippocampal ER stress following EC amyloidopathy. Aβ1-42 was bilaterally microinjected into the EC under stereotaxic surgery. Rats were daily treated with 30 μg of isradipine, nimodipine, or placebo over one week. Passive avoidance and novel object recognition (NOR) tasks were performed using shuttle box and NOR test, respectively. GRP78/BiP and CHOP levels were measured in the hippocampal dentate gyrus (DG) by western blot technique. The glutathione (GSH) level and PDI activity were also assessed in the hippocampus by colorimetric spectrophotometer. Aβ treated group developed passive avoidance and novel recognition memory deficit compared to the control group. However, treatment with calcium channel blockers reversed the impairment. BiP and CHOP level increased in the hippocampus following amyloidopathy in the EC. PDI activity and GSH level in the hippocampus decreased in the Aβ treated group, but calcium channel blockers restored them toward the control level. In conclusion, memory impairment due to EC amyloidopathy is associated with ER stress related bio-molecular changes in the hippocampus, and treatment with L-type calcium channel blockers may prevent the changes and ultimately improve cognitive performance.}, }
@article {pmid32640970, year = {2020}, author = {Nakanishi, H and Nonaka, S and Wu, Z}, title = {Microglial Cathepsin B and Porphyromonas gingivalis Gingipains as Potential Therapeutic Targets for Sporadic Alzheimer's Disease.}, journal = {CNS & neurological disorders drug targets}, volume = {19}, number = {7}, pages = {495-502}, doi = {10.2174/1871527319666200708125130}, pmid = {32640970}, issn = {1996-3181}, abstract = {Many efforts have been made to develop therapeutic agents for Alzheimer's Disease (AD) based on the amyloid cascade hypothesis, but there is no effective therapeutic agent at present. Now, much attention has been paid to infiltrate pathogens in the brain as a trigger of AD. These pathogens, or their virulence factors, may directly cross a weakened blood-brain barrier, reach the brain and cause neurological damage by eliciting neuroinflammation. Moreover, there is growing clinical evidence of a correlation between periodontitis and cognitive decline in AD patients. Recent studies have revealed that microglial cathepsin B is increasingly induced by lipopolysaccharide of Porphylomonas gingivalis, a major pathogen of periodontal disease. Moreover, gingipains produced by P. gingivalis play critical roles in neuroinflammation mediated by microglia and cognitive decline in mice. Furthermore, an orally bioavailable and brain-permeable inhibitor of gingipain is now being tested in AD patients. It is largely expected that clinical studies countering bacterial virulence factors may pave the way to establish the prevention and early treatment of AD.}, }
@article {pmid32640969, year = {2020}, author = {Kumar, R and Gulati, M and Singh, SK and Sharma, D and Porwal, O}, title = {Road From Nose to Brain for Treatment of Alzheimer: The Bumps and Humps.}, journal = {CNS & neurological disorders drug targets}, volume = {19}, number = {9}, pages = {663-675}, doi = {10.2174/1871527319666200708124726}, pmid = {32640969}, issn = {1996-3181}, abstract = {Vulnerability of the brain milieu to even the subtle changes in its normal physiology is guarded by a highly efficient blood brain barrier. A number of factors i.e. molecular weight of the drug, its route of administration, lipophilic character, etc. play a significant role in its sojourn through the Blood Brain Barrier (BBB) and limit the movement of drug into brain tissue through BBB. To overcome these problems, alternative routes of drug administration have been explored to target the drugs to brain tissue. Nasal route has been widely reported for the administration of drugs for treatment of Alzheimer. In this innovative approach, the challenge of BBB is bypassed. Through this route, both the larger as well as polar molecules can be made to reach the brain tissues. Generally, these systems are either pH dependent or temperature dependent. The present review highlights the anatomy of nose, mechanisms of drug delivery from nose to brain, critical factors in the formulation of nasal drug delivery system, nasal formulations of various drugs that have been tried for their nasal delivery for treatment of Alzheimer. It also dives deep to understand the factors that contribute to the success of such formulations to carve out a direction for this niche area to be explored further.}, }
@article {pmid32627495, year = {2020}, author = {Zhang, R and Zhang, JL and Li, BT and Hua, CL and Liu, RQ}, title = {[Study on mechanisms of anti-Alzheimer's disease action of absorbed components of Gardeniae Fructus based on network pharmacology].}, journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica}, volume = {45}, number = {11}, pages = {2601-2610}, doi = {10.19540/j.cnki.cjcmm.20200204.401}, pmid = {32627495}, issn = {1001-5302}, mesh = {*Alzheimer Disease ; *Drugs, Chinese Herbal ; *Gardenia ; Humans ; Molecular Docking Simulation ; Reproducibility of Results ; }, abstract = {Gardeniae Fructus has the traditional effects of promoting intelligence and inducing resuscitation, but its mechanism is unclear. In this study, the relationship between Gardeniae Fructus's traditional effect of promoting intelligence and inducing resuscitation and anti-Alzheimer's disease effect was taken as the starting point to investigate the anti-Alzheimer's disease mechanism of the major absorbed components in Gardeniae Fructus by the network pharmacology method. The network pharmacology research model of "absorbed composition-target-pathway-disease" was adopted. In this study, the active components screening and target prediction technology were used to determine the active components and targets of Gardeniae Fructus in treatment of Alzheimer's disease. The enrichment pathway and biological process of Gardeniae Fructus were studied by using the bioinformatics annotation database(DAVID), and the results of molecular docking validation network analysis were used to elaborate the mechanism of Gardeniae Fructus in treatment of Alzheimer's disease. It was found that 35 absorbed components of Gardeniae Fructus not only regulated 48 targets such as cholines-terase(BCHE) and carbonic anhydrase 2(CA2), but also affected 11 biological processes(e.g. transcription factor activity, nuclear receptor activity, steroid hormone receptor activity, amide binding and peptide binding) and 7 metabolic pathways(MAPK signaling pathway, Alzheimer disease and estrogen signaling pathway, etc.). Molecular docking results showed that more than 60% of the active components could be well docked with key targets, and the relevant literature also showed that the active components could inhibit the MAPK1 expression of key targets, indicating a high reliability of results. These results indicated that Gardeniae Fructus may play its anti-Alzheimer's disease action via a "multi-ingredients-multi-targets and multi-pathways" mode, providing a scientific basis for further drug research and development.}, }
@article {pmid32626709, year = {2020}, author = {Zhao, T and Hu, Y and Zang, T and Wang, Y}, title = {Identifying Protein Biomarkers in Blood for Alzheimer's Disease.}, journal = {Frontiers in cell and developmental biology}, volume = {8}, number = {}, pages = {472}, pmid = {32626709}, issn = {2296-634X}, abstract = {Background: At present, the main diagnostic methods for Alzheimer's disease (AD) are positron emission tomography (PET) scanning of the brain and analysis of cerebrospinal fluid (CSF) sample, but these methods are expensive and harmful to patients. Recently, more researchers focus on diagnosing AD by detecting biomarkers in blood, which is a cheaper and harmless way. Therefore, identifying AD-related proteins in blood can help treatment and diagnosis. Methods: We proposed a hypothesis that similar diseases share similar proteins. Diseases with similar symptoms are caused by abnormalities of similar proteins. Assuming that the similarities between AD and other diseases obey the normal distribution, we developed an iterative method based on disease similarity (IBDS). We combined Elastic Network (EN) with Minimum angle regression (MAR) to find the optimal solution. Finally, we used case studies and Summary data Mendelian Random (SMR) to verify our method. Results: We selected 39 diseases which are highly related to AD. They correspond 1,481 kinds of proteins. One hundred and eighty-four proteins are reported to be related to AD in Uniprot and the number would be 284 with our method. The AUC of our method by cross-validation is 0.9251 which is much higher than previous methods. Conclusion: In this paper, we presented a novel method for prioritizing AD-related proteins. Seven proteins have tissue specificity in blood among these 284 proteins, which could be used to diagnose AD in future. Case studies and SMR have been used to prove the relationship between these 7 proteins and AD. Availability and Implementation: https://github.com/zty2009/Identifying-Protein-Biomarkers-in-Blood-for-Alzheimer-s-Disease.}, }
@article {pmid32625049, year = {2020}, author = {Jahangard, Y and Monfared, H and Moradi, A and Zare, M and Mirnajafi-Zadeh, J and Mowla, SJ}, title = {Therapeutic Effects of Transplanted Exosomes Containing miR-29b to a Rat Model of Alzheimer's Disease.}, journal = {Frontiers in neuroscience}, volume = {14}, number = {}, pages = {564}, pmid = {32625049}, issn = {1662-4548}, abstract = {Alzheimer disease (AD) is a complex neurodegenerative disorder with no definite treatment. The expression of miR-29 family is significantly reduced in AD, suggesting a part for the family members in pathogenesis of the disease. The recent emergence of microRNA (miRNA)-based therapeutic approaches is emphasized on the efficiency of miRNA transfer to target cells. The endogenously made secretory vesicles could provide a biological vehicle for drug delivery. Characteristics such as small sizes, the ability to cross the blood-brain barrier, the specificity in binding to the right target cells, and most importantly the capacity to be engineered as drug carriers have made exosomes desirable vehicles to deliver genetic materials to the central nervous system. Here, we transfected rat bone marrow mesenchymal stem cells and HEK-293T cells (human embryonic kidney 293 cells) with recombinant expression vectors, carrying either mir-29a or mir-29b precursor sequences. A significant overexpression of miR-29 and downregulation of their targets genes, BACE1 (β-site amyloid precursor protein cleaving enzyme 1) and BIM [Bcl-2 interacting mediator of cell death (BCL2-like 11)], were confirmed in the transfected cells. Then, we confirmed the packaging of miR-29 in exosomes secreted from the transfected cells. Finally, we investigated a possible therapeutic effect of the engineered exosomes to reduce the pathological effects of amyloid-β (Aβ) peptide in a rat model of AD. Aβ-treated model rats showed some deficits in spatial learning and memory. However, in animals injected with miR-29-containing exosomes at CA1 (cornu ammonis area), the aforementioned impairments were prevented. In conclusion, our findings provide a new approach for the packaging of miR-29 in exosomes and that the engineered exosomes might have a therapeutic potential in AD.}, }
@article {pmid32623395, year = {2020}, author = {Shi, Y and Zhang, L and Gao, X and Zhang, J and Ben Abou, M and Liang, G and Meng, Q and Hepner, A and Eckenhoff, MF and Wei, H}, title = {Intranasal Dantrolene as a Disease-Modifying Drug in Alzheimer 5XFAD Mice.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {76}, number = {4}, pages = {1375-1389}, pmid = {32623395}, issn = {1875-8908}, support = {R01 AG061447/AG/NIA NIH HHS/United States ; R01 GM084979/GM/NIGMS NIH HHS/United States ; }, mesh = {Administration, Intranasal ; Alzheimer Disease/*drug therapy/mortality/pathology ; Amyloid beta-Protein Precursor/metabolism ; Animals ; Brain/*drug effects/pathology ; Dantrolene/*pharmacology ; Disease Models, Animal ; Memory/*drug effects ; Memory Disorders/pathology ; Mice ; Neuroprotective Agents/pharmacology ; }, abstract = {BACKGROUND/OBJECTIVE: This study compares the effectiveness and safety of intranasal versus subcutaneous administration of dantrolene in 5XFAD Alzheimer's disease (AD) mice.
METHODS: 5XFAD and wild type (WT) B6SJLF1/J mice were treated with intranasal or subcutaneous dantrolene (5 mg/kg, 3×/wk), or vehicle. The early (ETG) and late (LTG) treatment groups began treatment at 2 or 6 months of age, respectively, and both treatment groups finished at12 months of age. Behavior was assessed for olfaction (buried food test), motor function (rotarod), and cognition (fear conditioning, Morris water maze). Liver histology (H & E staining) and function, synaptic proteins, and brain amyloid immunohistochemistry were examined. Plasma and brain dantrolene concentrations were determined in a separate cohort after intranasal or subcutaneous administration.
RESULTS: Intranasal dantrolene achieved higher brain and lower plasma concentrations than subcutaneous administration. Dantrolene administration at both approaches significantly improved hippocampal-dependent and -independent memory in the ETG, whereas only intranasal dantrolene improved cognition in the LTG. Dantrolene treatment had no significant change in the amyloid burden or synaptic proteins and no significant side effects on mortality, olfaction, motor, or liver functions in 5XFAD mice. Intranasal dantrolene treatment significantly ameliorated memory loss when it was started either before or after the onset of AD symptoms in 5XFAD mice.
CONCLUSIONS: The long-term intranasal administration of dantrolene had therapeutic effects on memory compared to the subcutaneous approach even started after onset of AD symptoms, suggesting use as a disease-modifying drug, without significant effects on amyloid plaques, side effects, or mortality.}, }
@article {pmid32622090, year = {2020}, author = {Bhandari, RK and Wang, X and Saal, FSV and Tillitt, DE}, title = {Transcriptome analysis of testis reveals the effects of developmental exposure to bisphenol a or 17α-ethinylestradiol in medaka (Oryzias latipes).}, journal = {Aquatic toxicology (Amsterdam, Netherlands)}, volume = {225}, number = {}, pages = {105553}, pmid = {32622090}, issn = {1879-1514}, support = {R21 ES027123/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Benzhydryl Compounds/*toxicity ; Endocrine Disruptors/metabolism ; Estrogens/metabolism ; Ethinyl Estradiol/metabolism/*toxicity ; Female ; Gene Expression Profiling ; Larva/drug effects ; Male ; Oryzias/*physiology ; Phenols/*toxicity ; Reproduction/drug effects ; Testis/drug effects/*physiology ; Water Pollutants, Chemical/*toxicity ; }, abstract = {Endocrine disrupting chemicals (EDCs) can induce abnormalities in organisms via alteration of molecular pathways and subsequent disruption of endocrine functions. Bisphenol A (BPA) and 17α-ethinylestradiol (EE2) are ubiquitous EDCs in the environment. Many aquatic organisms, including fish, are often exposed to varying concentrations of BPA and EE2 throughout their lifespan. Both BPA and EE2 can activate estrogenic signaling pathways and cause adverse effects on reproduction via alteration of pathways associated with steroidogenesis. However, transcriptional pathways that are affected by chronic exposure to these two ubiquitous environmental estrogens during embryonic, larval, and juvenile stages are not clearly understood. In the present study, we examined transcriptional alterations in the testis of medaka fish (Oryzias latipes) chronically exposed to a low concentration of BPA or EE2. Medaka were exposed to BPA (10 μg/L) or EE2 (0.01 μg/L) from 8 h post-fertilization (as embryos) to adulthood 50 days post fertilization (dpf), and transcriptional alterations in the testis were examined by RNA sequencing (RNA-seq). Transcriptomic profiling revealed 651 differentially expressed genes (DEGs) between BPA-exposed and control testes, while 1475 DEGs were found between EE2-exposed and control testes. Gene ontology (GO) analysis showed a significant enrichment of "intracellular receptor signaling pathway", "response to steroid hormone" and "hormone-mediated signaling pathway" in the BPA-induced DEGs, and of "cilium organization", "microtubule-based process" and "organelle assembly" in the EE2-induced DEGs. Pathway analysis showed significant enrichment of "integrin signaling pathway" in both treatment groups, and of "cadherin signaling pathway", "Alzheimer disease-presenilin pathway" in EE2-induced DEGs. Single nucleotide polymorphism (SNP) and insertion-deletion (Indel) analysis found no significant differences in mutation rates with either BPA or EE2 treatments. Taken together, global gene expression differences in testes of medaka during early stages of gametogenesis were responsive to chronic BPA and EE2 exposure.}, }
@article {pmid32619176, year = {2020}, author = {Alam, J and Jaiswal, V and Sharma, L}, title = {Screening of Antibiotics against β-amyloid as Anti-amyloidogenic Agents: A Drug Repurposing Approach.}, journal = {Current computer-aided drug design}, volume = {}, number = {}, pages = {}, doi = {10.2174/1573409916666200703171732}, pmid = {32619176}, issn = {1875-6697}, abstract = {BACKGROUND: β-amyloid (Aβ) production and aggregation is the main culprit of Alzheimer's disease (AD). AD is becoming crisis where no treatment available for halting the disease progression. Antibiotics are used not only to treat infections, but also some of the non-contagious diseases and have found active as anti-amyloidogenic agents.
OBJECTIVE: The work aim's to investigate anti-amyloidogenic activity of antibiotics as re-purposing agents via inhibiting Aβ aggregation and fibril formation employing in-silico and in-vitro approaches. Mehtods: In-silico screening was designed with receptor and ligand preparation, grid formation, docking simulation and its analysis. Thioflavin T-amyloid binding and protease-digestion studies were intended as in-vitro assays. The pharmacological potential of antibiotics as anti-amyloidogenic agents was assessed by these methods.
RESULTS: Paromomycin and Neomycin were identified with higher order of estimated free energy of binding in in-silico sreening. In in-vitro screening, paromomycin significantly (p<0.01) reduced the fluorescence intensity and resistance to tryptic degradation of Aβ(1-42) peptides while neomycin had no or little effect (p<0.01) when compared to control. Results from docking and wet lab studies were found in correlation.
CONCLUSION: Paromomycin exhibited higher anti-Aβ aggregating and defibrillogenic activity than neomycin and leaves an indication for further in-vivo testing and could be a future promising anti-amyloidal candidate for the treatment of several amyloidoses.}, }
@article {pmid32617766, year = {2020}, author = {Schwartz, L and Peres, S and Jolicoeur, M and da Veiga Moreira, J}, title = {Cancer and Alzheimer's disease: intracellular pH scales the metabolic disorders.}, journal = {Biogerontology}, volume = {21}, number = {6}, pages = {683-694}, doi = {10.1007/s10522-020-09888-6}, pmid = {32617766}, issn = {1573-6768}, abstract = {Alzheimer's disease (AD) and cancer have much in common than previously recognized. These pathologies share common risk factors (inflammation and aging), with similar epidemiological and biochemical features such as impaired mitochondria. Metabolic reprogramming occurs during aging and inflammation. We assume that inflammation is directly responsible of the Warburg effect in cancer cells, with a decreased oxidative phosphorylation and a compensatory highthroughput glycolysis (HTG). Similarly, the Warburg effect in cancer is thought to support an alkaline intracellular pH (pHi), a key component of unrelenting cell growth. In the brain, inflammation results in increased secretion of lactate by astrocytes. The increased uptake of lactic acid by neurons results in the inverse Warburg effect, such as seen in AD. The neuronal activity is dampened by a fall of pHi. Pronounced cytosol acidification results in decreased mitochondrial energy yield as well as apoptotic cell death. The link between AD and cancer is reinforced by the fact that treatment aiming at restoring the mitochondrial activity have been experimentally shown to be effective in both diseases. Low carb diet, lipoic acid, and/or methylene blue could then appear promising in both sets of these clinically diverse diseases.}, }
@article {pmid32614485, year = {2020}, author = {Lau, YCC and Ding, JA and Simental, A and Mirzoyan, H and Lee, W and Diamante, G and Cely, I and Tran, M and Morselli, M and Dang, J and Kaczor-Urbanowicz, KE and Sayre, J and Stiles, L and Yang, X and Pellegrini, M and Fiala, M}, title = {Omega-3 fatty acids increase OXPHOS energy for immune therapy of Alzheimer disease patients.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {34}, number = {8}, pages = {9982-9994}, doi = {10.1096/fj.202000669RR}, pmid = {32614485}, issn = {1530-6860}, support = {5PO1GM099134-03 to M.P./GF/NIH HHS/United States ; DK104363, NS103088/GF/NIH HHS/United States ; NS111378 to X.Y/GF/NIH HHS/United States ; }, mesh = {Adult ; Aged ; Aged, 80 and over ; Alzheimer Disease/*drug therapy/genetics/immunology ; *Dietary Supplements ; Fatty Acids, Omega-3/*administration & dosage ; Female ; Humans ; Immunity, Innate/*drug effects ; Leukocytes, Mononuclear/*drug effects/immunology/metabolism ; Macrophages/drug effects/immunology/metabolism ; Male ; Middle Aged ; Neurodegenerative Diseases/*drug therapy/genetics/immunology ; *Oxidative Phosphorylation ; Phagocytosis ; Transcriptome/drug effects ; }, abstract = {Sporadic late-onset Alzheimer disease (LOAD) preceded by mild cognitive impairment (MCI) is the most common type of dementia. Long-term studies of immunity to pathogenic amyloid-β (Aβ) in LOAD are lacking. Innate immunity of LOAD patients is malfunctioning in phagocytosis and degradation of Aβ and LOAD patients' macrophage transcriptome and metabolome are deregulated. We previously showed omega-3 fatty acid (ω-3)-mediated repair of unfolded protein response and here we show much broader transcriptomic effects. ω-3 treatment in vitro and ω-3 supplementation by the drink Smartfish (SMF) in vivo increased the transcripts of the genes and pathways of immunity, glycolysis, tricarboxylic acid cycle, OX-PHOS, nicotinamide dinucleotide (NAD+) synthesis, and reversed the defects in Aβ phagocytosis. In both peripheral blood mononuclear cells (PBMC) and macrophages, ω-3 increased ATP-linked oxygen consumption rate (OCR) and ω-3 with carnitine was superior to ω-3. ω-3 treatment in vitro and supplementation by the ω-3 drink SMF in vivo rescued macrophage phagocytosis when glycolysis or glycosylation were blocked. ω-3 provide flexible energy for immune clearance of the brain throughout the diurnal cycle, even in hypo- or hyper-glycemia. In certain LOAD patients, ω-3 may delay progression to dementia.}, }
@article {pmid32609320, year = {2020}, author = {Yu, L and Tasaki, S and Schneider, JA and Arfanakis, K and Duong, DM and Wingo, AP and Wingo, TS and Kearns, N and Thatcher, GRJ and Seyfried, NT and Levey, AI and De Jager, PL and Bennett, DA}, title = {Cortical Proteins Associated With Cognitive Resilience in Community-Dwelling Older Persons.}, journal = {JAMA psychiatry}, volume = {77}, number = {11}, pages = {1172-1180}, doi = {10.1001/jamapsychiatry.2020.1807}, pmid = {32609320}, issn = {2168-6238}, support = {R01 AG017917/AG/NIA NIH HHS/United States ; P50 AG025688/AG/NIA NIH HHS/United States ; R01 AG015819/AG/NIA NIH HHS/United States ; R01 AG056533/AG/NIA NIH HHS/United States ; I01 BX003853/BX/BLRD VA/United States ; }, abstract = {Importance: Identifying genes and proteins for cognitive resilience (ie, targets that may be associated with slowing or preventing cognitive decline regardless of the presence, number, or combination of common neuropathologic conditions) provides a complementary approach to developing novel therapeutics for the treatment and prevention of Alzheimer disease and related dementias.
Objective: To identify proteins associated with cognitive resilience via a proteome-wide association study of the human dorsolateral prefrontal cortex.
This study used data from 391 community-dwelling older persons who participated in the Religious Orders Study and the Rush Memory and Aging Project. The Religious Orders Study began enrollment January 1, 1994, and the Rush Memory and Aging Project began enrollment September 1, 1997, and data were collected and analyzed through October 23, 2019.
Exposures: Participants had undergone annual detailed clinical examinations, postmortem evaluations, and tandem mass tag proteomics analyses.
Main Outcomes and Measures: The outcome of cognitive resilience was defined as a longitudinal change in cognition over time after controlling for common age-related neuropathologic indices, including Alzheimer disease, Lewy bodies, transactive response DNA-binding protein 43, hippocampal sclerosis, infarcts, and vessel diseases. More than 8000 high abundance proteins were quantified from frozen dorsolateral prefrontal cortex tissue using tandem mass tag and liquid chromatography-mass spectrometry.
Results: There were 391 participants (273 women); their mean (SD) age was 79.7 (6.7) years at baseline and 89.2 (6.5) years at death. Eight cortical proteins were identified in association with cognitive resilience: a higher level of NRN1 (estimate, 0.140; SE, 0.024; P = 7.35 × 10-9), ACTN4 (estimate, 0.321; SE, 0.065; P = 9.94 × 10-7), EPHX4 (estimate, 0.198; SE, 0.042; P = 2.13 × 10-6), RPH3A (estimate, 0.148; SE, 0.031; P = 2.58 × 10-6), SGTB (estimate, 0.211; SE, 0.045; P = 3.28 × 10-6), CPLX1 (estimate, 0.136; SE, 0.029; P = 4.06 × 10-6), and SH3GL1 (estimate, 0.179; SE, 0.039; P = 4.21 × 10-6) and a lower level of UBA1 (estimate, -0.366; SE, 0.076; P = 1.43 × 10-6) were associated with greater resilience.
Conclusions and Relevance: These protein signals may represent novel targets for the maintenance of cognition in old age.}, }
@article {pmid32602403, year = {2021}, author = {Zhang, Z and Kang, D and Li, H}, title = {Testosterone and Cognitive Impairment or Dementia in Middle-Aged or Aging Males: Causation and Intervention, a Systematic Review and Meta-Analysis.}, journal = {Journal of geriatric psychiatry and neurology}, volume = {34}, number = {5}, pages = {405-417}, doi = {10.1177/0891988720933351}, pmid = {32602403}, issn = {0891-9887}, abstract = {BACKGROUND AND PURPOSE: To investigate the association between testosterone levels and the risk of dementia and to assess the effectiveness of testosterone supplement treatment in patients with cognitive impairment or dementia.
METHODS: We searched Pubmed, Cochrane Library, and EMBASE on September 30, 2019.
RESULTS: The risk factor portion of the review included 27 studies with 18 599 participants. Studies revealed inconsistent findings on the association between testosterone levels and the risk of all-cause dementia or Alzheimer disease (AD). The result from our meta-analysis showed an increased risk of all-cause dementia with decreasing total testosterone (total-T, 4572 participants, hazard ratio: 1.14, 95% CI: 1.04-1.26). Some studies also found an increased risk of AD with a lower level of total-T, free testosterone, and bioavailable testosterone. Testosterone supplement treatment may improve general cognitive function and motor response in the short term as measured by the Developmental Test of Visual-Motor Integration (mean difference [MD]: 4.4, 95% CI: 1.20-7.59) and the Mini-Mental State Examination (MD: 3.4, 95% CI: 0.83-5.97) and verbal memory as measured by story recall delay at 3 months (MD: 8.4, 95% CI: 0.49-16.3).
CONCLUSION: Lower levels of testosterone may be associated with an increased risk of all-cause dementia or AD. Testosterone supplement treatment may or may not improve general cognitive function in patients with cognitive impairment/AD.}, }
@article {pmid32602279, year = {2020}, author = {Park, KH and Lim, JS and Seo, SW and Jeong, Y and Noh, Y and Koh, SH and Bae, JS and Park, SA and Yang, SJ and Kim, HJ and Chin, J and Roh, JH and An, SSA and , }, title = {Executive Summary of the 2019 International Conference of Korean Dementia Association: Exploring the Novel Concept of Alzheimer's Disease and Other Dementia: a Report from the Academic Committee of the Korean Dementia Association.}, journal = {Dementia and neurocognitive disorders}, volume = {19}, number = {2}, pages = {39-53}, pmid = {32602279}, issn = {2384-0757}, abstract = {Because of repeated failures of clinical trials, the concept of Alzheimer's disease (AD) has been changing rapidly in recent years. As suggested by the National Institute on Aging and the Alzheimer's Association Research Framework, the diagnosis and classification of AD is now based on biomarkers rather than on symptoms, allowing more accurate identification of proper candidates for clinical trials by pathogenesis and disease stage. Recent development in neuroimaging has provided a way to reveal the complex dynamics of amyloid and tau in the brain in vivo, and studies of blood biomarkers are taking another leap forward in diagnosis and treatment of AD. In the field of basic and translational research, the development of animal models and a deeper understanding of the role of neuroinflammation are taking a step closer to clarifying the pathogenesis of AD. Development of big data and the Internet of Things is also incorporating dementia care and research into other aspects. Large-scale genetic research has identified genetic abnormalities that can provide a foundation for precision medicine along with the aforementioned digital technologies. Through the first international conference of the Korean Dementia Association, experts from all over the world gathered to exchange opinions with association members on these topics. The Academic Committee of the Korean Dementia Association briefly summarizes the contents of the lectures to convey the depth of the conference and discussions. This will be an important milestone in understanding the latest trends in AD's pathogenesis, diagnostic and therapeutic research and in establishing a future direction.}, }
@article {pmid32601776, year = {2021}, author = {Iloun, P and Hooshmandi, E and Gheibi, S and Kashfi, K and Ghasemi, R and Ahmadiani, A}, title = {Roles and Interaction of the MAPK Signaling Cascade in Aβ25-35-Induced Neurotoxicity Using an Isolated Primary Hippocampal Cell Culture System.}, journal = {Cellular and molecular neurobiology}, volume = {41}, number = {7}, pages = {1497-1507}, pmid = {32601776}, issn = {1573-6830}, support = {958343//National Institute for Medical Research Development/ ; }, abstract = {Alzheimer's disease (AD) is characterized with increased formation of amyloid-β (Aβ) in the brain. Aβ peptide toxicity is associated with disturbances of several intracellular signaling pathways such as mitogen activated protein kinases (MAPKs). The aim of this study was to investigate the role of MAPKs and their interactions in Aβ-induced neurotoxicity using isolated hippocampal neurons from the rat. Primary hippocampal cells were cultured in neurobasal medium for 4 days. Cells were treated with Aβ25-35 and/or MAPKs inhibitors for 24 h. Cell viability was determined by an MTT assay and phosphorylated levels of P38, JNK, and ERK were measured by Western blots. Aβ treatment (10-40 µM) significantly decreased hippocampal cell viability in a dose-dependent manner. Inhibition of P38 and ERK did not restore cell viability, while JNK inhibition potentiated the Aβ-induced neurotoxicity. Compared to the controls, Aβ treatment increased levels of phosphorylated JNK, ERK, and c-Jun, while it had no effect on levels of phosphorylated P38. In addition, P38 inhibition led to decreased expression levels of phosphorylated ERK; inhibition of JNK resulted in decreased expression of c-Jun; and inhibition of ERK, decreased phosphorylated levels of JNK. These results strongly suggest that P38, ERK, and JNK are not independently involved in Aβ-induced toxicity in the hippocampal cells. In AD, which is a multifactorial disease, inhibiting a single member of the MAPK signaling pathway, does not seem to be sufficient to mitigate Aβ-induced toxicity and thus their interactions with each other or potentially with different signaling pathways should be taken into account.}, }
@article {pmid32597927, year = {2020}, author = {Grammatikopoulou, MG and Goulis, DG and Gkiouras, K and Theodoridis, X and Gkouskou, KK and Evangeliou, A and Dardiotis, E and Bogdanos, DP}, title = {To Keto or Not to Keto? A Systematic Review of Randomized Controlled Trials Assessing the Effects of Ketogenic Therapy on Alzheimer Disease.}, journal = {Advances in nutrition (Bethesda, Md.)}, volume = {11}, number = {6}, pages = {1583-1602}, pmid = {32597927}, issn = {2156-5376}, mesh = {*Alzheimer Disease ; Brain ; Cognition ; *Cognitive Dysfunction ; Humans ; Randomized Controlled Trials as Topic ; }, abstract = {Alzheimer disease (AD) is a global health concern with the majority of pharmacotherapy choices consisting of symptomatic treatment. Recently, ketogenic therapies have been tested in randomized controlled trials (RCTs), focusing on delaying disease progression and ameliorating cognitive function. The present systematic review aimed to aggregate the results of trials examining the effects of ketogenic therapy on patients with AD/mild cognitive impairment (MCI). A systematic search was conducted on PubMed, CENTRAL, clinicaltrials.gov, and gray literature for RCTs performed on adults, published in English until 1 April, 2019, assessing the effects of ketogenic therapy on MCI and/or AD compared against placebo, usual diet, or meals lacking ketogenic agents. Two researchers independently extracted data and assessed risk of bias with the Cochrane tool. A total of 10 RCTs were identified, fulfilling the inclusion criteria. Interventions were heterogeneous, acute or long term (45-180 d), including adherence to a ketogenic diet, intake of ready-to-consume drinks, medium-chain triglyceride (MCT) powder for drinks preparation, yoghurt enriched with MCTs, MCT capsules, and ketogenic formulas/meals. The use of ketoneurotherapeutics proved effective in improving general cognition using the Alzheimer's Disease Assessment Scale-Cognitive, in interventions of either duration. In addition, long-term ketogenic therapy improved episodic and secondary memory. Psychological health, executive ability, and attention were not improved. Increases in blood ketone concentrations were unanimous and correlated to the neurocognitive battery based on various tests. Cerebral ketone uptake and utilization were improved, as indicated by the global brain cerebral metabolic rate for ketones and [11C] acetoacetate. Ketone concentrations and cognitive performance differed between APOE ε4(+) and APOE ε4(-) participants, indicating a delayed response among the former and an improved response among the latter. Although research on the subject is still in the early stages and highly heterogeneous in terms of study design, interventions, and outcome measures, ketogenic therapy appears promising in improving both acute and long-term cognition among patients with AD/MCI. This systematic review was registered at www.crd.york.ac.uk/prospero as CRD42019128311.}, }
@article {pmid32597012, year = {2020}, author = {Ugrumov, M}, title = {Development of early diagnosis of Parkinson's disease: Illusion or reality?.}, journal = {CNS neuroscience & therapeutics}, volume = {}, number = {}, pages = {}, pmid = {32597012}, issn = {1755-5949}, support = {18-00-01334//Russian Foundation for Basic Research/ ; 18-00-01338//Russian Foundation for Basic Research/ ; }, abstract = {The fight against neurodegenerative diseases, Alzheimer disease and Parkinson's disease (PD), is a challenge of the 21st century. The low efficacy of treating patients is due to the late diagnosis and start of therapy, after the degeneration of most specific neurons and depletion of neuroplasticity. It is believed that the development of early diagnosis (ED) and preventive treatment will delay the onset of specific symptoms. This review evaluates methodologies for developing ED of PD. Since PD is a systemic disease, and the degeneration of certain neurons precedes that of nigrostriatal dopaminergic neurons that control motor function, the current methodology is based on searching biomarkers, such as premotor symptoms and changes in body fluids (BF) in patients. However, all attempts to develop ED were unsuccessful. Therefore, it is proposed to enhance the current methodology by (i) selecting among biomarkers found in BF in patients at the clinical stage those that are characteristics of animal models of the preclinical stage, (ii) searching biomarkers in BF in subjects at the prodromal stage, selected by detecting premotor symptoms and failure of the nigrostriatal dopaminergic system. Moreover, a new methodology was proposed for the development of ED of PD using a provocative test, which is successfully used in internal medicine.}, }
@article {pmid32594062, year = {2020}, author = {Volicer, L}, title = {Physiological and pathological functions of beta-amyloid in the brain and alzheimer's disease: A review.}, journal = {The Chinese journal of physiology}, volume = {63}, number = {3}, pages = {95-100}, doi = {10.4103/CJP.CJP_10_20}, pmid = {32594062}, issn = {0304-4920}, mesh = {Aging ; *Alzheimer Disease ; Amyloid beta-Peptides ; Brain ; Humans ; }, abstract = {Alzheimer's disease is a major health problem all over the world. The role of beta-amyloid (Aβ) is at the center of investigations trying to discover the disease pathogenesis and to develop drugs for treatment or prevention on Alzheimer's disease. This review summarizes both physiological and pathological functions of Aβ and factors that may participate in the disease development. Known genetic factors are trisomy of chromosome 21, mutations of presenilin 1 and 2, and apolipoprotein E4. Lifetime stresses that increase the risk of development of Alzheimer's disease are described. Another important factor is the level of education, especially of linguistic ability. Lifestyle factors include mental and physical exercise, head injury, social contacts, and diet. All these factors might potentiate the effect of aging on the brain to increase the risk of development of pathological changes. The review summarizes pathological features of Alzheimer brain, Aβ plaques, neurofibrillary tangles composed of hyperphosphorylated tau, and brain atrophy. Consequences of Alzheimer's disease that are reviewed include cognitive deficit, loss of function, and neuropsychiatric symptoms. Because there is no effective treatment, many persons with Alzheimer's disease survive to severe and terminal stages which they may fear. Alzheimer's disease at this stage should be considered a terminal disease for which palliative care is indicated. Importance of advance directives, promoting previous wishes of the person who was developing dementia and who subsequently lost decision-making capacity, and limitations of these directives are discussed. Information in this review is based on author's knowledge and clinical experience that were updated by searches of PubMed.}, }
@article {pmid32593241, year = {2020}, author = {Berezutsky, MA and Durnova, NA and Andronova, TA and Sinichkina, OV}, title = {[Alzheimer's disease: experimental and clinical researches of Chinese herbal medicine neurobiological effects (a review).].}, journal = {Advances in gerontology = Uspekhi gerontologii}, volume = {33}, number = {2}, pages = {273-281}, pmid = {32593241}, issn = {1561-9125}, mesh = {Alzheimer Disease/*drug therapy/metabolism ; Amyloid beta-Peptides/metabolism ; Animals ; Disease Models, Animal ; Drugs, Chinese Herbal/*pharmacology/*therapeutic use ; Glycogen Synthase Kinase 3 beta/metabolism ; Hippocampus/*drug effects ; Humans ; tau Proteins/metabolism ; }, abstract = {The analysis of experiments and clinical data about research of neurobiological effects of chinese herbal medicine, which is used by Alzheimer`s disease treatment, was presented in given overview. The rats with injection of Aβ1-42 or Aβ25-35 peptides, or ibotenic acid, or streptozotocin as well as the natural line of mice SAMP8 with the phenotype of accelerated aging and other were used as the experimental models of Alzheimer`s disease. Various neurobiological effects of various herbal decoctions in the cells of hippocampus were demonstrated - the inhibition of amyloid β peptides aggregation, increasing of neurons quantity with normal morphology and decreasing of apoptotic cells, decreasing of inducible nitric oxide synthase (iNOS) production, decreasing of reactive expression level of RAGE and increasing reactive expression level of LRP-1, decreasing of tau protein phosphorylation at Thr231 and Ser422, inhibition of expression of GSK-3β and CDK-5, decreasing of activation and inflammation of microglia, production of 15 types of N-glycans in the cerebral cortex layers, which are absent in experimental animals. The improvement of memorization and training abilities was established.}, }
@article {pmid32589559, year = {2020}, author = {Vo, VG and Pyun, JM and Bagyinszky, E and An, SSA and Kim, SY}, title = {Identification of a Pathogenic PSEN1 Ala285Val Mutation Associated with Early-Onset Alzheimer's Disease.}, journal = {Current Alzheimer research}, volume = {17}, number = {5}, pages = {438-445}, doi = {10.2174/1567205017666200626210727}, pmid = {32589559}, issn = {1875-5828}, mesh = {Alanine/*genetics ; Alzheimer Disease/diagnostic imaging/*genetics ; Amino Acid Sequence ; Female ; Humans ; Middle Aged ; Mutation/*genetics ; Pedigree ; Presenilin-1/chemistry/*genetics ; Protein Structure, Secondary ; Valine/*genetics ; }, abstract = {BACKGROUND: Presenilin 1 (PSEN1) was suggested as the most common causative gene of early onset Alzheimer's Disease (AD).
METHODS: Patient who presented progressive memory decline in her 40s was enrolled in this study. A broad battery of neuropsychological tests and neuroimaging was applied to make the diagnosis. Genetic tests were performed in the patient to evaluate possible mutations using whole exome sequencing. The pathogenic nature of missense mutation and its 3D protein structure prediction were performed by in silico prediction programs.
RESULTS: A pathogenic mutation in PSEN1 (NM_000021.3: c.1027T>C p.Ala285Val), which was found in a Korean EOAD patient. Magnetic resonance imaging scan showed mild left temporal lobe atrophy. Hypometabolism appeared through 18F-fludeoxyglucose Positron Emission Tomography (FDG-PET) scanning in bilateral temporal and parietal lobe, and 18F-Florbetaben-PET (FBB-PET) showed increased amyloid deposition in bilateral frontal, parietal, temporal lobe and hence presumed preclinical AD. Protein modeling showed that the p.Ala285Val is located in the random coil region and could result in extra stress in this region, resulting in the replacement of an alanine residue with a valine. This prediction was confirmed previous in vitro studies that the p.Trp165Cys resulted in an elevated Aβ42/Aβ40 ratio in both COS-1 and HEK293 cell lines compared that of wild-type control.
CONCLUSION: Together, the clinical characteristics and the effect of the mutation would facilitate our understanding of PSEN1 in AD pathogenesis for the disease diagnosis and treatment. Future in vivo study is needed to evaluate the role of PSEN1 p.Ala285Val mutation in AD progression.}, }
@article {pmid32584672, year = {2020}, author = {Hung, A and Schneider, M and Lopez, MH and McClellan, M}, title = {Preclinical Alzheimer Disease Drug Development: Early Considerations Based on Phase 3 Clinical Trials.}, journal = {Journal of managed care & specialty pharmacy}, volume = {26}, number = {7}, pages = {888-900}, doi = {10.18553/jmcp.2020.26.7.888}, pmid = {32584672}, issn = {2376-1032}, mesh = {Alzheimer Disease/*drug therapy/economics/epidemiology ; Clinical Trials, Phase III as Topic/economics/*methods ; *Drug Costs ; Drug Development/economics/*methods ; Drug Evaluation, Preclinical/economics/methods ; Endpoint Determination/economics/methods ; Humans ; }, abstract = {The number of people in the United States living with Alzheimer disease (AD) is growing, resulting in significant clinical and economic impact. Substantial research investment has led to drug development in stages of AD before symptomatic dementia, such as preclinical AD. Although there are no treatments approved for preclinical AD, there are currently 6 phase 3 clinical trials for preclinical AD treatments. In this article, we review these clinical trials and highlight considerations for future coverage decisions. In line with the definition of preclinical AD, enrollment in these trials focuses on cognitively unimpaired patients that are at high risk of AD because of family history and then genetic testing or brain imaging. Enrollment in most of these trials also allows for younger patients, including those aged under 65 years. Primary clinical trial endpoints focus on cognition often 4 or more years after treatment. Secondary endpoints include other measures of cognition and function, as well as biomarkers. Review of these trials brings to light a few potential considerations when covering these new medications in the future. First, novel and potentially costly approaches involving genetic testing and/or positron emission tomography imaging may be needed to identify appropriate patients and should be developed efficiently. Second, the long duration of these clinical trials suggest that there may be a need for alternative payment approaches in the United States that encourage early payers to pay for a medication for which the long-term benefits may not be realized until after the beneficiary is no longer with the health plan. Third, the value of AD treatments may differ across populations, creating a potential role for indication-based or population-based contracting. Finally, considering the potentially high budgetary impact and little real-world evidence for a new drug class, payers and manufacturers may want to consider outcomes-based payment approaches and coverage with evidence development to mitigate uncertainty about the value of the treatment demonstrated in well-defined populations in clinical trials versus more heterogeneous real-world settings. DISCLOSURES: This work was funded through a generous gift from the Global CEO Initiative on Alzheimer Disease. Hung reports grants from Agency for Healthcare Research and Quality and Pharmaceutical Research and Manufacturers of America outside the submitted work and past employment at CVS Health and BlueCross BlueShield Association. McClellan is an independent board member on the boards of Johnson & Johnson, Cigna, Alignment Healthcare, and Seer; co-chairs the Accountable Care Learning Collaborative and the Guiding Committee for the Health Care Payment Learning and Action Network; and receives fees for serving as an advisor for Cota and MITRE. Hamilton Lopez and Schneider have nothing to disclose. Part of this work was presented at the 2019 AMCP Nexus Meeting, October 29-November 1, 2019, in National Harbor, MD.}, }
@article {pmid32575531, year = {2020}, author = {Sut, S and Maggi, F and Bruno, S and Badalamenti, N and Quassinti, L and Bramucci, M and Beghelli, D and Lupidi, G and Dall'Acqua, S}, title = {Hairy Garlic (Allium subhirsutum) from Sicily (Italy): LC-DAD-MSn Analysis of Secondary Metabolites and In Vitro Biological Properties.}, journal = {Molecules (Basel, Switzerland)}, volume = {25}, number = {12}, pages = {}, pmid = {32575531}, issn = {1420-3049}, mesh = {*Adenocarcinoma/drug therapy/metabolism/pathology ; Allium/*chemistry ; Chromatography, High Pressure Liquid ; *Colonic Neoplasms/drug therapy/metabolism/pathology ; Cytotoxins/chemistry/*pharmacology ; Flavonoids/chemistry/*pharmacology ; HCT116 Cells ; Humans ; Mass Spectrometry ; Plant Extracts/chemistry/*pharmacology ; Sicily ; Sulfur Compounds/chemistry/*pharmacology ; }, abstract = {Allium subhirsutum, known as hairy garlic, is a bulbous plant widespread in the Mediterranean area and locally used as a food and spice. In the present study, the chemical profile of the ethanolic extracts from bulbs (BE) and aerial parts (APE) were analyzed by HPLC-ESI-MSn, and antioxidant properties were evaluated by DPPH, ABTS and TEAC assays. The traditional use in the diet, and the well documented biological activity of Allium species suggest a potential as a new nutraceutical. For this reason, the potential usefulness of this food can be considered in the treatment and prevention of degenerative Alzheimer disease. For this reason, acetylcholinesterase inhibitory property was investigated. Furthermore, due to the observed presence of sulfur-containing and phenolic constituents, the cytotoxicity on tumor cells line was investigated. Results revealed significant AChE inhibitory activity for BE and APE. Both extracts exhibited also moderate antioxidant properties in the in vitro assays. Finally, limited cytotoxic activity was observed towards Human colon carcinoma and adenocarcinoma cell line, with differences between the individual parts tested. HPLC-ESI-MSn analysis showed that hairy garlic is a good source of sulphur compounds, flavonoids and phenylpropanoids derivatives, thus being a valid alternative to the common garlic (A. sativum). This work opens new opportunities for the application of A. subhirsutum as a health-promoting food.}, }
@article {pmid32575439, year = {2020}, author = {Stracke, S and Lange, S and Bornmann, S and Kock, H and Schulze, L and Klinger-König, J and Böhm, S and Vogelgesang, A and von Podewils, F and Föel, A and Gross, S and Wenzel, K and Wallukat, G and Prüss, H and Dressel, A and Kunze, R and Grabe, HJ and Langner, S and Dörr, M}, title = {Immunoadsorption for Treatment of Patients with Suspected Alzheimer Dementia and Agonistic Autoantibodies against Alpha1a-Adrenoceptor-Rationale and Design of the IMAD Pilot Study.}, journal = {Journal of clinical medicine}, volume = {9}, number = {6}, pages = {}, pmid = {32575439}, issn = {2077-0383}, support = {201503IMAD//Fresenius Medical Care/ ; }, abstract = {BACKGROUND: agonistic autoantibodies (agAABs) against G protein-coupled receptors (GPCR) have been linked to cardiovascular disease. In dementia patients, GPCR-agAABs against the α1- and ß2-adrenoceptors (α1AR- and ß2AR) were found at a prevalence of 50%. Elimination of agAABs by immunoadsorption (IA) was successfully applied in cardiovascular disease. The IMAD trial (Efficacy of immunoadsorption for treatment of persons with Alzheimer dementia and agonistic autoantibodies against alpha1A-adrenoceptor) investigates whether the removal of α1AR-AABs by a 5-day IA procedure has a positive effect (improvement or non-deterioration) on changes of hemodynamic, cognitive, vascular and metabolic parameters in patients with suspected Alzheimer's clinical syndrome within a one-year follow-up period.
METHODS: the IMAD trial is designed as an exploratory monocentric interventional trial corresponding to a proof-of-concept phase-IIa study. If cognition capacity of eligible patients scores 19-26 in the Mini Mental State Examination (MMSE), patients are tested for the presence of agAABs by an enzyme-linked immunosorbent assay (ELISA)-based method, followed by a bioassay-based confirmation test, further screening and treatment with IA and intravenous immunoglobulin G (IgG) replacement. We aim to include 15 patients with IA/IgG and to complete follow-up data from at least 12 patients. The primary outcome parameter of the study is uncorrected mean cerebral perfusion measured in mL/min/100 gr of brain tissue determined by magnetic resonance imaging with arterial spin labeling after 12 months.
CONCLUSION: IMAD is an important pilot study that will analyze whether the removal of α1AR-agAABs by immunoadsorption in α1AR-agAAB-positive patients with suspected Alzheimer's clinical syndrome may slow the progression of dementia and/or may improve vascular functional parameters.}, }
@article {pmid32574818, year = {2020}, author = {Sivera, R and Capet, N and Manera, V and Fabre, R and Lorenzi, M and Delingette, H and Pennec, X and Ayache, N and Robert, P and , }, title = {Voxel-based assessments of treatment effects on longitudinal brain changes in the Multidomain Alzheimer Preventive Trial cohort.}, journal = {Neurobiology of aging}, volume = {94}, number = {}, pages = {50-59}, doi = {10.1016/j.neurobiolaging.2019.11.020}, pmid = {32574818}, issn = {1558-1497}, mesh = {Affect ; Aged ; Alzheimer Disease/*pathology/*prevention & control/psychology ; Behavior ; Brain/*pathology ; Cognition ; Cognitive Dysfunction/prevention & control ; Cohort Studies ; *Dietary Supplements ; Fatty Acids, Omega-3/*administration & dosage ; Female ; Humans ; Male ; Memory ; Organ Size ; Psychosocial Intervention/*methods ; Treatment Outcome ; }, abstract = {The Multidomain Alzheimer Preventive Trial was designed to assess the effect of omega-3 supplementation and multidomain intervention on cognitive decline of subjects with subjective memory complaint. In terms of cognitive testing, no significant effect was found. In this paper, we evaluate the effect of the interventions on the brain morphological changes. Subjects with magnetic resonance imaging acquisitions at baseline and at 36 months were included (N = 376). Morphological changes were characterized by volume measurements and nonlinear deformation. The multidomain intervention was associated with a significant effect on the 3-year brain morphological changes in the deformation-based approach. Differences were mainly located in the left periventricular area next to the temporoparietal junction. These changes were associated with better cognitive performance and mood/behavior stabilization. No effect of the omega-3 supplementation was observed. This result suggests a possible effect on cognition, not yet observable after 3 years. We argue that neuroimaging could help define whether early intervention strategies are effective to delay cognitive decline and dementia.}, }
@article {pmid32568367, year = {2020}, author = {Craft, S and Raman, R and Chow, TW and Rafii, MS and Sun, CK and Rissman, RA and Donohue, MC and Brewer, JB and Jenkins, C and Harless, K and Gessert, D and Aisen, PS}, title = {Safety, Efficacy, and Feasibility of Intranasal Insulin for the Treatment of Mild Cognitive Impairment and Alzheimer Disease Dementia: A Randomized Clinical Trial.}, journal = {JAMA neurology}, volume = {77}, number = {9}, pages = {1099-1109}, pmid = {32568367}, issn = {2168-6157}, support = {RF1 AG041845/AG/NIA NIH HHS/United States ; }, mesh = {Administration, Intranasal ; Aged ; Aged, 80 and over ; Alzheimer Disease/diagnostic imaging/*drug therapy/metabolism/physiopathology ; Cognitive Dysfunction/diagnostic imaging/*drug therapy/metabolism/physiopathology ; Double-Blind Method ; Feasibility Studies ; Female ; Humans ; Hypoglycemic Agents/administration & dosage/adverse effects/*pharmacology ; Insulin/administration & dosage/adverse effects/*pharmacology ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Neuropsychological Tests ; *Outcome Assessment, Health Care ; }, abstract = {Importance: Insulin modulates aspects of brain function relevant to Alzheimer disease and can be delivered to the brain using intranasal devices. To date, the use of intranasal insulin to treat persons with mild cognitive impairment and Alzheimer's disease dementia remains to be examined in a multi-site trial.
Objective: To examine the feasibility, safety, and efficacy of intranasal insulin for the treatment of persons with mild cognitive impairment and Alzheimer disease dementia in a phase 2/3 multisite clinical trial.
A randomized (1:1) double-blind clinical trial was conducted between 2014 and 2018. Participants received 40 IU of insulin or placebo for 12 months during the blinded phase, which was followed by a 6-month open-label extension phase. The clinical trial was conducted at 27 sites of the Alzheimer's Therapeutic Research Institute. A total of 432 adults were screened, and 144 adults were excluded. Inclusion criteria included adults aged 55 to 85 years with a diagnosis of amnestic mild cognitive impairment or Alzheimer disease (based on National Institute on Aging-Alzheimer Association criteria), a score of 20 or higher on the Mini-Mental State Examination, a clinical dementia rating of 0.5 or 1.0, and a delayed logical memory score within a specified range. A total of 289 participants were randomized. Among the first 49 participants, the first device (device 1) used to administer intranasal insulin treatment had inconsistent reliability. A new device (device 2) was used for the remaining 240 participants, who were designated the primary intention-to-treat population. Data were analyzed from August 2018 to March 2019.
Interventions: Participants received 40 IU of insulin (Humulin-RU-100; Lilly) or placebo (diluent) daily for 12 months (blinded phase) followed by a 6-month open-label extension phase. Insulin was administered with 2 intranasal delivery devices.
Main Outcomes and Measures: The primary outcome (mean score change on the Alzheimer Disease Assessment Scale-cognitive subscale 12) was evaluated at 3-month intervals. Secondary clinical outcomes were assessed at 6-month intervals. Cerebrospinal fluid collection and magnetic resonance imaging scans occurred at baseline and 12 months.
Results: A total of 289 participants (155 men [54.6%]; mean [SD] age, 70.9 [7.1] years) were randomized. Of those, 260 participants completed the blinded phase, and 240 participants completed the open-label extension phase. For the first 49 participants, the first device used to administer treatment had inconsistent reliability. A second device was used for the remaining 240 participants (123 men [51.3%]; mean [SD] age, 70.8 [7.1] years), who were designated the primary intention-to-treat population. No differences were observed between treatment arms for the primary outcome (mean score change on ADAS-cog-12 from baseline to month 12) in the device 2 ITT cohort (0.0258 points; 95% CI, -1.771 to 1.822 points; P = .98) or for the other clinical or cerebrospinal fluid outcomes in the primary (second device) intention-to-treat analysis. No clinically important adverse events were associated with treatment.
Conclusions and Relevance: In this study, no cognitive or functional benefits were observed with intranasal insulin treatment over a 12-month period among the primary intention-to-treat cohort.
Trial Registration: ClinicalTrials.gov Identifier: NCT01767909.}, }
@article {pmid32568366, year = {2020}, author = {Raghavan, NS and Dumitrescu, L and Mormino, E and Mahoney, ER and Lee, AJ and Gao, Y and Bilgel, M and Goldstein, D and Harrison, T and Engelman, CD and Saykin, AJ and Whelan, CD and Liu, JZ and Jagust, W and Albert, M and Johnson, SC and Yang, HS and Johnson, K and Aisen, P and Resnick, SM and Sperling, R and De Jager, PL and Schneider, J and Bennett, DA and Schrag, M and Vardarajan, B and Hohman, TJ and Mayeux, R and , }, title = {Association Between Common Variants in RBFOX1, an RNA-Binding Protein, and Brain Amyloidosis in Early and Preclinical Alzheimer Disease.}, journal = {JAMA neurology}, volume = {77}, number = {10}, pages = {1288-1298}, doi = {10.1001/jamaneurol.2020.1760}, pmid = {32568366}, issn = {2168-6157}, support = {R21 AG059941/AG/NIA NIH HHS/United States ; P30 AG066507/AG/NIA NIH HHS/United States ; R01 NS100980/NS/NINDS NIH HHS/United States ; R01 AG063689/AG/NIA NIH HHS/United States ; P30 AG010133/AG/NIA NIH HHS/United States ; U19 AG010483/AG/NIA NIH HHS/United States ; RF1 AG059869/AG/NIA NIH HHS/United States ; K23 AG062750/AG/NIA NIH HHS/United States ; K24 AG046373/AG/NIA NIH HHS/United States ; P30 AG062715/AG/NIA NIH HHS/United States ; K01 AG051718/AG/NIA NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; P50 AG008702/AG/NIA NIH HHS/United States ; R01 AG017917/AG/NIA NIH HHS/United States ; U01 AG061356/AG/NIA NIH HHS/United States ; U01 AG024904/AG/NIA NIH HHS/United States ; U19 AG033655/AG/NIA NIH HHS/United States ; RF1 AG054023/AG/NIA NIH HHS/United States ; R01 AG054047/AG/NIA NIH HHS/United States ; P30 AG066462/AG/NIA NIH HHS/United States ; R01 AG056534/AG/NIA NIH HHS/United States ; RF1 AG027161/AG/NIA NIH HHS/United States ; R01 AG019771/AG/NIA NIH HHS/United States ; R01 AG034962/AG/NIA NIH HHS/United States ; R01 AG015819/AG/NIA NIH HHS/United States ; R01 AG034570/AG/NIA NIH HHS/United States ; K01 AG049164/AG/NIA NIH HHS/United States ; R01 AG036836/AG/NIA NIH HHS/United States ; }, mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/diagnostic imaging/*genetics ; Amyloidosis/diagnostic imaging/*genetics ; *Brain/diagnostic imaging ; Cohort Studies ; Early Diagnosis ; Female ; Genetic Association Studies/*methods ; Genetic Variation/*genetics ; Humans ; Male ; Middle Aged ; Prodromal Symptoms ; RNA Splicing Factors/*genetics ; }, abstract = {Importance: Genetic studies of Alzheimer disease have focused on the clinical or pathologic diagnosis as the primary outcome, but little is known about the genetic basis of the preclinical phase of the disease.
Objective: To examine the underlying genetic basis for brain amyloidosis in the preclinical phase of Alzheimer disease.
In the first stage of this genetic association study, a meta-analysis was conducted using genetic and imaging data acquired from 6 multicenter cohort studies of healthy older individuals between 1994 and 2019: the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease Study, the Berkeley Aging Cohort Study, the Wisconsin Registry for Alzheimer's Prevention, the Biomarkers of Cognitive Decline Among Normal Individuals cohort, the Baltimore Longitudinal Study of Aging, and the Alzheimer Disease Neuroimaging Initiative, which included Alzheimer disease and mild cognitive impairment. The second stage was designed to validate genetic observations using pathologic and clinical data from the Religious Orders Study and Rush Memory and Aging Project. Participants older than 50 years with amyloid positron emission tomographic (PET) imaging data and DNA from the 6 cohorts were included. The largest cohort, the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease Study (n = 3154), was the PET screening cohort used for a secondary prevention trial designed to slow cognitive decline associated with brain amyloidosis. Six smaller, longitudinal cohort studies (n = 1160) provided additional amyloid PET imaging data with existing genetic data. The present study was conducted from March 29, 2019, to February 19, 2020.
Main Outcomes and Measures: A genome-wide association study of PET imaging amyloid levels.
Results: From the 4314 analyzed participants (age, 52-96 years; 2478 participants [57%] were women), a novel locus for amyloidosis was noted within RBFOX1 (β = 0.61, P = 3 × 10-9) in addition to APOE. The RBFOX1 protein localized around plaques, and reduced expression of RBFOX1 was correlated with higher amyloid-β burden (β = -0.008, P = .002) and worse cognition (β = 0.007, P = .006) during life in the Religious Orders Study and Rush Memory and Aging Project cohort.
Conclusions and Relevance: RBFOX1 encodes a neuronal RNA-binding protein known to be expressed in neuronal tissues and may play a role in neuronal development. The findings of this study suggest that RBFOX1 is a novel locus that may be involved in the pathogenesis of Alzheimer disease.}, }
@article {pmid32567070, year = {2020}, author = {Fantini, J and Chahinian, H and Yahi, N}, title = {Progress toward Alzheimer's disease treatment: Leveraging the Achilles' heel of Aβ oligomers?.}, journal = {Protein science : a publication of the Protein Society}, volume = {29}, number = {8}, pages = {1748-1759}, pmid = {32567070}, issn = {1469-896X}, mesh = {*Alzheimer Disease/drug therapy/metabolism/pathology ; Amyloid beta-Peptides/antagonists & inhibitors/metabolism ; Animals ; Antibodies, Monoclonal/*therapeutic use ; *Brain/metabolism/pathology ; Calcium/metabolism ; Calcium Signaling/drug effects ; Humans ; *Neurons/metabolism/pathology ; }, abstract = {After three decades of false hopes and failures, a pipeline of therapeutic drugs that target the actual root cause of Alzheimer's disease (AD) is now available. Challenging the old paradigm that focused on β-amyloid peptide (Aβ) aggregation in amyloid plaques, these compounds are designed to prevent the neurotoxicity of Aβ oligomers that form Ca2+ permeable pores in the membranes of brain cells. By triggering an intracellular Ca2+ overdose, Aβ oligomers induce a cascade of neurotoxic events including oxidative stress, tau hyperphosphorylation, and neuronal loss. Targeting any post-Ca2+ entry steps (e.g., tau) will not address the root cause of the disease. Thus, preventing Aβ oligomers formation and/or blocking their toxicity is by essence the best approach to stop any progression of AD. Three categories of anti-oligomer compounds are already available: antibodies, synthetic peptides, and small drugs. Independent in silico-based designs of a peptide (AmyP53) and a monoclonal antibody (PMN310) converged to identify a histidine motif (H13/H14) that is critical for oligomer neutralization. This "histidine trick" can be viewed as the Achilles' heel of Aβ in the fight against AD. Moreover, lipid rafts and especially gangliosides play a critical role in the formation and toxicity of Aβ oligomers. Recognizing AD as a membrane disorder and gangliosides as the key anti-oligomer targets will provide innovative opportunities to find an efficient cure. A "full efficient" solution would also need to be affordable to anyone, as the number of patients has been following an exponential increase, affecting every part of the globe.}, }
@article {pmid32561284, year = {2020}, author = {Dutta Gupta, S and Pan, CH}, title = {Recent update on discovery and development of Hsp90 inhibitors as senolytic agents.}, journal = {International journal of biological macromolecules}, volume = {161}, number = {}, pages = {1086-1098}, doi = {10.1016/j.ijbiomac.2020.06.115}, pmid = {32561284}, issn = {1879-0003}, mesh = {Animals ; Antineoplastic Agents/chemistry/pharmacology/therapeutic use ; Apoptosis/drug effects/genetics ; Cellular Senescence/drug effects/genetics ; Clinical Studies as Topic ; Drug Design ; *Drug Development/methods ; *Drug Discovery/methods ; Drug Evaluation, Preclinical ; HSP90 Heat-Shock Proteins/*antagonists & inhibitors/chemistry/metabolism ; Humans ; Molecular Targeted Therapy ; Protein Isoforms ; Signal Transduction/drug effects ; Structure-Activity Relationship ; }, abstract = {Hsp90 chaperone is an encouraging target for the development of novel anticancer agents. The failure of Hsp90 inhibitors to get regulatory approval for the treatment of cancer is hindered due to toxicity, cost involved in their development and formulation issues. The inhibitors against this chaperone are also being evaluated in pre-clinical models for the treatment of diseases other than cancer (Alzheimer, malaria, AIDS, etc.). Recently, Hsp90 inhibitors have shown promising senolytic effect that is helpful in increasing the health and life span of mice. The senolytic property of Hsp90 inhibitors will make them less toxic for use in humans. The review focuses on Hsp90 inhibitors discovered till date as senolytic agents along with their future prospects. Further, the various models used for the evaluation of senolytic effect are also discussed.}, }
@article {pmid32551234, year = {2020}, author = {Abou Baker, DH and Ibrahim, BMM and Hassan, NS and Yousuf, AF and Gengaihi, SE}, title = {Exploiting Citrus aurantium seeds and their secondary metabolites in the management of Alzheimer disease.}, journal = {Toxicology reports}, volume = {7}, number = {}, pages = {723-729}, pmid = {32551234}, issn = {2214-7500}, abstract = {Fruit by-products are considered nature's golden gift for human health and a good starting point to discover new drugs depending on the fact that they contain millions of bio-active compounds that are responsible for therapeutic activities. In this context, the main goal of this study is to recycle Citrus aurantium (C. aurantium) seeds to produce pharmaceutical molecules to be used in the prevention of the progressive neurological damage associated with Alzheimer disease (AD). Donepezil (0.75 mg/kg), hesperidin (125 and 250 mg/kg) and limonoids (50 and 100 mg/kg) were used for treatment of rats for 2 weeks prior to concomitant administration of AlCl3 for three successive weeks. Protection against cognitive deterioration was observed among study group with insignificant difference from normal control group and significant difference from positive control group in the Y-Maze test. On the other hand, treatment with both doses of hesperidin (125 and 250 mg/kg) and high dose of limonoids only (100 mg/kg) produced improvement in psychological state, observed by significant increase in ambulation frequency in comparison to positive control group, however it was not as frequent as normal group, as it was significantly less than normal group in the open field test. Regarding acetylcholine esterase (AChE) and beta-amyloid (β amyloid) levels, the effect of limonoids low dose was the best as it didn't have a significant effect when compared to normal control, also hesperidin in both doses showed insignificant effects on β amyloid levels when compared to normal control group. Our results encourage the use of C. aurantium seeds which are wasted in huge amounts, as Alzheimer prophylactic food additives.}, }
@article {pmid32547478, year = {2020}, author = {Loeffler, DA}, title = {AMBAR, an Encouraging Alzheimer's Trial That Raises Questions.}, journal = {Frontiers in neurology}, volume = {11}, number = {}, pages = {459}, pmid = {32547478}, issn = {1664-2295}, abstract = {Grifols' recent Alzheimer Management by Albumin Replacement ("AMBAR") study investigated the effects of plasmapheresis with albumin replacement, plus intravenous immunoglobulin (IVIG) in some subjects, in patients with mild-to-moderate Alzheimer's disease (AD). AMBAR was a phase IIb trial in the United States and a phase III trial in Europe. There were three treatment groups (plasmapheresis with albumin replacement; plasmapheresis with low dose albumin and IVIG; plasmapheresis with high dose albumin and IVIG) and sham-treated controls. Disease progression in pooled treated patients was 66% less than control subjects based on ADAS-Cog scores (p = 0.06) and 52% less based on ADCS-ADL scores (p = 0.03). Moderate AD patients had 61% less progression, based on both ADAS-Cog and ADCS-ADL scores, than their sham-treated counterparts (p-values 0.05 and 0.002), and their CDR-Sb scores declined 53% less than their sham-treated counterparts. However, ADAS-Cog and ADCS-ADL scores were not significantly different between actively-treated and sham-treated mild AD patients, although CDR-Sb scores improved vs. baseline for treated mild AD patients. Patients administered both IVIG and albumin had less reduction in brain glucose metabolism than sham-treated patients. Questions raised by these findings include: what mechanism(s) contributed to slowing of disease progression? Is this approach as effective in mild AD as in moderate AD? Must IVIG be included in the protocol? Does age, sex, or ApoE genotype influence treatment response? Does the protocol increase the risk for amyloid-related imaging abnormalities? How long does disease progression remain slowed post-treatment? A further study should allow this approach to be optimized.}, }
@article {pmid32547392, year = {2020}, author = {Rea, S and Della-Morte, D and Pacifici, F and Capuani, B and Pastore, D and Coppola, A and Arriga, R and Andreadi, A and Donadel, G and Di Daniele, N and Bellia, A and Lauro, D}, title = {Insulin and Exendin-4 Reduced Mutated Huntingtin Accumulation in Neuronal Cells.}, journal = {Frontiers in pharmacology}, volume = {11}, number = {}, pages = {779}, pmid = {32547392}, issn = {1663-9812}, abstract = {Patients with diabetes mellitus (DM) are more prone to develop cognitive decline and neurodegenerative diseases. A pathological association between an autosomal dominant neurological disorder caused by brain accumulation in mutated huntingtin (mHTT), known as Huntington disease (HD), and DM, has been reported. By using a diabetic mouse model, we previously suggested a central role of the metabolic pathways of HTT, further suggesting the relevance of this protein in the pathology of DM. Furthermore, it has also been reported that intranasal insulin (Ins) administration improved cognitive function in patients with neurodegenerative disorders such as Alzheimer disease, and that exendin-4 (Ex-4) enhanced lifespan and ameliorated glucose homeostasis in a mouse model of HD. Although antioxidant properties have been proposed, the underlying molecular mechanisms are still missing. Therefore, the aim of the present study was to investigate the intracellular pathways leading to neuroprotective effect of Ins and Ex-4 hypoglycemic drugs by using an in vitro model of HD, developed by differentiated dopaminergic neurons treated with the pro-oxidant neurotoxic compound 6-hydroxydopamine (6-ohda). Our results showed that 6-ohda increased mHTT expression and reduced HTT phosphorylation at Ser421, a post-translational modification, which protects against mHTT accumulation. Pre-treatment with Ins or Ex-4 reverted the harmful effect induced by 6-ohda by activating AKT1 and SGK1 kinases, and by reducing the phosphatase PP2B. AKT1 and SGK1 are crucial nodes on the Ins activation pathway and powerful antioxidants, while PP2B dephosphorylates HTT contributing to mHTT neurotoxic effect. In conclusion, present results highlight that Ins and Ex-4 may counteract the neurotoxic effect induced by mHTT, opening novel pharmacological therapeutic strategies against neurodegenerative disorders, with the main focus on HD, still considered an orphan illness.}, }
@article {pmid32544519, year = {2020}, author = {Aghajanzadeh, M and Andalib, S and Danafar, H and Rostamizadeh, K and Sharafi, A}, title = {The effect of baicalein-loaded Y-shaped miktoarm copolymer on spatial memory and hippocampal expression of DHCR24, SELADIN and SIRT6 genes in rat model of Alzheimer.}, journal = {International journal of pharmaceutics}, volume = {586}, number = {}, pages = {119546}, doi = {10.1016/j.ijpharm.2020.119546}, pmid = {32544519}, issn = {1873-3476}, mesh = {Alzheimer Disease/*drug therapy/genetics/physiopathology ; Animals ; Disease Models, Animal ; Drug Carriers/chemistry ; Flavanones/administration & dosage/*pharmacology ; Hippocampus/*drug effects/pathology ; Male ; Maze Learning/drug effects ; Nanoparticles ; Nerve Tissue Proteins/genetics ; Oxidative Stress ; Oxidoreductases Acting on CH-CH Group Donors/genetics ; Polyesters/chemistry ; Polyethylene Glycols/chemistry ; Polymers/chemistry ; Rats ; Rats, Wistar ; Sirtuins/genetics ; Spatial Memory/*drug effects ; }, abstract = {In the present study, we successfully synthesized nanocarriers (NCs) based on Y-shaped miktoarm copolymers, Poly Ethylene Glycol-Lysine-(Poly Caprolactone)2 (PEG-Lys-PCL2), which were loaded by baicalein (B) through the nanoprecipitation process to assess their in-vitro and in-vivo properties. We applied various methods and measurements including proton nuclear magnetic resonance (HNMR), dynamic light scattering (DLS), differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FTIR), MTT assay, hemolysis test, lethal dose, real-time PCR, and Morris water maze. The results of DLS indicated that the size and zeta potential of the obtained NCs and B-loaded NCs were acceptable. Also, in-vivo and in-vitro biocompatibility examinations proved that miktoarm-based NCs were safe, and all rats treated with miktoarm-based NCs did not exhibit any remarkable weight loss during the experiment. The results of the Morris water maze (in-vivo test) revealed that the normal saline-treated group, as well as B-miktoarm + Scopolamine (M + B + S) and B-miktoarm-Tween80 + Scopolamine (M + B + T + S) pretreatment groups, spent more time in the target quadrant. Thus, this experiment showed that pretreatment of rats with M + B + S and M + B + T + S had the most effects on spatial memory. According to quantitative PCR analysis, we hypothesized that, in comparison with other experimental groups, pretreatment of rats with M + B + T + S could be more effective in preventing cholinergic dysfunction, brain oxidative stress and cognitive deficits which cause by Scopolamine HBr. This outcome may be partially due to the upregulation of DHCR24, SELADIN, and SIRT6 in entire of the hippocampal region of normal saline-treated and M + B + T + S pretreatment groups. These results may be because mimicking the cell membrane structure would be an excellent feature for miktoarm, and partial coating of Tween-80 can play a critical role for PEG-Lys-PCL2-based NCs in crossing the brain cell membrane, and they can easily be uptaken by the cells. Eventually, all of the obtained data confirmed that PEG-Lys-PCL2 miktoarm star copolymers are suitable for delivering therapeutic agents to the brain for the treatment of Alzheimer's disease (AD). Also, it seems that baicalein should be taken into account as a potent compound for the treatment of AD.}, }
@article {pmid32533852, year = {2020}, author = {Ryder, MI}, title = {Porphyromonas gingivalis and Alzheimer disease: Recent findings and potential therapies.}, journal = {Journal of periodontology}, volume = {91 Suppl 1}, number = {}, pages = {S45-S49}, pmid = {32533852}, issn = {1943-3670}, mesh = {Adhesins, Bacterial ; *Alzheimer Disease/drug therapy ; Animals ; *Bacteroidaceae Infections/drug therapy ; Cysteine Endopeptidases ; Humans ; Mice ; *Periodontitis ; Porphyromonas gingivalis ; }, abstract = {Epidemiological studies have identified an association between periodontitis and Alzheimer disease (AD); however, the nature of this association has been unclear. Recent work suggests that brain colonization by the periodontal pathogen Porphyromonas gingivalis may link these two inflammatory and degenerative conditions. Evidence of P. gingivalis infiltration has been detected in autopsy specimens from the brains of people with AD and in cerebrospinal fluid of individuals diagnosed with AD. Gingipains, a class of P. gingivalis proteases, are found in association with neurons, tau tangles, and beta-amyloid in specimens from the brains of individuals with AD. The brains of mice orally infected with P. gingivalis show evidence of P. gingivalis infiltration, along with various neuropathological hallmarks of AD. Oral administration of gingipain inhibitors to mice with established brain infections decreases the abundance of P. gingivalis DNA in brain and mitigates the neurotoxic effects of P. gingivalis infection. Thus, gingipain inhibition could provide a potential approach to the treatment of both periodontitis and AD.}, }
@article {pmid32529139, year = {2020}, author = {Gandhidasan, S and Reddy, CA and Woody, NM and Stephans, KL and Freeman, M and Videtic, GMM}, title = {Outpatient Anesthesia Facilitates Stereotactic Body Radiation Therapy for Early Stage Lung Cancer Patients With Advanced Cognitive Impairments.}, journal = {Advances in radiation oncology}, volume = {5}, number = {3}, pages = {444-449}, pmid = {32529139}, issn = {2452-1094}, abstract = {Purpose: To report on the use of outpatient anesthesia (OPA) facilitating delivery of stereotactic body radiation therapy (SBRT) in patients with severe cognitive impairments (CI) diagnosed with inoperable early stage lung cancer.
Methods and Materials: We surveyed our institutional review board-approved prospective lung SBRT data registry to document the feasibility of using anesthesia in CI patients and to determine their SBRT outcomes.
Results: From 2004 to 2018, 8 from a total 2084 patients were identified for this analysis. The median age at treatment was 68 years (range, 44-78). Most patients were female (62.5%). CI diagnoses included Alzheimer-related dementia (3 patients), chronic schizophrenia (3 patients), severe anxiety disorder (1 patient), and severe developmental disability (1 patient). The median tumor size was 3.4 cm (range, 1.1-10.5), and 7 patients (87.5 %) had central lesions. The median follow-up time was 22.5 months. The most common (50%) SBRT schedule used was 50 Gy in 5 fractions. Intravenous propofol (10 mg/mL) was used for OPA in all cases at the time of simulation and with daily treatments. OPA was well tolerated and all patients completed SBRT as prescribed. There was one grade 5 but no other grade 3 or higher SBRT-related toxicities. One patient died with local failure and one of distant failure.
Conclusions: OPA made lung SBRT feasible for patients with CIs. SBRT outcomes were in keeping with those reported in the literature. CI should not be considered a contraindication per se to SBRT delivery in patients otherwise appropriate for this modality.}, }
@article {pmid32528227, year = {2020}, author = {Alamro, AA and Alsulami, EA and Almutlaq, M and Alghamedi, A and Alokail, M and Haq, SH}, title = {Therapeutic Potential of Vitamin D and Curcumin in an In Vitro Model of Alzheimer Disease.}, journal = {Journal of central nervous system disease}, volume = {12}, number = {}, pages = {1179573520924311}, pmid = {32528227}, issn = {1179-5735}, abstract = {Background: Alzheimer disease is a progressive neurodegenerative disease, affecting a very high proportion of the aging population. Several studies have demonstrated that one of the main contributors to this disease is oxidative stress (OS), which causes peroxidation of protein, lipids, and DNA resulting in the formation of advanced glycosylated end products (AGE) in the brain tissues. These AGE are usually associated with the amyloid β (Aβ), which could further aggravate its toxicity and its clearance. Antioxidants counteract the deterioration caused by OS.
Objective: We aimed to evaluate the effect of vitamin D3 and curcumin on primary cortical neuronal cultures exposed to Aβ1-42 toxicity for different time periods.
Methods: Primary cortical neuronal cultures were set up and exposed to Aβ1-42 for up to 72 hours. Cell viability was studied by 3[4,5-dimethylthiazole-2-yl]-2,5-dipheyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assay. Biochemical assays for OS such as lipid peroxidation, reduced Glutathione(GSH), Glutathione S-transferase (GST), catalase, and superoxide dismutase (SOD) were conducted. Sandwich enzyme-linked immunosorbent assay (ELISA) was used to study the neurotrophic growth factor (NGF) expression.
Results: Treatments with Aβ1-42 caused an elevation in lipid peroxidation products, which were ameliorated in the presence of vitamin D3 and curcumin. Both enzymatic (GST, catalase, and SOD) and nonenzymatic antioxidants (reduced GSH) were raised significantly in the presence of vitamin D3 and curcumin, which resulted in the better recovery of neuronal cells from Aβ1-42 treatment. Treatment with vitamin D3 and curcumin also resulted in the upregulation of NGF levels.
Conclusions: This study suggests that vitamin D3 and curcumin can be a promising natural therapy for the treatment of Alzheimer disease.}, }
@article {pmid32523525, year = {2020}, author = {Ordóñez-Gutiérrez, L and Wandosell, F}, title = {Nanoliposomes as a Therapeutic Tool for Alzheimer's Disease.}, journal = {Frontiers in synaptic neuroscience}, volume = {12}, number = {}, pages = {20}, pmid = {32523525}, issn = {1663-3563}, abstract = {The accumulation of extracellular amyloid-beta (Aβ), denoted as senile plaques, and intracellular neurofibrillary tangles (formed by hyperphosphorylated Tau protein) in the brain are two major neuropathological hallmarks of Alzheimer's disease (AD). The current and most accepted hypothesis proposes that the oligomerization of Aβ peptides triggers the polymerization and accumulation of amyloid, which leads to the senile plaques. Several strategies have been reported to target Aβ oligomerization/polymerization. Since it is thought that Aβ levels in the brain and peripheral blood maintain equilibrium, it has been hypothesized that enhancing peripheral clearance (by shifting this equilibrium towards the blood) might reduce Aβ levels in the brain, known as the sink effect. This process has been reported to be effective, showing a reduction in Aβ burden in the brain as a consequence of the peripheral reduction of Aβ levels. Nanoparticles (NPs) may have difficulty crossing the blood-brain barrier (BBB), initially due to their size. It is not clear whether particles in the range of 50-100 nm should be able to cross the BBB without being specifically modified for it. Despite the size limitation of crossing the BBB, several NP derivatives may be proposed as therapeutic tools. The purpose of this review is to summarize some therapeutic approaches based on nanoliposomes using two complementary examples: First, unilamellar nanoliposomes containing Aβ generic ligands, such as sphingolipids, gangliosides or curcumin, or some sphingolipid bound to the binding domain of ApoE; and second, nanoliposomes containing monoclonal antibodies against Aβ. Following similar rationale NPs of poly(lactide-co-glycolide)-poly (ethylene glycol) conjugated with curcumin-derivate (PLGA-PEG-B6/Cur) were reported to improve the spatial learning and memory capability of APP/PS1 mice, compared with native curcumin treatment. Also, some new nanostructures such as exosomes have been proposed as a putative therapeutic and prevention strategies of AD. Although the unquestionable interest of this issue is beyond the scope of this review article. The potential mechanisms and significance of nanoliposome therapies for AD, which are still are in clinical trials, will be discussed.}, }
@article {pmid32511043, year = {2020}, author = {Kinfe, T and Stadlbauer, A and Winder, K and Hurlemann, R and Buchfelder, M}, title = {Incisionless MR-guided focused ultrasound: technical considerations and current therapeutic approaches in psychiatric disorders.}, journal = {Expert review of neurotherapeutics}, volume = {20}, number = {7}, pages = {687-696}, doi = {10.1080/14737175.2020.1779590}, pmid = {32511043}, issn = {1744-8360}, mesh = {*High-Intensity Focused Ultrasound Ablation/methods/standards ; Humans ; *Magnetic Resonance Imaging/methods/standards ; Mental Disorders/diagnostic imaging/surgery/*therapy ; *Surgery, Computer-Assisted/methods/standards ; }, abstract = {INTRODUCTION: MR-guided focused ultrasound operating at higher intensities have been reported to effectively and precisely ablate deeper brain structures like the basal ganglia or the thalamic nuclei for the treatment of refractory movement disorders, neuropathic pain and most recently neuropsychiatric disorders, while low-intensity focused ultrasound represents an approach promoting mechanical blood-brain-barrier opening and neuromodulation. This narrative review summarizes the technical development and the therapeutic potential of incisionless MRgFUS in order to treat neuropsychiatric disorders.
AREAS COVERED: A narrative review of clinical trials assessing the safety and efficacy of MRgFUS. A literature review was performed using the following search terms: MR-guided focused ultrasound, psychiatric disorders, noninvasive and invasive brain modulation/stimulation techniques.
EXPERT OPINION: MRgFUS ablation is under clinical investigation (unblinded study design) for obsessive-compulsive disorders (OCDs) [capsulotomy; ALIC] and depression/anxiety disorders [capsulotomy] and has demonstrated an improvement in OCD and depression, although of preliminary character. Low-intensity ultrasound applications have been explored in Alzheimer´s disease (phase 1 study) and healthy subjects. Currently, limited evidence hinders comparison and selection between MRgFUS and noninvasive/invasive brain modulation therapies. However, comparative, sham-controlled trials are needed to reexamine the preliminary findings for the treatment of psychiatric disorders.}, }
@article {pmid32507686, year = {2020}, author = {Weinberg, MS and Patrick, RE and Schwab, NA and Owoyemi, P and May, R and McManus, AJ and Gerber, J and Harper, DG and Arnold, SE and Forester, B}, title = {Clinical Trials and Tribulations in the COVID-19 Era.}, journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry}, volume = {28}, number = {9}, pages = {913-920}, pmid = {32507686}, issn = {1545-7214}, support = {P30 AG062421/AG/NIA NIH HHS/United States ; R21 TR003040/TR/NCATS NIH HHS/United States ; R25 MH058818/MH/NIMH NIH HHS/United States ; R25 MH094612/MH/NIMH NIH HHS/United States ; }, mesh = {Aged ; Alzheimer Disease/drug therapy/prevention & control ; Betacoronavirus ; COVID-19 ; Clinical Trials as Topic/*methods/*standards ; Coronavirus Infections/*prevention & control ; Guidelines as Topic ; Humans ; Neurocognitive Disorders/*drug therapy/*prevention & control ; Pandemics/*prevention & control ; Pneumonia, Viral/*prevention & control ; SARS-CoV-2 ; }, abstract = {Advances in treating and preventing Alzheimer disease and other neurocognitive disorders of aging arise from rigorous preclinical and clinical research, with randomized controlled treatment trials as the last and definitive test. The COVID-19 pandemic has greatly disrupted ongoing interventional studies and researchers are scrambling to find ways to safely continue this critical work amidst rapidly shifting guidelines from sponsors, institutions, and state and federal guidelines. Here the authors describe novel approaches and work-flow adaptations to study visits, drug delivery and interim and endpoint safety and outcomes assessments to avoid sacrificing years of preparation and substantial financial investments, to work in the best interest of participants and their caregivers, and to continue on the path toward discovering disease-modifying treatments for the millions of individuals impacted by major neurocognitive disorders.}, }
@article {pmid32506864, year = {2020}, author = {Ren, B and Cheng, F and Wang, X and Wan, Y and Ji, W and Du, X and Zhang, S and Liu, S and Ma, C and Xiong, Y and Hao, G and Wang, Q}, title = {"Possible mechanisms underlying treatment of Alzheimer's disease with Traditional Chinese Medicine: active components, potential targets and synthetic pathways of Bulao Elixir".}, journal = {Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan}, volume = {40}, number = {3}, pages = {484-496}, doi = {10.19852/j.cnki.jtcm.2020.03.018}, pmid = {32506864}, issn = {2589-451X}, mesh = {Alzheimer Disease/*drug therapy/genetics/metabolism ; Drugs, Chinese Herbal/*administration & dosage/chemical synthesis/*chemistry ; Humans ; Medicine, Chinese Traditional ; Signal Transduction/drug effects ; }, abstract = {OBJECTIVE: To elucidate the mechanisms underlying the treatment of Alzheimer's disease (AD) with Traditional Chinese Medicine (TCM), by examining the active components, potential targets and synthetic pathways of Bulao Elixir (BLE).
METHODS: The Absorption, Distribution, Metabolism, Excretion (ADME) / Toxicology (T) calculation was used to screen the active components of Bulao Elixir. Based on the TCM Systems Pharmacology Analysis Platform (TCMSP database) and a text mining tool (GoPubMed database), we predicted and screened the active components of Bulao Elixir and its therapeutic targets for AD. Using the Database for Annotation, Visualization and Integrated Discovery (DAVID), we obtained the targets for AD. Cytoscape software was used to establish a network map of the active component-target and target-pathway of Bulao Elixir. Gene function, related biological processes and signaling pathways were analyzed using the DAVID database.
RESULTS: Twelve active components were selected from 196 components of Bulao Elixir. Among 2209 targets, 102 effective targets were selected, and 30 important targets were identified via matching with the disease targets. After further analysis, 14 core targets were identified. Enrichment analysis revealed that most of these important targets were involved in multiple biological processes, including apoptosis, inflammatory reactions, and cell regulation cycles. The synthetic pathways for AD treatment were identified after analyzing and confirming the relevant pathways, providing potentially useful information for diagnosis and treatment methods for AD.
CONCLUSION: The current study elucidated the potential treatment mechanisms of Bulao Elixir in AD using network pharmacology, providing a foundation for further clarification of its treatment targets.}, }
@article {pmid32504710, year = {2020}, author = {Mobed, A and Hasanzadeh, M}, title = {Biosensing: The best alternative for conventional methods in detection of Alzheimer's disease biomarkers.}, journal = {International journal of biological macromolecules}, volume = {161}, number = {}, pages = {59-71}, doi = {10.1016/j.ijbiomac.2020.05.257}, pmid = {32504710}, issn = {1879-0003}, mesh = {Alzheimer Disease/*diagnosis/*etiology/metabolism ; Amyloid beta-Peptides/metabolism ; *Biomarkers ; *Biosensing Techniques/methods ; Humans ; MicroRNAs ; *Molecular Diagnostic Techniques/methods ; Surface Plasmon Resonance/methods ; tau Proteins/metabolism ; }, abstract = {Conceivably the imperative reason for the absence of appropriate treatment for Alzheimer's disease (AD) is the late onset of clinical symptoms followed by late treatment. Specific biomarkers play a vital role in this area. The amyloid-beta peptide, tau protein and micRNA, are the most important biomarker associated in AD. There are many routine methods for identifying these biomarkers which molecular based methods with a high accuracy and sensitivity have been considered. These methods have some limitations such as; false positive and negative results, problem on the interpretation, complexity and time-consuming, high cost instruments and etc. To overcome these limitations, bioassays were developed extensively. There exist a multitude of possible applications for Alzheimer's disease biomarkers by using biosensors. This review mainly focuses on major biomarkers in Alzheimer's disease, routine and old methods in identifying biomarkers of AD and their advantages and limitation, and biosensors to the identification of amyloid beta, tau protein and micRNAs biomarkers. Furthermore, evaluation the strengths and weaknesses of the developed bioassays and introduce leading challenges are considered in this review.}, }
@article {pmid32502032, year = {2020}, author = {Chen, KH and Chen, HH and Li, L and Lin, HC and Chen, CL and Chen, NC}, title = {The impact of exercise on patients with dementia: A 2-year follow-up.}, journal = {Medicine}, volume = {99}, number = {23}, pages = {e20597}, doi = {10.1097/MD.0000000000020597}, pmid = {32502032}, issn = {1536-5964}, mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/*therapy ; Case-Control Studies ; *Exercise ; Female ; Follow-Up Studies ; Hospitalization/statistics & numerical data ; Humans ; Male ; Physical Fitness/*physiology ; Prospective Studies ; Severity of Illness Index ; Surveys and Questionnaires ; }, abstract = {The current absence of a disease-modifying treatment for Alzheimer disease highlights the necessity for the benefits of nonpharmacological approaches. We aimed to investigate the effect of exercise in older patients with Alzheimer dementia.This is an observational, prospective cohort study in medical center. Eighty older patients with Alzheimer dementia, including 54 with mild dementia and 26 with moderate dementia, were followed up over 2 years. Patients were divided into exercise and no-exercise groups according to their weekly exercise habit. Mini-Mental State Examination (MMSE), clinical dementia rating (CDR), and senior fitness test were checked initially. We defined death and unexpected hospitalization as the outcomes.Age, sex, education years, and MMSE showed no significant differences between the groups (P > .05) in all patients. All the patients of the exercise group had significantly better left upper body strength, higher aerobic endurance, and left and right balance maintenance time than those of the no-exercise group (P < .05). There were no changes in hospitalization and mortality between the exercise and non-exercise groups during the 2-year follow-ups in all participants. However, in the mild and moderate dementia subgroups, age, sex, education years, and MMSE showed no significant differences between the groups (P > .05). The exercise group had significantly better lower body strength, left upper body strength, aerobic endurance, right upper body flexibility, lower body flexibility, balance maintenance, and agility than the no-exercise group in patients with mild dementia (P < .05). Moreover, the exercise group had significantly lesser unexpected hospitalization than the no-exercise group in the patients with mild dementia (P = .037).Despite the similarity in the status of dementia, exercise habit was found to be associated with a better senior fitness test score status. Hence, exercise can decrease unexpected hospitalization in patients with mild dementia but not those with total dementia.}, }
@article {pmid32496629, year = {2020}, author = {Ahmad, R and Almubayedh, H and Ahmad, N and Naqvi, AA and Riaz, M}, title = {Ethnobotany, ethnopharmacology, phytochemistry, biological activities and toxicity of Pistacia chinensis subsp. integerrima: A comprehensive review.}, journal = {Phytotherapy research : PTR}, volume = {34}, number = {11}, pages = {2793-2819}, doi = {10.1002/ptr.6720}, pmid = {32496629}, issn = {1099-1573}, mesh = {Ethnobotany/*methods ; Ethnopharmacology/*methods ; Humans ; Phytochemicals/*therapeutic use ; Phytotherapy/*methods ; Pistacia/*chemistry ; Plant Extracts/*chemistry ; Plants, Medicinal/*drug effects ; }, abstract = {Pistacia chinensis subsp. integerrima (J. L. Stewart ex Brandis) Rech. F. is a valuable medicinal plant used in south Asian communities for the treatment of asthma, diarrhea, diabetes, liver diseases, fever, pain and inflammation. This review critically evaluates the available information on P. integerrima's ethnobotany, ethnopharmacology, phytochemistry, pharmacology and toxicology. Electronic databases such as Google Scholar, PubMed, Springer Link, and so forth, books and theses were used to find relevant information about P. integerrima using keywords such as "Pistacia integerrima," "P. integerrima," "Ethnopharmacology," "Phytochemistry," "Traditional uses". A number of in vitro and in vivo pharmacological activities have been reported; however, the most promising and attractive activity observed was its role in Alzheimer, diabetes, convulsions, cancer, asthma, diabetes, diarrhea and as an immunomodulatory, analgesic and antiinflammatory. In addition, Pistagremic acid exerted anti-Alzheimer's activity based on a hitherto unknown mechanism through interference with the amyloidogenic pathway. Most of the pharmacological activities were linked with traditional uses. A range of compounds have been reported from P. integerrima extracts including triterpenes, volatile oils, flavonoids, fatty acids, phenolic, phytosterols, tannins and oligosaccharides as well as unknown triterpenes and flavonoids. Pistagremic acid, a novel triterpene, was attributed to most of the activities. in vivo toxicological studies in animal suggested a toxic dose of 1,500 mg kg-1 , for its methanolic extract. All reported pharmacological activities were carried out in vitro and a gap in research, that is, preclinical and clinical investigation exists. Its outstanding activity as an antiglycating agent is the most promising and a so far unique activity and needs further evaluation. In-depth research and clinical trials on human subjects in order to investigate P. integerrima pharmacological activity, clinical efficacy and safety are crucial next steps.}, }
@article {pmid32493725, year = {2020}, author = {Wang, X and Li, W and Marcus, J and Pearson, M and Song, L and Smith, K and Terracina, G and Lee, J and Hong, KK and Lu, SX and Hyde, L and Chen, SC and Kinsley, D and Melchor, JP and Rubins, DJ and Meng, X and Hostetler, E and Sur, C and Zhang, L and Schachter, JB and Hess, JF and Selnick, HG and Vocadlo, DJ and McEachern, EJ and Uslaner, JM and Duffy, JL and Smith, SM}, title = {MK-8719, a Novel and Selective O-GlcNAcase Inhibitor That Reduces the Formation of Pathological Tau and Ameliorates Neurodegeneration in a Mouse Model of Tauopathy.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {374}, number = {2}, pages = {252-263}, doi = {10.1124/jpet.120.266122}, pmid = {32493725}, issn = {1521-0103}, mesh = {Animals ; Atrophy/drug therapy ; Brain/drug effects/metabolism/pathology ; Disease Models, Animal ; Enzyme Inhibitors/*pharmacology/therapeutic use ; Locomotion/drug effects ; Male ; Mice ; PC12 Cells ; Rats ; Tauopathies/*drug therapy/*metabolism/pathology/physiopathology ; beta-N-Acetylhexosaminidases/*antagonists & inhibitors ; tau Proteins/*metabolism ; }, abstract = {Deposition of hyperphosphorylated and aggregated tau protein in the central nervous system is characteristic of Alzheimer disease and other tauopathies. Tau is subject to O-linked N-acetylglucosamine (O-GlcNAc) modification, and O-GlcNAcylation of tau has been shown to influence tau phosphorylation and aggregation. Inhibition of O-GlcNAcase (OGA), the enzyme that removes O-GlcNAc moieties, is a novel strategy to attenuate the formation of pathologic tau. Here we described the in vitro and in vivo pharmacological properties of a novel and selective OGA inhibitor, MK-8719. In vitro, this compound is a potent inhibitor of the human OGA enzyme with comparable activity against the corresponding enzymes from mouse, rat, and dog. In vivo, oral administration of MK-8719 elevates brain and peripheral blood mononuclear cell O-GlcNAc levels in a dose-dependent manner. In addition, positron emission tomography imaging studies demonstrate robust target engagement of MK-8719 in the brains of rats and rTg4510 mice. In the rTg4510 mouse model of human tauopathy, MK-8719 significantly increases brain O-GlcNAc levels and reduces pathologic tau. The reduction in tau pathology in rTg4510 mice is accompanied by attenuation of brain atrophy, including reduction of forebrain volume loss as revealed by volumetric magnetic resonance imaging analysis. These findings suggest that OGA inhibition may reduce tau pathology in tauopathies. However, since hundreds of O-GlcNAcylated proteins may be influenced by OGA inhibition, it will be critical to understand the physiologic and toxicological consequences of chronic O-GlcNAc elevation in vivo. SIGNIFICANCE STATEMENT: MK-8719 is a novel, selective, and potent O-linked N-acetylglucosamine (O-GlcNAc)-ase (OGA) inhibitor that inhibits OGA enzyme activity across multiple species with comparable in vitro potency. In vivo, MK-8719 elevates brain O-GlcNAc levels, reduces pathological tau, and ameliorates brain atrophy in the rTg4510 mouse model of tauopathy. These findings indicate that OGA inhibition may be a promising therapeutic strategy for the treatment of Alzheimer disease and other tauopathies.}, }
@article {pmid32488540, year = {2020}, author = {Gao, F and Zhang, J and Ni, T and Lin, N and Lin, H and Luo, H and Guo, H and Chi, J}, title = {Herpud1 deficiency could reduce amyloid-β40 expression and thereby suppress homocysteine-induced atherosclerosis by blocking the JNK/AP1 pathway.}, journal = {Journal of physiology and biochemistry}, volume = {76}, number = {3}, pages = {383-391}, doi = {10.1007/s13105-020-00741-5}, pmid = {32488540}, issn = {1877-8755}, support = {81873120//National Natural Science Foundation of China/ ; 2018KY172//Zhejiang Medical and Health Science and Technology Plan Project/ ; }, mesh = {Amyloid beta-Peptides/*metabolism ; Animals ; Atherosclerosis/chemically induced/*metabolism ; Cells, Cultured ; Homocysteine ; Human Umbilical Vein Endothelial Cells ; Humans ; MAP Kinase Signaling System ; Male ; Membrane Proteins/genetics/*metabolism ; Mice ; Mice, Inbred C57BL ; Peptide Fragments/*metabolism ; }, abstract = {Homocysteine (Hcy) is considered an independent risk factor for various cardiovascular diseases including atherosclerosis which is associated with lipid metabolism, inflammation, and oxidative stress. Results from our previous study suggested that Hcy-induced atherosclerosis could be reversed by Herpud1 knockout which inhibits vascular smooth muscle cell (VSMC) phenotype switching. Here, we aim to investigate more precise mechanisms behind the improvement in Hcy-induced atherosclerosis. Amyloid-β40 (Aβ40), a vital protein in Alzheimer disease (AD), has been regarded as an important component in the atherosclerosis program in recent years due to the biological similarity between AD and atherosclerosis. Thus, we determined to assess the value of Aβ40 in a Herpud1 knockout Hcy-induced atherosclerosis mouse model by measuring Aβ40 expression in tissue and biomarkers of lipid metabolism, inflammation, and oxidative stress in serum. Additionally, since endothelial dysfunction plays a prominent role in atherosclerosis, we tested human umbilical vein endothelial cell (HUVEC) function following Herpud1 silencing in vitro and evaluated JNK/AP1 signaling activation in our models because of its close relationship with Aβ40. As a result, our animal models showed that Herpud1 knockout reduced Aβ40 expression, inflammation, and oxidative stress levels other than lipid metabolism and alleviated atherosclerosis via JNK/AP1 signaling inhibition. Similarly, our cell experiments implied that Hcy-induced Aβ40 elevation and HUVEC dysfunction involving cell proliferation and apoptosis could be restored by Herpud1 silence through restraining JNK/AP1 pathway. Collectively, our study demonstrates that Herpud1 deficiency could reduce Aβ40 expression, thereby suppressing Hcy-induced atherosclerosis by blocking the JNK/AP1 pathway. This may provide novel potential targets for atherosclerosis prevention or treatment.}, }
@article {pmid32485470, year = {2020}, author = {Patel, DV and Patel, NR and Kanhed, AM and Teli, DM and Patel, KB and Joshi, PD and Patel, SP and Gandhi, PM and Chaudhary, BN and Prajapati, NK and Patel, KV and Yadav, MR}, title = {Novel carbazole-stilbene hybrids as multifunctional anti-Alzheimer agents.}, journal = {Bioorganic chemistry}, volume = {101}, number = {}, pages = {103977}, doi = {10.1016/j.bioorg.2020.103977}, pmid = {32485470}, issn = {1090-2120}, mesh = {Alzheimer Disease/*drug therapy ; Humans ; Molecular Docking Simulation ; Molecular Structure ; Stilbenes/*therapeutic use ; Structure-Activity Relationship ; }, abstract = {Molecules capable of engaging with multiple targets associated with pathological condition of Alzheimer's disease have proved to be potential anti-Alzheimer's agents. In our goal to develop multitarget-directed ligands for the treatment of Alzheimer's disease, a novel series of carbazole-based stilbene derivatives were designed by the fusion of carbazole ring with stilbene scaffold. The designed compounds were synthesized and evaluated for their anti-AD activities including cholinesterase inhibition, Aβ aggregation inhibition, antioxidant and metal chelation properties. Amongst them, (E)-1-(4-(2-(9-ethyl-9H-carbazol-3-yl)vinyl)phenyl)-3-(2-(pyrrolidin-1-yl)ethyl)thiourea (50) appeared to be the best candidate with good inhibitory activities against AChE (IC50 value of 2.64 μM) and BuChE (IC50 value of 1.29 μM), and significant inhibition of self-mediated Aβ1-42 aggregation (51.29% at 25 μM concentration). The metal chelation study showed that compound (50) possessed specific copper ion chelating property. Additionally, compound (50) exhibited moderate antioxidant activity. To understand the binding mode of 50, molecular docking studies were performed, and the results indicated strong non-covalent interactions of 50 with the enzymes in the active sites of AChE, BuChE as well as of the Aβ1-42 peptide. Additionally, it showed promising in silico ADMET properties. Putting together, these findings evidently showed compound (50) as a potential multitarget-directed ligand in the course of developing novel anti-AD drugs.}, }
@article {pmid32485345, year = {2020}, author = {Lorenzoni, R and Davies, S and Cordenonsi, LM and Viçosa, JADS and Mezzomo, NJ and de Oliveira, AL and Carmo, GMD and Raffin, RP and Alves, OL and Vaucher, RA and Rech, VC}, title = {Lipid-core nanocapsules containing simvastatin improve the cognitive impairment induced by obesity and hypercholesterolemia in adult rats.}, journal = {European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences}, volume = {151}, number = {}, pages = {105397}, doi = {10.1016/j.ejps.2020.105397}, pmid = {32485345}, issn = {1879-0720}, mesh = {Animals ; *Cognitive Dysfunction/drug therapy/etiology ; *Hypercholesterolemia/drug therapy ; Lipids ; *Nanocapsules ; Obesity/drug therapy ; Rats ; Simvastatin ; }, abstract = {The development of cognitive impairment may be related to high levels of plasma cholesterol and obesity. Simvastatin (SV) and lovastatin (LV) are drugs that can potentially be used for the treatment of cognitive deficit. This study aimed to develop and characterize lipid-core nanocapsules (LNC) containing SV (SV-LNC) or LV (LV-LNC), evaluating the effects of SV-LNC in an animal model of cognitive deficit. The formulations SV-LNC and LV-LNC presented a particle average size around 200 nm, a low-polydispersity index, and negative zeta potential. Analysis of differential scanning calorimetry, Fourier transform infrared spectroscopy, X-ray diffraction, and scanning electron microscopy showed that there is no reaction among LNC components: LV was crystallized in the suspensions, and SV was molecularly dispersed. The encapsulation efficiency of the SV was high (98.9 ± 1.4%), while that of the LV was low (21.5 ± 1.5%).Based on these results, SV-LNC was used in the preclinical studies. Animals fed with a hyperlipidic diet (HD) developed obesity, hypercholesterolemia, and cognitive impairment, which was corroborated by the brain lesions indicated by histological analysis of some of the animals that received the high-fat diet. We observed that free simvastatin (CS3) was able to reduce the enzymatic activity of pyruvate kinase, an important enzyme for brain energy homeostasis, without affecting the memory of the animals that received a standard diet. However, it failed to improve the cognitive damage caused by a diet high in cholesterol and saturated fats. On the other hand, when simvastatin is "camouflaged" in the lipid-core nanocapsules (HNS3), this cognitive impairment improves. Thus, SV-LNC is a promising alternative therapy for the treatment of cognitive impairment.}, }
@article {pmid32483988, year = {2020}, author = {Inglet, S and Winter, B and Yost, SE and Entringer, S and Lian, A and Biksacky, M and Pitt, RD and Mortensen, W}, title = {Clinical Data for the Use of Cannabis-Based Treatments: A Comprehensive Review of the Literature.}, journal = {The Annals of pharmacotherapy}, volume = {54}, number = {11}, pages = {1109-1143}, doi = {10.1177/1060028020930189}, pmid = {32483988}, issn = {1542-6270}, mesh = {Clinical Trials as Topic ; Drug Utilization Review/*trends ; Humans ; Medical Marijuana/administration & dosage/adverse effects/*therapeutic use ; Multiple Sclerosis/drug therapy ; Nausea/drug therapy ; Pain/drug therapy ; Practice Guidelines as Topic ; Vomiting/drug therapy ; }, abstract = {OBJECTIVE: To compile and synthesize the available literature describing medical cannabis use across various disease states.
DATA SOURCES: PubMed, EBSCO, and Google Scholar searches were conducted using MeSH and/or keywords.
Studies were included if they described the use of cannabis-based products and medications in the treatment of a predefined list of disease states in humans and were published in English. The extraction period had no historical limit and spanned through April 2019.
DATA SYNTHESIS: Evidence was compiled and summarized for the following medical conditions: Alzheimer disease, amyotrophic lateral sclerosis, autism, cancer and cancer-associated adverse effects, seizure disorders, human immunodeficiency virus, inflammatory bowel disease, multiple sclerosis (MS), nausea, pain, posttraumatic stress disorder, and hospice care.
Based on identified data, the most robust evidence suggests that medical cannabis may be effective in the treatment of chemotherapy-induced nausea and vomiting, seizure disorders, MS-related spasticity, and pain (excluding diabetic neuropathy). Overall, the evidence is inconsistent and generally limited by poor quality. The large variation in cannabis-based products evaluated in studies limits the ability to make direct comparisons. Regardless of the product, a gradual dose titration was utilized in most studies. Cannabis-based therapies were typically well tolerated, with the most common adverse effects being dizziness, somnolence, dry mouth, nausea, and euphoria.
CONCLUSIONS: As more states authorize medical cannabis use, there is an increasing need for high-quality clinical evidence describing its efficacy and safety. This review is intended to serve as a reference for clinicians, so that the risks and realistic benefits of medical cannabis are better understood.}, }
@article {pmid32483406, year = {2020}, author = {Molaei, A and Hatami, H and Dehghan, G and Sadeghian, R and Khajehnasiri, N}, title = {Synergistic effects of quercetin and regular exercise on the recovery of spatial memory and reduction of parameters of oxidative stress in animal model of Alzheimer's disease.}, journal = {EXCLI journal}, volume = {19}, number = {}, pages = {596-612}, pmid = {32483406}, issn = {1611-2156}, abstract = {It has widely been reported that the brain in Alzheimer's disease (AD) is affected by increased oxidative stress, and this may have a role in the pathogenesis of this disorder. Quercetin, a polyphenol extensively found in nature, has recently been considered. Also, physical activities have a paradoxical effect on brain function in older adults. Therefore, this study aimed at investigating the synergic effects of quercetin (as chemical treatment) and exercise (as physical treatment) on AD-induced learning and memory impairment. Fifty-six adult male Wistar rats were randomly assigned into one of the following eight groups (n=7): The Control, Sham (saline), AD (intracerebroventricular administration of streptozotocin (STZ)), AD+80 mg/kg Quercetin (STZ+Q80), Quercetin vehicle (1 % Ethanol)+STZ, Exercise pretreatment (EX)+STZ, Off the treadmill+STZ, and EX+Q80+STZ. Quercetin administration was done intraperitoneally for 21 days after STZ injection. The rats ran on the treadmill for one hour a day for 60 days at a speed of 20-22 m/min. After the treatment, the spatial memory and levels of oxidative stress parameters were evaluated. The results showed that STZ caused spatial memory impairment and increased oxidative stress in the hippocampus. Exercise pretreatment or Quercetin injection improved the spatial memory impairment and oxidative stress caused by STZ injection. However, the combination of quercetin and exercise pretreatment was more effective. It can be concluded that the combined exercise pretreatment and Quercetin injection affected the antioxidant defense system and improved STZ-induced memory impairment.}, }
@article {pmid32482057, year = {2020}, author = {Ban, JY and Park, HK and Kim, SK}, title = {Effect of Glycyrrhizic Acid on Scopolamine-Induced Cognitive Impairment in Mice.}, journal = {International neurourology journal}, volume = {24}, number = {Suppl 1}, pages = {S48-55}, pmid = {32482057}, issn = {2093-4777}, support = {//Dankook University/ ; }, abstract = {PURPOSE: Cognitive impairment is one of the main symptoms of Alzheimer disease and other dementias. Glycyrrhiza uralensis is a natural product that has a protective effect against cognitive impairment. In this study, we investigated whether glycyrrhizic acid, among the main bioactive components of Glycyrrhiza uralensis, has a neuroprotective effect on scopolamine-induced cognitive impairment.
METHODS: Twenty-week-old male Institute of Cancer Research mice were used in this study. The scopolamine-induced cognitive impairment mice model was used. Glycyrrhizic acid was orally administered to mice once daily for 21 days, while scopolamine (1 mg/kg) treatment was delivered 30 minutes before behavioral tests. Donepezil (2 mg/kg) was used as a positive drug control. To evaluate the effect of glycyrrhizic acid, the following assessments were performed on hippocampal tissue: Y-maze test, acetylcholinesterase activity, antioxidant enzymes' activity (superoxide dismutase, catalase). Western blotting for phosphor-extracellular signal-regulated kinase, P38, and c-Jun NH2-terminal kinase was conducted.
RESULTS: We found that glycyrrhizic acid administration significantly improved scopolamine-induced cognitive impairment in the Y-maze test. The acetylcholinesterase activity, superoxide dismutase, and catalase activity in the glycyrrhizic acid-treated group showed a significant reversal of cognitive impairment compared with the scopolamine-treated group.
CONCLUSION: Our results suggest that glycyrrhizic acid has a neuroprotective effect on cognitive function in scopolamine-induced cognitive impairment.}, }
@article {pmid32480198, year = {2020}, author = {Chiu, WT and Lee, TY and Chan, L and Wu, D and Huang, LK and Chen, DY and Lee, YT and Hu, CJ and Hong, CT}, title = {Deep cerebral microbleeds are associated with poor cholinesterase inhibitor treatment response in people with Alzheimer disease.}, journal = {Clinical neurology and neurosurgery}, volume = {195}, number = {}, pages = {105959}, doi = {10.1016/j.clineuro.2020.105959}, pmid = {32480198}, issn = {1872-6968}, mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/complications/diagnostic imaging/*drug therapy ; Brain/*diagnostic imaging ; Cerebral Hemorrhage/*complications/diagnostic imaging ; Cholinesterase Inhibitors/*therapeutic use ; Disease Progression ; Female ; Humans ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Retrospective Studies ; Treatment Outcome ; }, abstract = {OBJECTIVES: Cholinesterase inhibitors (ChEIs) are the most effective treatment for Alzheimer disease (AD), but the response to treatment varies. Vascular lesions are associated with the pathogenesis of AD, and cerebral microbleeds (CMBs) are an indicator of hemorrhagic vascular pathology, which can be detected through susceptibility-weighted magnetic resonance imaging (SWMRI). This study investigated the association between CMBs and ChEI treatment response in patients with AD.
PATIENTS AND METHODS: We reviewed the medical records of 112 Taiwanese people with mild to moderate AD and at least 2 years of ChEI treatment between 2009 and 2016. Their baseline CMBs were quantified using the Microbleed Anatomical Rating Scale on SWMRI. Cognitive function of the patients was assessed using the Mini-Mental State Examination (MMSE) and Cognitive Abilities Screening Instrument (CASI). Student t test and multivariable logistic regression were used to analyze the association between cognitive decline and CMBs.
RESULTS: The mean age of the study population was 76.0 ± 8.0 years. In total, 79 out of 112 patients were women. The presence of deep, but not lobar CMBs at baseline was associated with a significant cognitive decline according to the MMSE and CASI, particularly in long-term memory, attention, orientation, mental manipulation, and verbal fluency. Among deep CMBs, those in the basal ganglia and thalamus were significantly associated with cognitive decline.
CONCLUSIONS: Deep CMBs, particularly those in the basal ganglia and thalamus, but not lobar CMBs, are associated with poor response to ChEI treatment in people with AD. This can serve as a biomarker for predicting ChEI treatment response.}, }
@article {pmid32479249, year = {2020}, author = {Mazza, M and Marano, G and Traversi, G and Sani, G and Janiri, L}, title = {Evidence on the New Drug Lumateperone (ITI-007) for Psychiatric and Neurological Disorders.}, journal = {CNS & neurological disorders drug targets}, volume = {19}, number = {4}, pages = {243-247}, doi = {10.2174/1871527319666200601145653}, pmid = {32479249}, issn = {1996-3181}, abstract = {Lumateperone (ITI-007) is a tosylate salt with binding affinities to receptors implicated in the therapeutic actions of antipsychotic medications, including the serotonin 5HT2A receptors, dopamine D2 and D1 receptors and the serotonin transporter. It has a unique mechanism of action because it simultaneously modulates serotonin, dopamine, and glutamate neurotransmission, implicated in serious mental illness. It can be considered a multi-target-directed ligand and a multifunctional modulator of serotoninergic system with possible precognitive, antipsychotic, antidepressant and anxiolytic properties. Lumateperone has been investigated as a novel agent for the treatment of schizophrenia, but it represents a new potential option for other psychiatric and neurological diseases, such as behavioural symptoms of dementia or Alzheimer's disease, sleep disturbances, bipolar depression. Besides, it has demonstrated a favourable safety profile without significant extrapyramidal side effects, hyperprolactinemia or changes in cardiometabolic or endocrine factors versus placebo. Additional studies are warranted to confirm and examine the benefit of lumateperone and possible therapeutic targets. This paper is a comprehensive and thorough summary of the most important findings and potential future role of this particular compound in personalized treatments.}, }
@article {pmid32474901, year = {2020}, author = {de Oliveira, FF and Chen, ES and Smith, MC and Bertolucci, PHF}, title = {Selected LDLR and APOE Polymorphisms Affect Cognitive and Functional Response to Lipophilic Statins in Alzheimer's Disease.}, journal = {Journal of molecular neuroscience : MN}, volume = {70}, number = {10}, pages = {1574-1588}, doi = {10.1007/s12031-020-01588-7}, pmid = {32474901}, issn = {1559-1166}, support = {1067/10//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; 2015/10109-5//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; 2015/18125-0//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; }, mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/*genetics ; Apolipoproteins E/*genetics ; *Cognition ; Epistasis, Genetic ; Female ; Haplotypes ; Heterozygote ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/*therapeutic use ; Hypercholesterolemia/drug therapy/*genetics ; Male ; *Polymorphism, Single Nucleotide ; Receptors, LDL/*genetics ; Treatment Outcome ; }, abstract = {Effects of statins over clinical changes in Alzheimer's disease (AD) are usually non-significant, but epistatic interactions between genetic variants involved in cholesterol metabolism could be important for such effects. We aimed to investigate whether LDLR single-nucleotide polymorphisms rs11669576 (LDLR8), rs5930 (LDLR10), and rs5925 (LDLR13) are associated with cognitive and functional changes in AD, while also considering APOE haplotypes and lipid-lowering treatment with lipophilic statins for stratification. Consecutive outpatients with late-onset AD were screened with cognitive tests, while caregivers scored functionality and caregiver burden, with prospective neurotranslational correlations documented for 1 year. For 179 patients, minor allele frequencies were 0.078 for rs11669576-A (14.5% heterozygotes), 0.346 for rs5930-A (42.5% heterozygotes), and 0.444 for rs5925-C (56.4% heterozygotes), all in Hardy-Weinberg equilibrium; 134 patients had hypercholesterolemia, and 133 used lipophilic statins. Carriers of rs11669576-G had faster cognitive decline, while functional decline was slower for carriers of rs11669576-A who used lipophilic statins. APOE-ε4 carriers who also carried rs5930-AA had improved caregiver burden, while carriers of haplotypes that included rs5930-AG had worse cognitive and functional outcomes, though carriers of the A allele of rs5930 had better cognitive and functional response to lipophilic statins. APOE-ε4 non-carriers who carried rs5925-TT had slower cognitive decline, while lipophilic statins protected carriers of the other genotypes. We preliminarily conclude that reportedly protective variants of LDLR and APOE against risk of AD also slowed cognitive decline, regardless of cholesterol variations, while therapy with lipophilic statins might benefit carriers of specific genetic variants.}, }
@article {pmid32468465, year = {2020}, author = {Revi, M}, title = {Alzheimer's Disease Therapeutic Approaches.}, journal = {Advances in experimental medicine and biology}, volume = {1195}, number = {}, pages = {105-116}, pmid = {32468465}, issn = {0065-2598}, mesh = {Alzheimer Disease/*drug therapy/metabolism/pathology ; Amyloid beta-Peptides ; Brain/metabolism/pathology ; Humans ; Neurofibrillary Tangles ; Plaque, Amyloid ; tau Proteins ; }, abstract = {Alzheimer's disease (AD) was first described and diagnosed by Dr. Alois Alzheimer in 1906 (Hippius and Neundorfer, Dialogues Clin Neurosc 5:101-108, 2003). According to World Health Organization (WHO), AD is the most common cause of dementia, accounting for as many as 60-70% of senile dementia cases and affecting 47.5 million people worldwide (data from 2015) (Dementia Fact Sheet No 362. http://who.int/mediacentre/factsheets/fs362/en/). The median survival time after the onset of dementia ranges from 3.3 to 11.7 years (Todd et al. Int J Geriatr Psychiatry 28:1109-1124, 2013). AD is characterized as a severe, chronic, incurable, and progressive neurodegenerative disorder, associated with memory loss and cognition impairment accompanied by abnormal behavior and personality changes (Godyn et al. Pharmacol Rep 68:127-138, 2016). AD is characterized by neuronal death, which usually correlates with the appearance of key neuropathological changes, including acetylcholine deficiency, glutamate excitotoxicity, extracellular deposition of β-amyloid (Aβ plaques), intracellular neurofibrillary tangles by hyperphosphorylated tau protein deposits, neuroinflammation, and widespread neuronal loss (Godyn et al. Pharmacol Rep 68:127-138, 2016; Graham et al. Annu Rev. Med 68:413-430, 2017). The discovery of the degeneration of cholinergic neurons and the reduction of acetylcholine levels in postmortem studies of patients resulted in the use of drugs that leads to the increase of acetylcholine levels in brain (Dubois et al. Lacet Neurol 13:614-629, 2014). At present there is no preventative or curative treatment that interferes with the development of the disease. However, in recent years progress was made in the development of cholinergic drugs which have a positive effect on disease progression. Nowadays, specific drugs that can inhibit the enzyme that degrades acetylcholine are used. The development of new effective drugs involves a difficult and time-consuming process, accompanied by a very high failure rate. In the absence of effective therapies, the estimated number of people with dementia will reach 115 to 131, five million by 2050 (Dubois et al. Lacet Neurol 13:614-629, 2014; Cummings et al. Alzheimers Res Ther 6:37, 2014). Novel therapies and new targets required for developing more effective drugs for the treatment of AD patients are urgently needed.}, }
@article {pmid32467645, year = {2020}, author = {Ghatak, S and Dolatabadi, N and Gao, R and Wu, Y and Scott, H and Trudler, D and Sultan, A and Ambasudhan, R and Nakamura, T and Masliah, E and Talantova, M and Voytek, B and Lipton, SA}, title = {NitroSynapsin ameliorates hypersynchronous neural network activity in Alzheimer hiPSC models.}, journal = {Molecular psychiatry}, volume = {}, number = {}, pages = {}, pmid = {32467645}, issn = {1476-5578}, support = {DP1 DA041722/DA/NIDA NIH HHS/United States ; R01 AG056259/AG/NIA NIH HHS/United States ; R01 GM134363/GM/NIGMS NIH HHS/United States ; RF1 AG057409/AG/NIA NIH HHS/United States ; R01 GM134363/GM/NIGMS NIH HHS/United States ; }, abstract = {Beginning at early stages, human Alzheimer's disease (AD) brains manifest hyperexcitability, contributing to subsequent extensive synapse loss, which has been linked to cognitive dysfunction. No current therapy for AD is disease-modifying. Part of the problem with AD drug discovery is that transgenic mouse models have been poor predictors of potential human treatment. While it is undoubtedly important to test drugs in these animal models, additional evidence for drug efficacy in a human context might improve our chances of success. Accordingly, in order to test drugs in a human context, we have developed a platform of physiological assays using patch-clamp electrophysiology, calcium imaging, and multielectrode array (MEA) experiments on human (h)iPSC-derived 2D cortical neuronal cultures and 3D cerebral organoids. We compare hiPSCs bearing familial AD mutations vs. their wild-type (WT) isogenic controls in order to characterize the aberrant electrical activity in such a human context. Here, we show that these AD neuronal cultures and organoids manifest increased spontaneous action potentials, slow oscillatory events (~1 Hz), and hypersynchronous network activity. Importantly, the dual-allosteric NMDAR antagonist NitroSynapsin, but not the FDA-approved drug memantine, abrogated this hyperactivity. We propose a novel model of synaptic plasticity in which aberrant neural networks are rebalanced by NitroSynapsin. We propose that hiPSC models may be useful for screening drugs to treat hyperexcitability and related synaptic damage in AD.}, }
@article {pmid32466248, year = {2020}, author = {Ornoy, A and Becker, M and Weinstein-Fudim, L and Ergaz, Z}, title = {S-Adenosine Methionine (SAMe) and Valproic Acid (VPA) as Epigenetic Modulators: Special Emphasis on their Interactions Affecting Nervous Tissue during Pregnancy.}, journal = {International journal of molecular sciences}, volume = {21}, number = {10}, pages = {}, pmid = {32466248}, issn = {1422-0067}, mesh = {Animals ; Autism Spectrum Disorder/etiology/*genetics ; *Epigenesis, Genetic ; Female ; Humans ; Methionine/*adverse effects/analogs & derivatives ; Nervous System/drug effects/embryology ; Pregnancy ; Prenatal Exposure Delayed Effects/etiology/*genetics ; Valproic Acid/*adverse effects ; }, abstract = {S-adenosylmethionine (SAMe) is involved in many transmethylation reactions in most living organisms and is also required in the synthesis of several substances such as monoamine neurotransmitters and the N-methyl-D-aspartate (NMDA) receptor. Due to its important role as an epigenetic modulator, we discuss in some length the process of DNA methylation and demethylation and the critical periods of epigenetic modifications in the embryo, fetus, and thereafter. We also discuss the effects of SAMe deficiency and the attempts to use SAMe for therapeutic purposes such as the treatment of major depressive disorder, Alzheimer disease, and other neuropsychiatric disorders. SAMe is an approved food additive and as such is also used during pregnancy. Yet, there seems to scanty data on the possible effects of SAMe on the developing embryo and fetus. Valproic acid (VPA) is a well-tolerated and effective antiepileptic drug that is also used as a mood stabilizer. Due to its high teratogenicity, it is contraindicated in pregnancy. A major mechanism of its action is histone deacetylase inhibition, and therefore, it acts as an epigenetic modulator, mainly on the brain. This prompted clinical trials using VPA for additional indications i.e., treating degenerative brain disease such as Alzheimer disease, dementia, HIV, and even cancer. Therefore, we discuss the possible effects of VPA and SAMe on the conceptus and early postnatally, during periods of susceptibility to epigenetic modifications. VPA is also used as an inducer of autistic-like behavior in rodents and was found by us to modify gene expression when administered during the first postnatal week but not when administered to the pregnant dams on day 12 of gestation. In contrast, SAMe modified gene expression when administered on day 12 of pregnancy but not postnatally. If administered together, VPA prevented the changes in gene expression induced by prenatal SAMe administration, and SAMe prevented the gene expression changes and autistic-like behavior induced by early postnatal VPA. It is concluded that both VPA and SAMe are powerful epigenetic modifiers with antagonistic actions on the brain that will probably be used in the future more extensively for the treatment of a variety of epigenetic diseases of the nervous system.}, }
@article {pmid32463470, year = {2020}, author = {Maier, F and Spottke, A and Bach, JP and Bartels, C and Buerger, K and Dodel, R and Fellgiebel, A and Fliessbach, K and Frölich, L and Hausner, L and Hellmich, M and Klöppel, S and Klostermann, A and Kornhuber, J and Laske, C and Peters, O and Priller, J and Richter-Schmidinger, T and Schneider, A and Shah-Hosseini, K and Teipel, S and von Arnim, CAF and Wiltfang, J and Jessen, F}, title = {Bupropion for the Treatment of Apathy in Alzheimer Disease: A Randomized Clinical Trial.}, journal = {JAMA network open}, volume = {3}, number = {5}, pages = {e206027}, pmid = {32463470}, issn = {2574-3805}, mesh = {Aged ; Alzheimer Disease/drug therapy/*psychology ; Antidepressive Agents, Second-Generation/adverse effects/*therapeutic use ; Apathy/*drug effects ; Bupropion/adverse effects/*therapeutic use ; Double-Blind Method ; Female ; Humans ; Male ; Mental Status and Dementia Tests ; }, abstract = {Importance: Apathy is a frequent neuropsychiatric symptom in dementia of Alzheimer type and negatively affects the disease course and patients' and caregivers' quality of life. Effective treatment options are needed.
Objective: To examine the efficacy and safety of the dopamine and noradrenaline reuptake inhibitor bupropion in the treatment of apathy in patients with dementia of Alzheimer type.
This 12-week, multicenter, double-blind, placebo-controlled, randomized clinical trial was conducted in a psychiatric and neurological outpatient setting between July 2010 and July 2014 in Germany. Patients with mild-to-moderate dementia of Alzheimer type and clinically relevant apathy were included. Patients with additional clinically relevant depressed mood were excluded. Data analyses were performed between August 2018 and August 2019.
Interventions: Patients received either bupropion or placebo (150 mg for 4 weeks plus 300 mg for 8 weeks). In case of intolerability of 300 mg, patients continued to receive 150 mg throughout the study.
Main Outcomes and Measures: Change on the Apathy Evaluation Scale-Clinician Version (AES-C) (score range, 18-72 points) between baseline and week 12 was the primary outcome parameter. Secondary outcome parameters included measures of neuropsychiatric symptoms, cognition, activities of daily living, and quality of life. Outcome measures were assessed at baseline and at 4, 8, and 12 weeks.
Results: A total of 108 patients (mean [SD] age, 74.8 [5.9] years; 67 men [62%]) were included in the intention-to-treat analysis, with 54 randomized to receive bupropion and 54 randomized to receive placebo. The baseline AES-C score was comparable between the bupropion group and the placebo group (mean [SD], 52.2 [8.7] vs 50.4 [8.2]). After controlling for the baseline AES-C score, site, and comedication with donepezil or galantamine, the mean change in the AES-C score between the bupropion and placebo groups was not statistically significant (mean change, 2.22; 95% CI, -0.47 to 4.91; P = .11). Results on secondary outcomes showed statistically significant differences between bupropion and placebo in terms of total neuropsychiatric symptoms (mean change, 5.52; 95% CI, 2.00 to 9.04; P = .003) and health-related quality of life (uncorrected for multiple comparisons; mean change, -1.66; 95% CI, -3.01 to -0.31; P = .02) with greater improvement in the placebo group. No statistically significant changes between groups were found for activities of daily living (mean change, -2.92; 95% CI, -5.89 to 0.06; P = .05) and cognition (mean change, -0.27; 95% CI, -3.26 to 2.73; P = .86). The numbers of adverse events (bupropion group, 39 patients [72.2%]; placebo group, 33 patients [61.1%]) and serious adverse events (bupropion group, 5 patients [9.3%]; placebo group, 2 patients [3.7%]) were comparable between groups.
Conclusions and Relevance: Although it is safe, bupropion was not superior to placebo for the treatment of apathy in patients with dementia of Alzheimer type in the absence of clinically relevant depressed mood.
Trial Registration: EU Clinical Trials Register Identifier: 2007-005352-17.}, }
@article {pmid32459184, year = {2020}, author = {Thomas, NWD and Beattie, Z and Marcoe, J and Wright, K and Sharma, N and Mattek, N and Dodge, H and Wild, K and Kaye, J}, title = {An Ecologically Valid, Longitudinal, and Unbiased Assessment of Treatment Efficacy in Alzheimer Disease (the EVALUATE-AD Trial): Proof-of-Concept Study.}, journal = {JMIR research protocols}, volume = {9}, number = {5}, pages = {e17603}, pmid = {32459184}, issn = {1929-0748}, support = {KL2 TR002370/TR/NCATS NIH HHS/United States ; R01 AG043398/AG/NIA NIH HHS/United States ; UL1 TR002369/TR/NCATS NIH HHS/United States ; U2C AG054397/AG/NIA NIH HHS/United States ; R01 AG024059/AG/NIA NIH HHS/United States ; P30 AG008017/AG/NIA NIH HHS/United States ; U01 AG010483/AG/NIA NIH HHS/United States ; R01 AG056102/AG/NIA NIH HHS/United States ; U2C AG057441/AG/NIA NIH HHS/United States ; R01 AG033581/AG/NIA NIH HHS/United States ; P01 AG043362/AG/NIA NIH HHS/United States ; R01 AG051628/AG/NIA NIH HHS/United States ; P30 AG024978/AG/NIA NIH HHS/United States ; P30 AG066518/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: The current clinical trial assessment methodology relies on a combination of self-report measures, cognitive and physical function tests, and biomarkers. This methodology is limited by recall bias and recency effects in self-reporting and by assessments that are brief, episodic, and clinic based. Continuous monitoring of ecologically valid measures of cognition and daily functioning in the community may provide a more sensitive method to detect subtle, progressive changes in patients with cognitive impairment and dementia.
OBJECTIVE: This study aimed to present an alternative trial approach using a home-based sensing and computing system to detect changes related to common treatments employed in Alzheimer disease (AD). This paper introduces an ongoing study that aims to determine the feasibility of capturing sensor-based data at home and to compare the sensor-based outcomes with conventional outcomes. We describe the methodology used in the assessment protocol and present preliminary results of feasibility measures and examples of data related to medication-taking behavior, activity levels, and sleep.
METHODS: The EVALUATE-AD (Ecologically Valid, Ambient, Longitudinal and Unbiased Assessment of Treatment Efficacy in Alzheimer's Disease) trial is a longitudinal naturalistic observational cohort study recruiting 30 patients and 30 spouse coresident care partners. Participants are monitored continuously using a home-based sensing and computing system for up to 24 months. Outcome measures of the automated system are compared with conventional clinical outcome measures in AD. Acceptance of the home system and protocol are assessed by rates of dropout and protocol adherence. After completion of the study monitoring period, a composite model using multiple functional outcome measures will be created that represents a behavioral-activity signature of initiating or discontinuing AD-related medications, such as cholinesterase inhibitors, memantine, or antidepressants.
RESULTS: The home-based sensing and computing system has been well accepted by individuals with cognitive impairment and their care partners. Participants showed good adherence to the completion of a weekly web-based health survey. Daily activity, medication adherence, and total time in bed could be derived from algorithms using data from the sensing and computing system. The mean monitoring time for current participants was 14.6 months. Medication adherence, as measured with an electronic pillbox, was 77% for participants taking AD-related medications.
CONCLUSIONS: Continuous, home-based assessment provides a novel approach to test the impact of new or existing dementia treatments generating objective, clinically meaningful measures related to cognition and everyday functioning. Combining this approach with the current clinical trial methodology may ultimately reduce trial durations, sample size needs, and reliance on a clinic-based assessment.
DERR1-10.2196/17603.}, }
@article {pmid32457210, year = {2020}, author = {Yin, J and Reiman, EM and Beach, TG and Serrano, GE and Sabbagh, MN and Nielsen, M and Caselli, RJ and Shi, J}, title = {Effect of ApoE isoforms on mitochondria in Alzheimer disease.}, journal = {Neurology}, volume = {94}, number = {23}, pages = {e2404-e2411}, pmid = {32457210}, issn = {1526-632X}, support = {U24 NS072026/NS/NINDS NIH HHS/United States ; }, mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/genetics/*metabolism/psychology ; Apolipoprotein E4/genetics/physiology ; Apolipoproteins E/*physiology ; Brain Chemistry ; Female ; Humans ; Male ; Mental Status and Dementia Tests ; Mitochondria/*metabolism/ultrastructure ; Mitochondrial Dynamics ; Mitochondrial Proteins/analysis ; Nerve Tissue Proteins/analysis ; Neuronal Plasticity/genetics ; Organelle Biogenesis ; Oxidative Stress ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/analysis ; Protein Isoforms/physiology ; Sirtuin 3/analysis ; Verbal Learning ; }, abstract = {OBJECTIVE: To test the hypothesis that ApoE isoforms affect mitochondrial structure and function that are related to cognitive impairment in Alzheimer disease (AD), we systematically investigated the effects of ApoE isoforms on mitochondrial biogenesis and dynamics, oxidative stress, synapses, and cognitive performance in AD.
METHODS: We obtained postmortem human brain tissues and measured proteins that are responsible for mitochondrial biogenesis (peroxisome proliferator-activated receptor-gamma coactivator-1α [PGC-1α] and sirtuin 3 [SIRT3]), for mitochondrial dynamics (mitofusin 1 [MFN1], mitofusin 2 [MFN2], and dynamin-like protein 1 [DLP1]), for oxidative stress (superoxide dismutase 2 [SOD2] and forkhead-box protein O3a [Foxo3a]), and for synapses (postsynaptic density protein 95 [PSD95] and synapsin1 [Syn1]). A total of 46 cases were enrolled, including ApoE-ɛ4 carriers (n = 21) and noncarriers (n = 25).
RESULTS: Levels of these proteins were compared between ApoE-ɛ4 carriers and noncarriers. ApoE-ɛ4 was associated with impaired mitochondrial structure and function, oxidative stress, and synaptic integrity in the human brain. Correlation analysis revealed that mitochondrial proteins and the synaptic protein were strongly associated with cognitive performance.
CONCLUSION: ApoE isoforms influence mitochondrial structure and function, which likely leads to alteration in oxidative stress, synapses, and cognitive function. These mitochondria-related proteins may be a harbinger of cognitive decline in ApoE-ɛ4 carriers and provide novel therapeutic targets for prevention and treatment of AD.}, }
@article {pmid32456229, year = {2020}, author = {Obrenovich, M and Jaworski, H and Tadimalla, T and Mistry, A and Sykes, L and Perry, G and Bonomo, RA}, title = {The Role of the Microbiota-Gut-Brain Axis and Antibiotics in ALS and Neurodegenerative Diseases.}, journal = {Microorganisms}, volume = {8}, number = {5}, pages = {}, pmid = {32456229}, issn = {2076-2607}, abstract = {: The human gut hosts a wide and diverse ecosystem of microorganisms termed the microbiota, which line the walls of the digestive tract and colon where they co-metabolize digestible and indigestible food to contribute a plethora of biochemical compounds with diverse biological functions. The influence gut microbes have on neurological processes is largely yet unexplored. However, recent data regarding the so-called leaky gut, leaky brain syndrome suggests a potential link between the gut microbiota, inflammation and host co-metabolism that may affect neuropathology both locally and distally from sites where microorganisms are found. The focus of this manuscript is to draw connection between the microbiota-gut-brain (MGB) axis, antibiotics and the use of "BUGS AS DRUGS" for neurodegenerative diseases, their treatment, diagnoses and management and to compare the effect of current and past pharmaceuticals and antibiotics for alternative mechanisms of action for brain and neuronal disorders, such as Alzheimer disease (AD), Amyotrophic Lateral Sclerosis (ALS), mood disorders, schizophrenia, autism spectrum disorders and others. It is a paradigm shift to suggest these diseases can be largely affected by unknown aspects of the microbiota. Therefore, a future exists for applying microbial, chemobiotic and chemotherapeutic approaches to enhance translational and personalized medical outcomes. Microbial modifying applications, such as CRISPR technology and recombinant DNA technology, among others, echo a theme in shifting paradigms, which involve the gut microbiota (GM) and mycobiota and will lead to potential gut-driven treatments for refractory neurologic diseases.}, }
@article {pmid32439028, year = {2020}, author = {Nowrangi, MA}, title = {Neuropsychiatric Aspects of Alzheimer Dementia: From Mechanism to Treatment.}, journal = {The Psychiatric clinics of North America}, volume = {43}, number = {2}, pages = {383-397}, doi = {10.1016/j.psc.2020.02.012}, pmid = {32439028}, issn = {1558-3147}, support = {K23 AG055626/AG/NIA NIH HHS/United States ; }, mesh = {Aggression ; Alzheimer Disease/*therapy ; Apathy ; Depression/therapy ; Disease Progression ; Humans ; Neuropsychological Tests ; Psychomotor Agitation/therapy ; }, abstract = {Developing disease-modifying treatments for Alzheimer dementia requires innovative approaches to identify novel biological targets during the course of the disease. Treatment development for the neuropsychiatric symptoms of Alzheimer may benefit from a mechanistic approach to treatment. There has been progress in identifying mild forms of behavioral impairment along the Alzheimer spectrum that may lead to additional insights into progression to dementia as well as the fundamental mechanisms of the symptoms. Developing therapies for complex neurobehavioral syndromes may require the translation of mechanistic insights into therapy, which may both improve the symptoms and delay progression to dementia in certain patients.}, }
@article {pmid32434685, year = {2020}, author = {Vicario, A and Cerezo, GH}, title = {[The cognitive-behavioural impact of hypertension].}, journal = {Hipertension y riesgo vascular}, volume = {37}, number = {3}, pages = {125-132}, doi = {10.1016/j.hipert.2020.04.003}, pmid = {32434685}, issn = {1989-4805}, mesh = {Aged ; Alzheimer Disease/etiology/physiopathology ; Cognitive Dysfunction/*etiology/physiopathology ; Dementia/*etiology/physiopathology ; Humans ; Hypertension/*complications/physiopathology/psychology ; Prognosis ; Risk Factors ; }, abstract = {Arterial hypertension is considered the main modifiable vascular risk factor that causes silent damage to brain vessels. This vascular brain injury could be the common nucleus that justifies the cognitive (cognitive impairment, dementia and Alzheimer's disease) and behavioural symptoms (late-life depression) of target organ damage mediated-hypertension. Incomplete knowledge about the complex pathophysiology that links hypertension with cognitive-behavioural changes is overlooking brain involvement and underestimating cardio and cerebrovascular risk. The confluence of cognitive impairment, depression and arterial hypertension in elderly adults, warns of the need for a comprehensive evaluation to plan treatment, improve prognosis and contribute to reducing the risk of dementia and its incidence.}, }
@article {pmid32434047, year = {2020}, author = {Peters, C and Bascuñán, D and Burgos, CF and Bobadilla, C and González-Sanmiguel, J and Boopathi, S and Riffo, N and Fernández-Pérez, EJ and Tarnok, ME and Aguilar, LF and Gonzalez, W and Aguayo, LG}, title = {Characterization of a new molecule capable of inhibiting several steps of the amyloid cascade in Alzheimer's disease.}, journal = {Neurobiology of disease}, volume = {141}, number = {}, pages = {104938}, doi = {10.1016/j.nbd.2020.104938}, pmid = {32434047}, issn = {1095-953X}, mesh = {Alzheimer Disease/*metabolism ; Amyloid beta-Peptides/*metabolism ; Animals ; Computer Simulation ; Hippocampus/drug effects/metabolism ; Mitochondria/drug effects/metabolism ; Molecular Docking Simulation ; Neurons/drug effects/metabolism ; Neuroprotective Agents/*administration & dosage ; PC12 Cells ; Protein Aggregation, Pathological/metabolism/*prevention & control ; Rats ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder in elderly people. Existent therapies are directed at alleviating some symptoms, but are not effective in altering the course of the disease.
METHODS: Based on our previous study that showed that an Aβ-interacting small peptide protected against the toxic effects of amyloid-beta peptide (Aβ), we carried out an array of in silico, in vitro, and in vivo assays to identify a molecule having neuroprotective properties.
RESULTS: In silico studies showed that the molecule, referred to as M30 (2-Octahydroisoquinolin-2(1H)-ylethanamine), was able to interact with the Aβ peptide. Additionally, in vitro assays showed that M30 blocked Aβ aggregation, association to the plasma membrane, synaptotoxicity, intracellular calcium, and cellular toxicity, while in vivo experiments demonstrated that M30 induced a neuroprotective effect by decreasing the toxicity of Aβ in the dentate gyrus of the hippocampus and improving the alteration in spatial memory in behavior assays.
DISCUSSION: Therefore, we propose that this new small molecule could be a useful candidate for the additional development of a treatment against AD since it appears to block multiple steps in the amyloid cascade. Overall, since there are no drugs that effectively block the progression of AD, this approach represents an innovative strategy.
SIGNIFICANCE: Currently, there is no effective treatment for AD and the expectations to develop an effective therapy are low. Using in silico, in vitro, and in vivo experiments, we identified a new compound that is able to inhibit Aβ-induced neurotoxicity, specifically aggregation, association to neurons, synaptic toxicity, calcium dyshomeostasis and memory impairment induced by Aβ. Because Aβ toxicity is central to AD progression, the inhibition mediated by this new molecule might be useful as a therapeutic tool.}, }
@article {pmid32433996, year = {2020}, author = {Muñoz, P and Ardiles, ÁO and Pérez-Espinosa, B and Núñez-Espinosa, C and Paula-Lima, A and González-Billault, C and Espinosa-Parrilla, Y}, title = {Redox modifications in synaptic components as biomarkers of cognitive status, in brain aging and disease.}, journal = {Mechanisms of ageing and development}, volume = {189}, number = {}, pages = {111250}, doi = {10.1016/j.mad.2020.111250}, pmid = {32433996}, issn = {1872-6216}, mesh = {Animals ; Biomarkers/metabolism ; Brain/*metabolism/pathology ; Brain Diseases/*metabolism/pathology ; *Cognition ; *Gene Expression Regulation ; Humans ; MicroRNAs/*biosynthesis ; Oxidation-Reduction ; Synapses/*metabolism/pathology ; }, abstract = {Aging is a natural process that includes several changes that gradually make organisms degenerate and die. Harman's theory proposes that aging is a consequence of the progressive accumulation of oxidative modifications mediated by reactive oxygen/nitrogen species, which plays an essential role in the development and progression of many neurodegenerative diseases. This review will focus on how abnormal redox modifications induced by age impair the functionality of neuronal redox-sensitive proteins involved in axonal elongation and guidance, synaptic plasticity, and intercellular communication. We will discuss post-transcriptional regulation of gene expression by microRNAs as a mechanism that controls the neuronal redox state. Finally, we will discuss how some brain-permeant antioxidants from the diet have a beneficial effect on cognition. Taken together, the evidence revised here indicates that oxidative-driven modifications of specific proteins and changes in microRNA expression may be useful biomarkers for aging and neurodegenerative diseases. Also, some specific antioxidant therapies have undoubtedly beneficial neuroprotective effects when admini