@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 = {}, number = {}, pages = {}, doi = {10.1007/s00709-020-01534-9}, pmid = {32651872}, issn = {1615-6102}, support = {031B0065A//Bundesministerium für Bildung und Forschung/ ; }, 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}, 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 {pmid32649324, year = {2020}, author = {Schipke, CG and Menne, F and Rubow, S and Sigle, JP and Peters, O and Grimmer, T}, title = {Value of a Panel of 6 Serum Biomarkers to Differentiate between Healthy Controls and Mild Cognitive Impairment Due to Alzheimer Disease.}, journal = {Alzheimer disease and associated disorders}, volume = {}, number = {}, pages = {}, doi = {10.1097/WAD.0000000000000397}, pmid = {32649324}, issn = {1546-4156}, abstract = {BACKGROUND: There is considerable evidence suggesting that inflammatory responses may be involved in the neurodegenerative cascade of Alzheimer disease (AD). Blood-based biomarker analysis of inflammatory markers indicative of dementia could serve as a minimally invasive and easy-to-administer diagnostic tool in primary care.

MATERIAL AND METHODS: The authors quantified 6 markers (brain-derived neurotrophic factor, insulin-like growth factor 1, vascular endothelial growth factor, transforming growth factor-beta type 1, monocyte chemoattractant protein 1, and interleukin-18) in blood serum of 68 healthy blood donors (controls), 42 patients with AD at the dementia stage, 55 patients with AD at the stage of mild cognitive impairment (MCI-AD), and 25 patients with MCI non-AD. All patients have been fully characterized, including AD biomarker analyses in cerebrospinal fluid. Data were analyzed in an algorithm that was trained, validated, and then used for dichotomous classification of unknown data into data sets suspicious and not suspicious of AD.

RESULTS: Using this algorithm, 47 of 55 MCI-AD (85.5%) and 20 of 25 MCI non-AD (80%) cases were classified as suspicious of AD.

CONCLUSIONS: This panel of 6 markers in blood serum may indicate underlying neurodegenerative processes in patients with AD at the MCI stage. The authors assume that a deranged equilibrium of neuroprotective and inflammatory processes is an overall major cause for neurodegeneration and cognitive decline.}, } @article {pmid32648923, year = {2020}, author = {Koch, M and DeKosky, ST and Goodman, M and Sun, J and Furtado, JD and Fitzpatrick, AL and Mackey, RH and Cai, T and Lopez, OL and Kuller, LH and Mukamal, KJ and Jensen, MK}, title = {Association of Apolipoprotein E in Lipoprotein Subspecies With Risk of Dementia.}, journal = {JAMA network open}, volume = {3}, number = {7}, pages = {e209250}, doi = {10.1001/jamanetworkopen.2020.9250}, pmid = {32648923}, issn = {2574-3805}, abstract = {Importance: The ε4 allele of the apolipoprotein E (APOE) gene and lower apolipoprotein E (apoE) protein levels in plasma are risk factors for Alzheimer disease, but the underlying biological mechanisms are not fully understood. Half of plasma apoE circulates on high-density lipoproteins (HDLs). Higher apoE levels in plasma HDL were previously found to be associated with lower coronary heart disease risk, but the coexistence of another apolipoprotein, apoC3, modified this lower risk.

Objective: To investigate associations between the presence of apoE in different lipoproteins with cognitive function, particularly the risk of dementia.

This prospective case-cohort study embedded in the Ginkgo Evaluation of Memory Study (2000-2008) analyzed data from 1351 community-dwelling participants 74 years and older. Of this group, 995 participants were free of dementia at baseline (recruited from September 2000 to June 2002) and 521 participants were diagnosed with incident dementia during follow-up until 2008. Data analysis was performed from January 2018 to December 2019.

Exposures: Enzyme-linked immunosorbent assay-measured concentration of apoE in whole plasma, HDL-depleted plasma (non-HDL), HDL, and HDL subspecies that contain or lack apoC3 or apoJ.

Main Outcomes and Measures: Adjusted hazard ratios for risk of dementia and Alzheimer disease during follow-up and adjusted differences (β coefficients) in Alzheimer Disease Assessment-Cognitive Subscale (ADAS-cog) and Modified Mini-Mental State Examination scores at baseline.

Results: Among 1351 participants, the median (interquartile range) age was 78 (76-81) years; 639 (47.3%) were women. The median (interquartile range) follow-up time was 5.9 (3.7-6.5) years. Higher whole plasma apoE levels and higher apoE levels in HDL were associated with better cognitive function assessed by ADAS-cog (whole plasma, β coefficient, -0.15; 95% CI, -0.24 to -0.06; HDL, β coefficient, -0.20; 95% CI, -0.30 to -0.10) but were unassociated with dementia or Alzheimer disease risk. When separated by apoC3, a higher apoE level in HDL that lacks apoC3 was associated with better cognitive function (ADAS-cog per SD: β coefficient, 0.17; 95% CI, -0.27 to -0.07; Modified Mini-Mental State Examination score per SD: β coefficient, 0.25; 95% CI, 0.07 to 0.42) and lower risk of dementia (hazard ratio per SD, 0.86; 95% CI, 0.76 to 0.99). In contrast, apoE levels in HDL that contains apoC3 were unassociated with any of these outcomes.

Conclusions and Relevance: In a prospective cohort of older adults with rigorous follow-up of dementia, the apoE level in HDL that lacked apoC3 was associated with better cognitive function and lower dementia risk. This finding suggests that the cardioprotective associations of this novel lipoprotein extend to dementia.}, } @article {pmid32648626, year = {2020}, author = {Sušjan, P and Lainšček, D and Strmšek, Ž and Hodnik, V and Anderluh, G and Hafner-Bratkovič, I}, title = {Selective inhibition of NLRP3 inflammasome by designed peptide originating from ASC.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {}, number = {}, pages = {}, doi = {10.1096/fj.201902938RR}, pmid = {32648626}, issn = {1530-6860}, support = {ICGEB grant CRP-SVN18-01//International Centre for Genetic Engineering and Biotechnology (ICGEB)/ ; J3-5503//Slovenian Research Agency/ ; J3-6791//Slovenian Research Agency/ ; J3-1746//Slovenian Research Agency/ ; Z3-9276//Slovenian Research Agency/ ; P4-176//Core funding/ ; }, abstract = {NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome is a multiprotein complex which forms within cells in response to various microbial and self-derived triggers. Mutations in the gene encoding NLRP3 cause rare cryopyrin-associated periodic syndromes (CAPS) and growing evidence links NLRP3 inflammasome to common diseases such as Alzheimer´s disease. In order to modulate different stages of NLRP3 inflammasome assembly nine peptides whose sequences correspond to segments of inflammasome components NLRP3 and apoptosis-associated speck-like protein containing a CARD (ASC) were selected. Five peptides inhibited IL-1β release, caspase-1 activation and ASC oligomerization in response to soluble and particulate NLRP3 triggers. Modulatory peptides also attenuated IL-1β maturation induced by constitutive CAPS-associated NLRP3 mutants. Peptide corresponding to H2-H3 segment of ASC pyrin domain selectively inhibited NLRP3 inflammasome by binding to NLRP3 pyrin domain in the micromolar range. The peptide had no effect on AIM2 and NLRC4 inflammasomes as well as NF-κB pathway. The peptide effectively dampened neutrophil infiltration in the silica-induced peritonitis and when equipped with Antennapedia or Angiopep-2 motifs crossed the blood-brain barrier in a mouse model. Our study demonstrates that peptides represent an important tool for targeting multiprotein inflammatory complexes and can serve as the basis for the development of novel anti-inflammatory strategies for neurodegeneration.}, } @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 = {}, number = {}, pages = {}, doi = {10.1111/jcmm.15555}, pmid = {32648620}, issn = {1582-4934}, support = {81671262//National Nature Scientific Fund of China/ ; 81601123//National Nature Scientific Fund of China/ ; 81401062//National Nature Scientific Fund of China/ ; }, 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 {pmid32647856, year = {2020}, author = {Rendina, A and Drongitis, D and Donizetti, A and Fucci, L and Milan, G and Tripodi, F and Giustezza, F and Postiglione, A and Pappatà, S and Ferrari, R and Bossù, P and Angiolillo, A and di Costanzo, A and Caiazzo, M and Vitale, E}, title = {CD33 and SIGLECL1 Immunoglobulin Superfamily Involved in Dementia.}, journal = {Journal of neuropathology and experimental neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnen/nlaa055}, pmid = {32647856}, issn = {1554-6578}, abstract = {Sialic acid-binding immunoglobulin-type lectins, which are predominantly expressed in immune cells, represent a family of immunomodulatory receptors with inhibitory and activating signals, in both healthy and disease states. Genetic factors are important in all forms of dementia, especially in early onset dementia. CD33 was recently recognized as a genetic risk factor for Alzheimer disease (AD). Here, we present a 2-generation family with 4 members, the father and the 3 siblings, characterized by an early form of unusual dementia exhibiting a behavioral variant close to behavioral variant frontotemporal dementia phenotype and severe forms of memory loss suggestive of AD. We analyzed the CD33 gene in this family and identified 10 single nucleotide polymorphisms (SNPs) in a linkage disequilibrium block associated with the disease. We also identified a tag SNP, rs2455069-A>G, in CD33 exon 2 that could be involved with dementia risk. Additionally, we excluded the presence of C9orf72 expansion mutations and other mutations previously associated with sporadic FTD and AD. The tag SNP association was also analyzed in selected sporadic AD patients from the same Southern Italy region. We demonstrate that CD33 and SIGLECL1 have a significantly increased level of expression in these patients.}, } @article {pmid32647257, year = {2020}, author = {Alić, I and Goh, PA and Murray, A and Portelius, E and Gkanatsiou, E and Gough, G and Mok, KY and Koschut, D and Brunmeir, R and Yeap, YJ and O'Brien, NL and Groet, J and Shao, X and Havlicek, S and Dunn, NR and Kvartsberg, H and Brinkmalm, G and Hithersay, R and Startin, C and Hamburg, S and Phillips, M and Pervushin, K and Turmaine, M and Wallon, D and Rovelet-Lecrux, A and Soininen, H and Volpi, E and Martin, JE and Foo, JN and Becker, DL and Rostagno, A and Ghiso, J and Krsnik, Ž and Šimić, G and Kostović, I and Mitrečić, D and , and Francis, PT and Blennow, K and Strydom, A and Hardy, J and Zetterberg, H and Nižetić, D}, title = {Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain.}, journal = {Molecular psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41380-020-0806-5}, pmid = {32647257}, issn = {1476-5578}, support = {0000000//Fondation pour la Recherche Médicale (Foundation for Medical Research in France)/ ; NRF-NRFF2016-03//National Research Foundation Singapore (National Research Foundation-Prime Minister's office, Republic of Singapore)/ ; A2015275S//BrightFocus Foundation (BrightFocus)/ ; A2015275S//BrightFocus Foundation (BrightFocus)/ ; AG059695//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; AG059695//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; #2017-00915//Svenska Forskningsrådet Formas (Swedish Research Council Formas)/ ; 098330/Z/12/Z//Wellcome Trust (Wellcome)/ ; 098330/Z/12/Z//Wellcome Trust (Wellcome)/ ; 098330/Z/12/Z//Wellcome Trust (Wellcome)/ ; }, abstract = {A population of more than six million people worldwide at high risk of Alzheimer's disease (AD) are those with Down Syndrome (DS, caused by trisomy 21 (T21)), 70% of whom develop dementia during lifetime, caused by an extra copy of β-amyloid-(Aβ)-precursor-protein gene. We report AD-like pathology in cerebral organoids grown in vitro from non-invasively sampled strands of hair from 71% of DS donors. The pathology consisted of extracellular diffuse and fibrillar Aβ deposits, hyperphosphorylated/pathologically conformed Tau, and premature neuronal loss. Presence/absence of AD-like pathology was donor-specific (reproducible between individual organoids/iPSC lines/experiments). Pathology could be triggered in pathology-negative T21 organoids by CRISPR/Cas9-mediated elimination of the third copy of chromosome 21 gene BACE2, but prevented by combined chemical β and γ-secretase inhibition. We found that T21 organoids secrete increased proportions of Aβ-preventing (Aβ1-19) and Aβ-degradation products (Aβ1-20 and Aβ1-34). We show these profiles mirror in cerebrospinal fluid of people with DS. We demonstrate that this protective mechanism is mediated by BACE2-trisomy and cross-inhibited by clinically trialled BACE1 inhibitors. Combined, our data prove the physiological role of BACE2 as a dose-sensitive AD-suppressor gene, potentially explaining the dementia delay in ~30% of people with DS. We also show that DS cerebral organoids could be explored as pre-morbid AD-risk population detector and a system for hypothesis-free drug screens as well as identification of natural suppressor genes for neurodegenerative diseases.}, } @article {pmid32647089, year = {2020}, author = {Jeong, JH and Lee, SE and Lee, JH and Kim, HD and Seo, KH and Kim, DH and Han, SY}, title = {Aster ageratoides Turcz. extract attenuates Alzheimer's disease-associated cognitive deficits and vascular dementia-associated neuronal death.}, journal = {Anatomy & cell biology}, volume = {53}, number = {2}, pages = {216-227}, doi = {10.5115/acb.20.011}, pmid = {32647089}, issn = {2093-3665}, abstract = {Dementia is the common neurodegenerative disorder affecting the elderly, with a progressive cognitive decline and memory loss. Since Alzheimer's disease (AD) and vascular dementia (VD) share key pathologies including oxidative damage, oral supplement of phytochemical medicines, which are well-known for their antioxidant properties, can be a viable therapy for both types of dementia. In this study, the therapeutic potential of the Aster ageratoides extract (AAE), an oriental drug with multiple medicinal properties, was tested on experimental rat models of AD and VD. After confirming the in vitro attenuation of neuronal excitotoxicity by AAE, rats were orally administered with AAE for 7 days and subsequently tested under 2 different experimental paradigms: efficacy screening against #1 AD and #2 VD. For paradigm #1, the rats received intraperitoneal scopolamine and subsequently underwent 3 different behavior tests i.e., the Y-maze, novel object recognition, and passive avoidance tests. For paradigm #2, the rats were operated with the 2-vessel occlusion and hypovolemia (2VO/H) technique, and at postoperative day 7, their hippocampal neuronal viability and the neuroinflammatory changes were quantified. The results showed that the scopolamine-induced impairment of memory performance was significantly improved by AAE intake. Furthermore, while the 2VO/H operation induced marked hippocampal neuronal death and microglial activation, both these effects were significantly attenuated by AAE supplements. Some of the aforementioned effects of AAE intake were dose-dependent. These results provided evidence that AAE supplements can exert anti-AD and -VD efficacies and suggested that AAE might be used as an edible phytotherapeutic for the 2 major types of dementia.}, } @article {pmid32646634, year = {2020}, author = {Krell-Roesch, J and Syrjanen, JA and Vassilaki, M and Lowe, VJ and Vemuri, P and Mielke, MM and Machulda, MM and Stokin, GB and Christianson, TJ and Kremers, WK and Jack, CR and Knopman, DS and Petersen, RC and Geda, YE}, title = {Brain Regional Glucose Metabolism, Neuropsychiatric Symptoms, and the Risk of Incident Mild Cognitive Impairment: The Mayo Clinic Study of Aging.}, journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jagp.2020.06.006}, pmid = {32646634}, issn = {1545-7214}, abstract = {OBJECTIVE: The authors conducted a prospective cohort study to examine the risk of incident mild cognitive impairment (MCI) as predicted by baseline neuropsychiatric symptoms (NPS) and brain regional glucose metabolic dysfunction.

METHODS: About 1,363 cognitively unimpaired individuals (52.8% males) aged ≥50 years were followed for a median of 4.8 years to the outcome of incident MCI. NPS were assessed using Beck Depression and Anxiety Inventories and Neuropsychiatric Inventory Questionnaire. Glucose hypometabolism was measured by fluorodeoxyglucose positron emission tomography and defined as standardized uptake value ratio ≤ 1.47 in regions typically affected in Alzheimer disease. Cox proportional hazards models were adjusted for age, sex, education, and APOE ε4 status.

RESULTS: Participants with regional glucose hypometabolism and depression (Beck Depression Inventory-II ≥13) had a more than threefold increased risk of incident MCI (hazard ratio [95% confidence interval], 3.66 [1.75, 7.65], p <0.001, χ2 = 11.83, degree of freedom [df] = 1) as compared to the reference group (normal regional glucose metabolism and no depression), and the risk was also significantly elevated (7.21 [3.54, 14.7], p <0.001, χ2 = 29.68, df = 1) for participants with glucose hypometabolism and anxiety (Beck Anxiety Inventory ≥10). Having glucose hypometabolism and ≥1 NPS (3.74 [2.40, 5.82], p <0.001, χ2 = 34.13, df = 1) or ≥2 NPS (3.89 [2.20, 6.86], p <0.001, χ2 = 21.92, df = 1) increased the risk of incident MCI by more than three times, and having ≥3 NPS increased the risk by more than four times (4.12 [2.03, 8.37], p <0.001, χ2 = 15.39, df = 1).

CONCLUSION: Combined presence of NPS with regional glucose hypometabolism is associated with an increased risk of incident MCI, with fluorodeoxyglucose positron emission tomography appearing to be a stronger driving force of cognitive decline than NPS.}, } @article {pmid32646202, year = {2020}, author = {Mun, SK and Chae, H and Piao, XY and Lee, HJ and Kim, YK and Oh, SH and Chang, M}, title = {MicroRNAs Related to Cognitive Impairment After Hearing Loss.}, journal = {Clinical and experimental otorhinolaryngology}, volume = {}, number = {}, pages = {}, doi = {10.21053/ceo.2019.01382}, pmid = {32646202}, issn = {1976-8710}, abstract = {Objectives: Our research group has previously demonstrated that hearing loss might be a risk factor for synaptic loss within the hippocampus and impairment of cognition using an animal model of Alzheimer disease. In this study, after inducing hearing loss in a rat model of Alzheimer disease, the associations of various microRNAs (miRNAs) with cognitive impairment were investigated.

Methods: Rats were divided randomly into two experimental groups: the control group, which underwent sham surgery and subthreshold amyloid-β infusion and the deaf group, which underwent bilateral cochlear ablation and subthreshold amyloid-β infusion. All rats completed several cognitive function assessments 11 weeks after surgery, including the object-in-place task (OPT), the novel object recognition task (NOR), the object location task (OLT), and the Y-maze test. After the rats completed these tests, hippocampus tissue samples were assessed using miRNA microarrays. Candidate miRNAs were selected based on the results and then validated with quantitative reverse transcriptionpolymerase chain reaction (qRT-PCR) analyses.

Results: The deaf group showed considerably lower scores on the OPT, OLT, and Y-maze test than the control group. The microarray analysis revealed that miR-29b-3p, -30e-5p, -153-3p, -376a-3p, -598-3p, -652-5p, and -873-3p were candidate miRNAs, and qRT-PCR showed significantly higher levels of miR-376a-3p and miR-598-3p in the deaf group.

Conclusion: These results indicate that miR-376a-3p and miR-598-3p were related to cognitive impairment after hearing loss.}, } @article {pmid32645971, year = {2020}, author = {Ellegaard Nielsen, J and Sofie Pedersen, K and Vestergård, K and Georgiana Maltesen, R and Christiansen, G and Lundbye-Christensen, S and Moos, T and Risom Kristensen, S and Pedersen, S}, title = {Novel Blood-Derived Extracellular Vesicle-Based Biomarkers in Alzheimer's Disease Identified by Proximity Extension Assay.}, journal = {Biomedicines}, volume = {8}, number = {7}, pages = {}, doi = {10.3390/biomedicines8070199}, pmid = {32645971}, issn = {2227-9059}, support = {NA//Speciallæge Heinrich Kopps Legat/ ; NA//Fonden til Lægevidenskabens Fremme/ ; }, abstract = {Easily accessible biomarkers for Alzheimer's dementia (AD) are lacking and established clinical markers are limited in applicability. Blood is a common biofluid for biomarker discoveries, and extracellular vesicles (EVs) may provide a matrix for exploring AD related biomarkers. Thus, we investigated proteins related to neurological and inflammatory processes in plasma and EVs. By proximity extension assay (PEA), 182 proteins were measured in plasma and EVs from patients with AD (n = 10), Mild Cognitive Impairment (MCI, n = 10), and healthy controls (n = 10). Plasma-derived EVs were enriched by 20,000× g, 1 h, 4 °C, and confirmed using nanoparticle tracking analysis (NTA), western blotting, and transmission electron microscopy with immunolabelling (IEM). Presence of CD9+ EVs was confirmed by western blotting and IEM. No group differences in particle concentration or size were detected by NTA. However, significant protein profiles were observed among subjects, particularly for EVs. Several proteins and their ratios could distinguish cognitively affected from healthy individuals. For plasma TGF-α│CCL20 (AUC = 0.96, 95% CI = 0.88-1.00, p = 0.001) and EVs CLEC1B│CCL11 (AUC = 0.95, 95% CI = 0.86-1.00, p = 0.001) showed diagnostic capabilities. Using PEA, we identified protein profiles capable of distinguishing healthy controls from AD patients. EVs provided additional biological information related to AD not observed in plasma alone.}, } @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 = {}, number = {}, pages = {}, 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. Results: 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. Conclusion: 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 {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 = {}, number = {}, pages = {101848}, doi = {10.1016/j.jchemneu.2020.101848}, pmid = {32645433}, issn = {1873-6300}, abstract = {Alzheimer disease's (AD) is a neurodegenerative disease induced by amyloid-β 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}, doi = {10.22037/ijpr.2019.111532.13216}, 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 {pmid32641520, year = {2020}, author = {Switzer, AR and Cheema, I and McCreary, CR and Zwiers, A and Charlton, A and Alvarez-Veronesi, A and Sekhon, R and Zerna, C and Stafford, RB and Frayne, R and Goodyear, BG and Smith, EE}, title = {Cerebrovascular reactivity in cerebral amyloid angiopathy, Alzheimer disease, and mild cognitive impairment.}, journal = {Neurology}, volume = {}, number = {}, pages = {}, doi = {10.1212/WNL.0000000000010201}, pmid = {32641520}, issn = {1526-632X}, abstract = {OBJECTIVE: To assess cerebrovascular reactivity in response to a visual task in participants with cerebral amyloid angiopathy (CAA), Alzheimer's disease (AD), and mild cognitive impairment (MCI) using functional magnetic resonance imaging (fMRI).

METHODS: Prospective cohort study including 40 CAA, 22 AD, 27 MCI, and 25 healthy controls. Each participant underwent a visual fMRI task using a contrast-reversing checkerboard stimulus. Visual evoked potentials (VEP) were used to compare visual cortex neuronal activity in 83 subjects. General linear models using least-squares means, adjusting for multiple comparisons using Tukey's test, were used to estimate: a) mean BOLD signal change during the task, and b) VEP differences between groups.

RESULTS: After adjusting for age and hypertension, estimated mean BOLD response amplitude was: CAA 1.88% (95% CI 1.60-2.15%), AD 2.26% (1.91%-2.61%), MCI 2.15% (1.84%-2.46%), and control 2.65% (2.29%-3.00%). Only CAA subjects differed from controls (p=0.01). In the subset with VEPs, group was not associated with prolonged latencies or lower amplitudes. Lower BOLD amplitude response was associated with higher WMH volumes in CAA (for each 0.1% lower BOLD response amplitude the WMH volume was 9.2% higher, 95% CI 6.0%-12.4%) but not other groups (p=0.002 for interaction) when controlling for age and hypertension.

CONCLUSIONS: Mean visual BOLD response amplitude was lowest in CAA compared to controls, without differences in VEP latencies and amplitudes. This suggests that the impaired visual BOLD response is due to reduced vascular reactivity in CAA. In contrast to CAA, the visual BOLD response amplitude did not differ between AD or MCI and controls.}, } @article {pmid32638218, year = {2020}, author = {Hernández-Rodríguez, M and Arciniega-Martínez, IM and García-Marín, ID and Correa-Basurto, J and Rosales-Hernández, MC}, title = {Chronic Administration of Scopolamine Increased GSK3βP9, Beta Secretase, Amyloid Beta, and Oxidative Stress in the Hippocampus of Wistar Rats.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, doi = {10.1007/s12035-020-02009-x}, pmid = {32638218}, issn = {1559-1182}, support = {CB286653//Consejo Nacional de Ciencia y Tecnología/ ; 254600//Consejo Nacional de Ciencia y Tecnología/ ; 782//Consejo Nacional de Ciencia y Tecnología/ ; SIP20195089//SIPCOFAA-IPN/ ; }, abstract = {The increase of amyloid beta (Aβ) release and hyperphosphorylation of Tau protein represents the main events related to Alzheimer's disease (AD). Furthermore, the sporadic type represents the most common form of AD. Therefore, the establishment of a non-transgenic animal model that resembles the characteristics of the disease is of particular importance. Scopolamine has been linked to increases in both Aβ production and oxidative stress in rat and mice brains. Thus, the purpose of the present work was to identify changes in biomarkers that are related to AD after chronic administration of scopolamine (2 mg/kg i.p., during 6 and 12 weeks) to male Wistar rats. The results showed increased Aβ deposition at rat hippocampus which could be due to an increase of β-site amyloid-β-protein precursor cleaving enzyme 1 (BACE1) expression and activity. These findings could be related to the increase of glycogen synthase kinase 3 phosphorylated (GSK3βP9) expression. Finally, the establishment of a state of oxidative stress in groups treated with scopolamine was demonstrated by an increase in free radical content and MDA levels. The present study facilitates our understanding of the changes that occur in biomolecules related to AD in Wistar rats after the chronic administration of scopolamine.}, } @article {pmid32637632, year = {2020}, author = {Tang, M and Alaniz, ME and Felsky, D and Vardarajan, B and Reyes-Dumeyer, D and Lantigua, R and Medrano, M and Bennett, DA and de Jager, PL and Mayeux, R and Santa-Maria, I and Reitz, C}, title = {Synonymous variants associated with Alzheimer disease in multiplex families.}, journal = {Neurology. Genetics}, volume = {6}, number = {4}, pages = {e450}, doi = {10.1212/NXG.0000000000000450}, pmid = {32637632}, issn = {2376-7839}, abstract = {Objective: Synonymous variants can lead to disease; nevertheless, the majority of sequencing studies conducted in Alzheimer disease (AD) only assessed coding variation.

Methods: To detect synonymous variants modulating AD risk, we conducted a whole-genome sequencing study on 67 Caribbean Hispanic (CH) families multiply affected by AD. Identified disease-associated variants were further assessed in an independent cohort of CHs, expression quantitative trait locus (eQTL) data, brain autopsy data, and functional experiments.

Results: Rare synonymous variants in 4 genes (CDH23, SLC9A3R1, RHBDD2, and ITIH2) segregated with AD status in multiplex families and had a significantly higher frequency in these families compared with reference populations of similar ancestry. In comparison to subjects without dementia, expression of CDH23 (β = 0.53, p = 0.006) and SLC9A3R1 (β = 0.50, p = 0.02) was increased, and expression of RHBDD2 (β = -0.70, p = 0.02) decreased in individuals with AD at death. In line with this finding, increased expression of CDH23 (β = 0.26 ± 0.08, p = 4.9E-4) and decreased expression of RHBDD2 (β = -0.60 ± 0.12, p = 5.5E-7) were related to brain amyloid load (p = 0.0025). SLC9A3R1 expression was associated with burden of TDP43 pathology (β = 0.58 ± 0.17, p = 5.9E-4). Using eQTL data, the CDH23 variant was in linkage disequilibrium with variants modulating CDH23 expression levels (top single nucleotide polymorphism: rs11000035, p = 4.85E-6, D' = 1.0). Using minigene splicing assays, the CDH23 and SLC9A3R1 variants affected splicing efficiency.

Conclusions: These findings suggest that CDH23, SLC9A3R1, RHBDD2, and possibly ITIH2, which are involved in synaptic function, the glutamatergic system, and innate immunity, contribute to AD etiology. In addition, this study supports the notion that synonymous variants contribute to AD risk and that comprehensive scrutinization of this type of genetic variation is warranted and critical.}, } @article {pmid32636723, year = {2020}, author = {Zhou, Y and Hu, Y and Lu, X and Yang, H and Li, Q and Du, C and Chen, Y and Hong, KH and Sun, H}, title = {Discovery of a Selective 6-Hydroxy-1, 4-Diazepan-2-one Containing Butyrylcholinesterase Inhibitor by Virtual Screening and MM-GBSA Rescoring.}, journal = {Dose-response : a publication of International Hormesis Society}, volume = {18}, number = {2}, pages = {1559325820938526}, doi = {10.1177/1559325820938526}, pmid = {32636723}, issn = {1559-3258}, abstract = {Alzheimer disease (AD) is the most common form of dementia characterized by the loss of cognitive abilities through the death of central neuronal cells. In this study, structure-based virtual screens of 2 central nervous system-targeted libraries followed by molecular mechanics/generalized born surface area rescoring were performed to discover novel, selective butyrylcholinesterase (BChE) inhibitors, which are one of the most effective therapeutic strategies for the treatments in late-stage AD. Satisfyingly, compound 5 was identified as a highly selective low micromolar inhibitor of BChE (BChE IC50 = 1.4 μM). The binding mode prediction and kinetic analysis were performed to obtain detailed information about compound 5. Besides, a preliminary structure-activity relationship investigation of compound 5 was carried out for further development of the series. The present results provided a valuable chemical template with a novel scaffold for the development of selective BChE inhibitors.}, } @article {pmid32636320, year = {2020}, author = {Yoshida, D and Ohara, T and Hata, J and Shibata, M and Hirakawa, Y and Honda, T and Furuta, Y and Oishi, E and Sakata, S and Kanba, S and Kitazono, T and Ninomiya, T}, title = {Lifetime cumulative incidence of dementia in a community-dwelling elderly population in Japan.}, journal = {Neurology}, volume = {}, number = {}, pages = {}, doi = {10.1212/WNL.0000000000009917}, pmid = {32636320}, issn = {1526-632X}, abstract = {OBJECTIVE: To estimate the lifetime cumulative incidence of dementia and its subtypes from a community-dwelling elderly population in Japan.

METHODS: A total of 1,193 community-dwelling Japanese individuals without dementia, aged 60 years or older, were followed up prospectively for 17 years. The cumulative incidence of dementia was estimated based on a death- and dementia-free survival function and the hazard functions of dementia at each year, which were computed by using a Weibull proportional hazards model. The lifetime risk of dementia was defined as the cumulative incidence of dementia at the point in time when the survival probability of the population was estimated to be less than 0.5%.

RESULTS: During the follow-up, 350 participants experienced some type of dementia; among them, 191 participants developed Alzheimer disease (AD) and 117 developed vascular dementia (VaD). The lifetime risk of dementia was 55% (95% confidence interval, 49%-60%). Women had an approximately 1.5 times greater lifetime risk of dementia than men (65% [57%-72%] vs 41% [33%-49%]). The lifetime risks of developing AD and VaD were 42% (35%-50%) and 16% (12%-21%) in women vs 20% (7%-34%) and 18% (13%-23%) in men, respectively.

CONCLUSION: Lifetime risk of all dementia for Japanese elderly was substantial at approximately 50% or higher. This study suggests that the lifetime burden attributable to dementia in contemporary Japanese communities is immense.}, } @article {pmid32631408, year = {2020}, author = {Suire, CN and Abdul-Hay, SO and Sahara, T and Kang, D and Brizuela, MK and Saftig, P and Dickson, DW and Rosenberry, TL and Leissring, MA}, title = {Cathepsin D regulates cerebral Aβ42/40 ratios via differential degradation of Aβ42 and Aβ40.}, journal = {Alzheimer's research & therapy}, volume = {12}, number = {1}, pages = {80}, doi = {10.1186/s13195-020-00649-8}, pmid = {32631408}, issn = {1758-9193}, support = {AG052718/AG/NIA NIH HHS/United States ; GM115617/GM/NIGMS NIH HHS/United States ; A2009-013//American Health Assistance Foundation/ ; IIRG-07-59693//Alzheimer's Association/United States ; SFB877//Deutsche Forschungsgemeinschaft/ ; }, abstract = {BACKGROUND: Cathepsin D (CatD) is a lysosomal protease that degrades both the amyloid β-protein (Aβ) and the microtubule-associated protein, tau, and has been genetically linked to late-onset Alzheimer disease (AD). Here, we sought to examine the consequences of genetic deletion of CatD on Aβ proteostasis in vivo and to more completely characterize the degradation of Aβ42 and Aβ40 by CatD.

METHODS: We quantified Aβ degradation rates and levels of endogenous Aβ42 and Aβ40 in the brains of CatD-null (CatD-KO), heterozygous null (CatD-HET), and wild-type (WT) control mice. CatD-KO mice die by ~ 4 weeks of age, so tissues from younger mice, as well as embryonic neuronal cultures, were investigated. Enzymological assays and surface plasmon resonance were employed to quantify the kinetic parameters (KM, kcat) of CatD-mediated degradation of monomeric human Aβ42 vs. Aβ40, and the degradation of aggregated Aβ42 species was also characterized. Competitive inhibition assays were used to interrogate the relative inhibition of full-length human and mouse Aβ42 and Aβ40, as well as corresponding p3 fragments.

RESULTS: Genetic deletion of CatD resulted in 3- to 4-fold increases in insoluble, endogenous cerebral Aβ42 and Aβ40, exceeding the increases produced by deletion of an insulin-degrading enzyme, neprilysin or both, together with readily detectable intralysosomal deposits of endogenous Aβ42-all by 3 weeks of age. Quite significantly, CatD-KO mice exhibited ~ 30% increases in Aβ42/40 ratios, comparable to those induced by presenilin mutations. Mechanistically, the perturbed Aβ42/40 ratios were attributable to pronounced differences in the kinetics of degradation of Aβ42 vis-à-vis Aβ40. Specifically, Aβ42 shows a low-nanomolar affinity for CatD, along with an exceptionally slow turnover rate that, together, renders Aβ42 a highly potent competitive inhibitor of CatD. Notably, the marked differences in the processing of Aβ42 vs. Aβ40 also extend to p3 fragments ending at positions 42 vs. 40.

CONCLUSIONS: Our findings identify CatD as the principal intracellular Aβ-degrading protease identified to date, one that regulates Aβ42/40 ratios via differential degradation of Aβ42 vs. Aβ40. The finding that Aβ42 is a potent competitive inhibitor of CatD suggests a possible mechanistic link between elevations in Aβ42 and downstream pathological sequelae in AD.}, } @article {pmid32630447, year = {2020}, author = {Martins, S and Müller-Schiffmann, A and Erichsen, L and Bohndorf, M and Wruck, W and Sleegers, K and Van Broeckhoven, C and Korth, C and Adjaye, J}, title = {IPSC-Derived Neuronal Cultures Carrying the Alzheimer's Disease Associated TREM2 R47H Variant Enables the Construction of an Aβ-Induced Gene Regulatory Network.}, journal = {International journal of molecular sciences}, volume = {21}, number = {12}, pages = {}, doi = {10.3390/ijms21124516}, pmid = {32630447}, issn = {1422-0067}, support = {305299//Seventh Framework Programme/ ; }, abstract = {Genes associated with immune response and inflammation have been identified as genetic risk factors for late-onset Alzheimer´s disease (LOAD). The rare R47H variant within triggering receptor expressed on myeloid cells 2 (TREM2) has been shown to increase the risk for developing Alzheimer's disease (AD) 2-3-fold. Here, we report the generation and characterization of a model of late-onset Alzheimer's disease (LOAD) using lymphoblast-derived induced pluripotent stem cells (iPSCs) from patients carrying the TREM2 R47H mutation, as well as from control individuals without dementia. All iPSCs efficiently differentiated into mature neuronal cultures, however AD neuronal cultures showed a distinct gene expression profile. Furthermore, manipulation of the iPSC-derived neuronal cultures with an Aβ-S8C dimer highlighted metabolic pathways, phagosome and immune response as the most perturbed pathways in AD neuronal cultures. Through the construction of an Aβ-induced gene regulatory network, we were able to identify an Aβ signature linked to protein processing in the endoplasmic reticulum (ER), which emphasized ER-stress, as a potential causal role in LOAD. Overall, this study has shown that our AD-iPSC based model can be used for in-depth studies to better understand the molecular mechanisms underlying the etiology of LOAD and provides new opportunities for screening of potential therapeutic targets.}, } @article {pmid32629192, year = {2020}, author = {Serafín, V and Gamella, M and Pedrero, M and Montero-Calle, A and Razzino, CA and Yáñez-Sedeño, P and Barderas, R and Campuzano, S and Pingarrón, JM}, title = {Enlightening the advancements in electrochemical bioanalysis for the diagnosis of Alzheimer's disease and other neurodegenerative disorders.}, journal = {Journal of pharmaceutical and biomedical analysis}, volume = {189}, number = {}, pages = {113437}, doi = {10.1016/j.jpba.2020.113437}, pmid = {32629192}, issn = {1873-264X}, abstract = {Neurodegenerative disorders (NDD), and particularly Alzheimer's disease (AD), are one of the greatest challenges facing our current medicine and society because of its increasing incidence and the high burden imposed both on patients' families and health systems. Despite this, their accurate diagnosis, mostly conducted by cerebrospinal fluid (CSF) analysis or neuroimaging techniques, costly, time-consuming, and unaffordable for most of the population, remains a complex task. In this situation, electrochemical biosensors are flourishing as promising alternative tools for the simple, fast, and low-cost diagnosis of NDD/AD. This review article provides the relevant clinical details of NDD/AD along with the closely related genetic (genetic mutations, polymorphisms of ApoE and specific miRNAs) and proteomic (amyloid-β peptides, total and phosphorylated tau protein) biomarkers circulating mostly in CSF. In addition, the article systematically enlightens a general view of the electrochemical affinity biosensors (mostly aptasensors and immunosensors) reported in the past two years for the determination of such biomarkers. The different developed strategies, analytical performances and applications are comprehensively discussed. Recent advancements in signal amplification methodologies involving smart designs and the use of nanomaterials and rational surface chemistries, as well as the challenges that must be struggled and the prospects in electrochemical affinity biosensing to bring more accessibility to NDD/AD diagnosis, prognosis, and follow-up, are also pointed out.}, } @article {pmid32628880, year = {2020}, author = {}, title = {Correction: Physicians and Alzheimer Dementia: Past, Present, and Future.}, journal = {Annals of internal medicine}, volume = {173}, number = {1}, pages = {78-79}, doi = {10.7326/L20-0648}, pmid = {32628880}, issn = {1539-3704}, } @article {pmid32628119, year = {2020}, author = {Du, Y and Paiva, K and Cebula, A and Kim, S and Lopez, K and Li, C and White, C and Myneni, S and Seshadri, S and Wang, J}, title = {Diabetes-Related Topics in an Online Forum for Caregivers of Individuals Living With Alzheimer Disease and Related Dementias: Qualitative Inquiry.}, journal = {Journal of medical Internet research}, volume = {22}, number = {7}, pages = {e17851}, doi = {10.2196/17851}, pmid = {32628119}, issn = {1438-8871}, abstract = {BACKGROUND: Diabetes and Alzheimer disease and related dementias (ADRD) are the seventh and sixth leading causes of death in the United States, respectively, and they coexist in many older adults. Caring for a loved one with both ADRD and diabetes is challenging and burdensome.

OBJECTIVE: This study aims to explore diabetes-related topics in the Alzheimer's Association ALZConnected caregiver forum by family caregivers of persons living with ADRD.

METHODS: User posts on the Alzheimer's Association ALZConnected caregiver forum were extracted. A total of 528 posts related to diabetes were included in the analysis. Of the users who generated the 528 posts, approximately 96.1% (275/286) were relatives of the care recipient with ADRD (eg, child, grandchild, spouse, sibling, or unspecified relative). Two researchers analyzed the data independently using thematic analysis. Any divergence was discussed among the research team, and an agreement was reached with a senior researcher's input as deemed necessary.

RESULTS: Thematic analysis revealed 7 key themes. The results showed that comorbidities of ADRD were common topics of discussions among family caregivers. Diabetes management in ADRD challenged family caregivers. Family caregivers might neglect their own health care because of the caring burden, and they reported poor health outcomes and reduced quality of life. The online forum provided a platform for family caregivers to seek support in their attempts to learn more about how to manage the ADRD of their care recipients and seek support for managing their own lives as caregivers.

CONCLUSIONS: The ALZConnected forum provided a platform for caregivers to seek informational and emotional support for caring for persons living with ADRD and diabetes. The overwhelming burdens with these two health conditions were apparent for both caregivers and care recipients based on discussions from the online forum. Studies are urgently needed to provide practical guidelines and interventions for diabetes management in individuals with diabetes and ADRD. Future studies to explore delivering diabetes management interventions through online communities in caregivers and their care recipients with ADRD and diabetes are warranted.}, } @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}, 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 &quot;absorbed composition-target-pathway-disease&quot; 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 &quot;multi-ingredients-multi-targets and multi-pathways&quot; mode, providing a scientific basis for further drug research and development.}, } @article {pmid32627121, year = {2020}, author = {Sedighi, M and Baluchnejadmojarad, T and Afshin-Majd, S and Amiri, M and Aminzade, M and Roghani, M}, title = {Anti-aging Klotho Protects SH-SY5Y Cells Against Amyloid β1-42 Neurotoxicity: Involvement of Wnt1/pCREB/Nrf2/HO-1 Signaling.}, journal = {Journal of molecular neuroscience : MN}, volume = {}, number = {}, pages = {}, doi = {10.1007/s12031-020-01621-9}, pmid = {32627121}, issn = {1559-1166}, support = {grant # 95-01-87-27994//Iran University of Medical Sciences/ ; }, abstract = {Alzheimer's disease (AD) is considered a prevalent neurological disorder with a neurodegenerative nature in elderly people. Oxidative stress and neuroinflammation due to amyloid β (Aβ) peptides are strongly involved in AD pathogenesis. Klotho is an anti-aging protein with multiple protective effects that its deficiency is involved in development of age-related disorders. In this study, we investigated the beneficial effect of Klotho pretreatment at different concentrations of 0.5, 1, and 2 nM against Aβ1-42 toxicity at a concentration of 20 μM in human SH-SY5Y neuroblastoma cells. Our findings showed that Klotho could significantly and partially restore cell viability and decrease reactive oxygen species (known as ROS) and improve superoxide dismutase activity (SOD) in addition to reduction of caspase 3 activity and DNA fragmentation following Aβ1-42 challenge. In addition, exogenous Klotho also reduced inflammatory biomarkers consisting of nuclear factor-kB (NF-kB), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) in Aβ-exposed cells. Besides, Klotho caused downregulation of Wnt1 level, upregulation of phosphorylated cyclic AMP response element binding (pCREB), and mRNA levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) with no significant alteration of epsilon isoform of protein kinase C (PKCε) after Aβ toxicity. In summary, Klotho could alleviate apoptosis, oxidative stress, and inflammation in human neuroblastoma cells after Aβ challenge and its beneficial effect is partially exerted through appropriate modulation of Wnt1/pCREB/Nrf2/HO-1 signaling.}, } @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}, doi = {10.3389/fcell.2020.00472}, 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}, doi = {10.3389/fnins.2020.00564}, 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 = {}, number = {}, pages = {}, doi = {10.3233/JAD-200227}, pmid = {32623395}, issn = {1875-8908}, 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 {pmid32623364, year = {2020}, author = {Borrelli, S and Genoud-Prachex, T and Meyer, M and Démonet, JF and Rouaud, O}, title = {Unsuspected Alzheimer disease in a patient with Multiple sclerosis and progressive aphasia.}, journal = {Multiple sclerosis and related disorders}, volume = {45}, number = {}, pages = {102349}, doi = {10.1016/j.msard.2020.102349}, pmid = {32623364}, issn = {2211-0356}, } @article {pmid32622867, year = {2020}, author = {Bernstein, HG and Keilhoff, G and Dobrowolny, H and Lendeckel, U and Steiner, J}, title = {From putative brain tumor marker to high cognitive abilities: emerging roles of a disintegrin and metalloprotease (ADAM) 12 in the brain.}, journal = {Journal of chemical neuroanatomy}, volume = {}, number = {}, pages = {101846}, doi = {10.1016/j.jchemneu.2020.101846}, pmid = {32622867}, issn = {1873-6300}, abstract = {ADAM (a disintergin and metalloprotease) 12 is a member of the large family of multidomain metalloprotease-disintegrins, which possess cell-binding and metalloprotease properties. The enzyme is responsible for the shedding of a number of membrane-bound proteins (heparin-binding-EGF, insulin-like growth factor 2-binding proteins 3 and 5, oxytocinase, glycoprotein non-metastatic melanoma protein B and basigin). In rat and human CNS, ADAM12 is predominantly localized in white and gray matter oligodendrocytes. In addition it can be detected in astrocytes, neurons and endothelial cells. Its function in healthy brain is not well established yet, but prominent roles in CNS development, myelination and high cognitive abilities are discussed. There is increasing evidence that ADAM12 is involved in numerous major diseases of the CNS, which are summarized in the present review (brain tumors, multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer´s disease, stroke, schizophrenia, autism and bipolar disorder).}, } @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}, doi = {10.1016/j.aquatox.2020.105553}, pmid = {32622090}, issn = {1879-1514}, 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 {pmid32621295, year = {2020}, author = {Reiter, RJ and Sharma, R and Ma, Q}, title = {Switching Diseased Cells from Cytosolic Aerobic Glycolysis to Mitochondrial Oxidative Phosphorylation: A Metabolic Rhythm Regulated by Melatonin?.}, journal = {Journal of pineal research}, volume = {}, number = {}, pages = {e12677}, doi = {10.1111/jpi.12677}, pmid = {32621295}, issn = {1600-079X}, abstract = {This commentary reviews the concept of the circadian melatonin rhythm playing an essential role in reducing the development of diseases such as solid tumors which adopt cytosolic aerobic glycolysis (Warburg effect) to support their enhanced metabolism. Experimental data shows that solid mammary tumors depend on aerobic glycolysis during the day but likely revert to mitochondrial oxidative phosphorylation at night for ATP production. This conversion of diseased cells during the day to a healthier phenotype at night occurs under control of the circulating melatonin rhythm. When the nocturnal melatonin rise is inhibited by light exposure at night, cancer cells function in the diseased state 24/7. The ability of melatonin to switch cancer cells as well as other diseased cells, e.g., Alzheimer disease, fibrosis, hyperactivation of macrophages, etc., from aerobic glycolysis to mitochondrial oxidative phosphorylation may be a basic protective mechanism to reduce pathologies.}, } @article {pmid32619270, year = {2020}, author = {Kamohara, C and Nakajima, M and Kawamura, K and Akiba, C and Ogino, I and Xu, H and Karagiozov, K and Arai, H and Miyajima, M}, title = {Neuropsychological tests are useful for predicting comorbidities of idiopathic normal-pressure hydrocephalus.}, journal = {Acta neurologica Scandinavica}, volume = {}, number = {}, pages = {}, doi = {10.1111/ane.13306}, pmid = {32619270}, issn = {1600-0404}, abstract = {OBJECTIVES: Comorbidities of idiopathic normal-pressure hydrocephalus (iNPH), such as Alzheimer's disease (AD) and Parkinson's spectrum (PS) disorder, can affect the long-term prognosis of cerebrospinal fluid (CSF) shunting. Therefore, it is important to be able to predict comorbidities in the early stage of the disease. This study aimed to predict the comorbidities of iNPH using neuropsychological tests and cognitive performance evaluation.

MATERIALS & METHODS: Forty-nine patients with possible iNPH were divided into three groups: iNPH without AD or PS comorbidity (group-1), iNPH with AD comorbidity (group-2), and iNPH with PS comorbidity (group-3), according to CSF biomarkers such as phosphorylated tau and dopamine transporter imaging. Scores on the new EU-iNPH-scale, which is based on 4 neuropsychological tests (Rey Auditory Verbal Learning Test, Grooved Pegboard test, Stroop colour-naming test and interference test), were compared for each group. In addition, the scores before and 12 months after CSF shunting for each group were compared.

RESULTS: EU-iNPH-scale using 4 neuropsychological tests could distinguish group-1 from group-2 or group-3 by area under the curve values of 0.787 and 0.851, respectively. Patients in group-1 showed a remarkable increase in memory and learning ability after surgery. Group-2 performed significantly poorer than group-1 patients on memory testing, but otherwise showed improvements in most of the neuropsychological tests. Group-3 performed significantly worse than group-1 patients-especially on Stroop tests-but showed post-surgery improvement on only the Stroop colour-naming test.

CONCLUSIONS: The 4 neuropsychological tests of the EU-iNPH-scale can help predict iNPH comorbidities and evaluate the prognosis of CSF shunting.}, } @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 = {}, number = {}, pages = {}, 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 {pmid32617740, year = {2020}, author = {Kim, S and Kim, JO and Kwon, KJ and Han, SH and Moon, Y}, title = {Associations of truncal body composition with cognitive status in patients with dementia.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {}, number = {}, pages = {}, doi = {10.1007/s10072-020-04503-5}, pmid = {32617740}, issn = {1590-3478}, support = {2018M3C7A1056571//Ministry of Science and ICT/ ; }, abstract = {BACKGOUND: Central obesity in midlife is a risk factor of cognitive decline and dementia, and also one of the factors that make cognitive functions deteriorate rapidly.

OBJECTIVE: The objective of this study is to investigate the relationship between truncal body composition (fat and muscle) and cognitive impairment in patients with dementia.

METHODS: A total of 81 female over 60 years of age with probable Alzheimer's disease were recruited between November 2014 and September 2015. The Mini-Mental State Examination, Global Deterioration Scale, and Clinical Dementia Rating Scale were used to assess the cognitive functions. Both truncal fat and muscle mass were measured using body dual-energy X-ray absorptiometry and used as a percentage of body weight (TMM% and TFM%). Correlations between truncal composition and cognitive status were assessed by simple correlation analysis, which was followed by partial correlation analysis with age and educational years.

RESULTS: TFM% was not related to cognitive impairment. In contrast, TMM% had a significantly negative correlation with all three cognitive assessment scores. After further adjusting for age, educational years, and vascular factors, there was still a relationship between TMM% and cognitive functions.

CONCLUSIONS: Unlike truncal fat mass that showed no relevance with cognitive functions, the truncal muscle mass was negatively correlated with cognitive status. The truncal muscle mass is thought to affect cognitive status in dementia patients somehow.}, } @article {pmid32617597, year = {2020}, author = {Orimaye, SO and Southerland, JL and Oke, AO and Ajibade, A}, title = {Increased Prevalence in Alzheimer Disease in the Northeast Tennessee Region of the United States.}, journal = {Southern medical journal}, volume = {113}, number = {7}, pages = {351-355}, doi = {10.14423/SMJ.0000000000001116}, pmid = {32617597}, issn = {1541-8243}, abstract = {OBJECTIVES: This study describes the changes in prevalence odds ratios (PORs) for Alzheimer disease (AD) in the northeast Tennessee region (NTR) during a 3-year period, describes the statistical assessment process, and critically assesses the database from which the statistical association was derived. The article also examines several beliefs pertinent to the clinical management of AD in the NTR from the perspective of professionals delivering services.

METHODS: We extracted prevalence data for NTR counties for 2013, 2014, and 2015 from the Centers for Medicare & Medicaid Services Geographic Variation Public Use File. We used the crude prevalence and the 2010 US Census Data fixed population for each county to compute the POR. The 2013 Economic Research Service Rural-Urban Continuum Codes were used to identify rural and urban counties in the NTR. We collected primary data on the perceived observation of the increasing prevalence in the NTR during the last 3 years and barriers to early diagnosis through an online survey from 44 experts and professionals working in AD-related fields within the NTR.

RESULTS: The PORs of AD in rural counties in NTR increased by 18.3%, 4.7%, and 19% compared with urban counties for 2013, 2014, and 2015, respectively. The POR of AD for the entire NTR region increased by 22.7%, 22.5%, and 21.2% compared with other regions in Tennessee for 2013, 2014, and 2015, respectively. Compared with 2012, 68.4% of respondents currently work with more individuals with AD; 71.8% reported that the NTR has a higher number of late-stage diagnoses of AD. A total of 92.3% strongly agreed that early detection of AD is important, and 95% agreed that early diagnosis could prolong the lives of patients with AD; 51.2% were unaware of existing AD screening services. Reported barriers were denial, lack of patient awareness, inefficient screening methods, communication, and lack of community resources.

CONCLUSIONS: Increased prevalence of AD among inhabitants in the NTR and identified barriers to early screening or diagnosis in the management of AD were identified. Access to early screening techniques must be prioritized in deprived areas within the NTR. Healthcare providers and medical professionals in the NTR must be well equipped with the required training and resources to respond adequately to the increasing prevalence of AD.}, } @article {pmid32616652, year = {2020}, author = {Marinelli, R and Torquato, P and Bartolini, D and Mas-Bargues, C and Bellezza, G and Gioiello, A and Borras, C and De Luca, A and Fallarino, F and Sebastiani, B and Mani, S and Sidoni, A and Vina, J and Leri, M and Bucciantini, M and Nardiello, P and Casamenti, F and Galli, F}, title = {Garcinoic acid prevents β-amyloid (Aβ) deposition in the mouse brain.}, journal = {The Journal of biological chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1074/jbc.RA120.013303}, pmid = {32616652}, issn = {1083-351X}, abstract = {Garcinoic acid (GA or δ-T3-13'COOH), is a natural vitamin E metabolite that has preliminarily been identified as a modulator of nuclear receptors involved in β-amyloid (Aβ) metabolism and progression of Alzheimer's disease (AD). In this study, we investigated GA's effects on Aβ oligomer formation and deposition. Specifically, we compared them with those of other vitamin E analogs and the soy isoflavone genistein, a natural agonist of peroxisome proliferator-activated receptor γ (PPARγ) that has therapeutic potential for managing AD. GA significantly reduced Aβ aggregation and accumulation in mouse cortical astrocytes. Similarly to genistein, GA up-regulated PPARγ expression and apolipoprotein E (ApoE) efflux in these cells with an efficacy that was comparable to that of its metabolic precursor δ-tocotrienol and higher than those of α-tocopherol metabolites. Unlike for genistein and the other vitamin E compounds, the GA-induced restoration of ApoE efflux was not affected by pharmacological inhibition of PPARγ activity, and specific activation of pregnane X receptor (PXR) was observed together with ApoE and multidrug resistance protein 1 (MDR1) membrane transporter up-regulation in both the mouse astrocytes and brain tissue. These effects of GA were associated with reduced Aβ deposition in the brain of TgCRND8 mice, a transgenic AD model. In conclusion, GA holds potential for preventing Aβ oligomerization and deposition in the brain. The mechanistic aspects of GA's properties appear to be distinct from those of other vitamin E metabolites and of genistein.}, } @article {pmid32614686, year = {2020}, author = {Zhang, L and Pasha, EP and Liu, J and Xing, CY and Cardim, D and Tarumi, T and Womack, K and Hynan, LS and Cullum, CM and Zhang, R}, title = {Steady-State Cerebral Autoregulation in Older Adults with Amnestic Mild Cognitive Impairment: Linear Mixed Model Analysis.}, journal = {Journal of applied physiology (Bethesda, Md. : 1985)}, volume = {}, number = {}, pages = {}, doi = {10.1152/japplphysiol.00193.2020}, pmid = {32614686}, issn = {1522-1601}, support = {R01AG033106//HHS | National Institutes of Health (NIH)/ ; R01HL102457//HHS | National Institutes of Health (NIH)/ ; }, abstract = {We examined whether steady-state cerebral autoregulation (CA) is impaired in older adults with amnestic mild cognitive impairment (aMCI), a prodromal stage of clinical Alzheimer disease (AD). Forty-two patients with aMCI and 27 cognitively normal older adults (NC) of similar age, sex, and education underwent stepwise decreases and increases in mean arterial pressure (MAP) induced by intravenous infusion of sodium nitroprusside and phenylephrine, respectively. Changes in cerebral blood flow (CBF) were measured in the internal carotid and vertebral artery. Linear mixed modelling, including random effects of both individual intercept and regression slope, was used to quantify the MAP-CBF relationship accounting for the non-independent CBF measures. Changes in end-tidal CO2 (ETCO2) associated with changes in MAP were also included in the model to account for their effects on CBF. Marginal mean values of MAP were reduced by 13-14 mmHg during sodium nitroprusside and increased by 20-24 mmHg during phenylephrine infusion in both groups with similar doses of drug infusion. A steeper slope of changes in CBF in response to changes in MAP was observed in aMCI relative to NC, indicating impaired CA (MAP*Group, P < 0.05). These findings indicate CA was impaired in older adults with aMCI, suggesting that cerebrovascular dysfunction may occur early in the development of AD.}, } @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 = {}, number = {}, pages = {}, 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 ; //Smartfish company to M.F./ ; //American Diabetes Association Postdoctoral Fellowship to G.D./ ; }, 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 {pmid32614373, year = {2020}, author = {Margeta, MA and Letcher, SM and Igo, RP and Cooke Bailey, JN and Pasquale, LR and Haines, JL and Butovsky, O and Wiggs, JL and , }, title = {Association of APOE With Primary Open-Angle Glaucoma Suggests a Protective Effect for APOE ε4.}, journal = {Investigative ophthalmology & visual science}, volume = {61}, number = {8}, pages = {3}, doi = {10.1167/iovs.61.8.3}, pmid = {32614373}, issn = {1552-5783}, abstract = {Purpose: Prior studies have demonstrated that microglial activation is involved in the pathogenesis of primary open-angle glaucoma (POAG). Here we sought to identify genetic associations between POAG and variants in APOE and TREM2, genes associated with Alzheimer disease (AD) that critically regulate microglial neurodegeneration-associated molecular signature.

Methods: APOE genotypes were called using imputed data from the NEIGHBOR consortium (2120 POAG cases, 2262 controls) and a second cohort from the Massachusetts Eye and Ear Infirmary (MEEI; 486 cases, 344 controls). TREM2 coding variants were genotyped by means of the Illumina HumanExome BeadArray. The data set was analyzed for association with POAG overall, as well as the high-tension glaucoma (HTG) and normal-tension glaucoma (NTG) subgroups, using logistic regression adjusting for age and sex.

Results: In the combined NEIGHBOR-MEEI data set, significant association was observed for APOE ε4 in POAG overall (odds ratio [OR], 0.83; 95% confidence interval [CI], 0.74-0.94; P = 0.0022) and in both the HTG subgroup (OR, 0.81; 95% CI, 0.70-0.94; P = 0.0052) and NTG subgroup (OR, 0.71; 95% CI, 0.58-0.87; P = 0.0014). A rare TREM2 variant (A105V) was found only in HTG cases (3 of 2863 cases) and in none of the controls (P = 0.03). Three TREM2 rare variants associated with AD were not significantly associated with POAG (P > 0.05).

Conclusions: We have found that the APOE ε4 allele is associated with a reduced risk of POAG. Interestingly, the same allele is adversely associated with AD, suggesting a mechanistic difference between neurodegenerative diseases of the eye and the brain. TREM2 variants associated with AD did not significantly contribute to POAG risk.}, } @article {pmid32612522, year = {2020}, author = {Marlats, F and Bao, G and Chevallier, S and Boubaya, M and Djabelkhir-Jemmi, L and Wu, YH and Lenoir, H and Rigaud, AS and Azabou, E}, title = {SMR/Theta Neurofeedback Training Improves Cognitive Performance and EEG Activity in Elderly With Mild Cognitive Impairment: A Pilot Study.}, journal = {Frontiers in aging neuroscience}, volume = {12}, number = {}, pages = {147}, doi = {10.3389/fnagi.2020.00147}, pmid = {32612522}, issn = {1663-4365}, abstract = {Background: Neurofeedback (NF) training, as a method of self-regulation of brain activity, may be beneficial in elderly patients with mild cognitive impairment (MCI). In this pilot study, we investigated whether a sensorimotor (SMR)/theta NF training could improve cognitive performance and brain electrical activity in elderly patients with MCI. Methods: Twenty elderly patients with MCI were assigned to 20 consecutive sessions of sensorimotor (SMR)/theta NF training, during 10 weeks, on a basis of two sessions each week. Neuropsychological assessments and questionnaires, as well as electroencephalogram (EEG), were performed and compared between baseline (T0), after the last NF training session at 10 weeks (T1), and 1-month follow-up (T2). Results: Repeated measures ANOVA revealed that from baseline to post-intervention, participants showed significant improvement in the Montreal cognitive assessment (MoCa, F = 4.78; p = 0.012), the delayed recall of the Rey auditory verbal learning test (RAVLT, F = 3.675; p = 0.032), the Forward digit span (F = 13.82; p < 0.0001), the Anxiety Goldberg Scale (F = 4.54; p = 0.015), the Wechsler Adult Intelligence Score-Fourth Edition (WAIS-IV; F = 24.75; p < 0.0001), and the Mac Nair score (F = 4.47; p = 0.016). EEG theta power (F = 4.44; p = 0.016) and alpha power (F = 3.84; p = 0.027) during eyes-closed resting-state significantly increased after the NF training and showed sustained improvement at a 1-month follow-up. Conclusion: Our results suggest that NF training could be effective to reduce cognitive deficits in elderly patients with MCI and improve their EEG activity. If these findings are confirmed by randomized controlled studies with larger samples of patients, NF could be seen as a useful non-invasive, non-pharmacological tool for preventing further decline, rehabilitation of cognitive function in the elderly. Clinical Trial Registration: This pilot study was a preliminary step before the trial registered in www.ClinicalTrials.gov, under the number of NCT03526692.}, } @article {pmid32612262, year = {2020}, author = {Scearce-Levie, K and Sanchez, PE and Lewcock, JW}, title = {Leveraging preclinical models for the development of Alzheimer disease therapeutics.}, journal = {Nature reviews. Drug discovery}, volume = {19}, number = {7}, pages = {447-462}, doi = {10.1038/s41573-020-0065-9}, pmid = {32612262}, issn = {1474-1784}, abstract = {A large number of mouse models have been engineered, characterized and used to advance biomedical research in Alzheimer disease (AD). Early models simply damaged the rodent brain through toxins or lesions. Later, the spread of genetic engineering technology enabled investigators to develop models of familial AD by overexpressing human genes such as those encoding amyloid precursor protein (APP) or presenilins (PSEN1 or PSEN2) carrying mutations linked to early-onset AD. Recently, more complex models have sought to explore the impact of multiple genetic risk factors in the context of different biological challenges. Although none of these models has proven to be a fully faithful reproduction of the human disease, models remain essential as tools to improve our understanding of AD biology, conduct thorough pharmacokinetic and pharmacodynamic analyses, discover translatable biomarkers and evaluate specific therapeutic approaches. To realize the full potential of animal models as new technologies and knowledge become available, it is critical to define an optimal strategy for their use. Here, we review progress and challenges in the use of AD mouse models, highlight emerging scientific innovations in model development, and introduce a conceptual framework for use of preclinical models for therapeutic development.}, } @article {pmid32611641, year = {2020}, author = {Wolters, FJ and Chibnik, LB and Waziry, R and Anderson, R and Berr, C and Beiser, A and Bis, JC and Blacker, D and Bos, D and Brayne, C and Dartigues, JF and Darweesh, SK and Davis-Plourde, KL and de Wolf, F and Debette, S and Dufouil, C and Fornage, M and Goudsmit, J and Grasset, L and Gudnason, V and Hadjichrysanthou, C and Helmer, C and Ikram, MA and Ikram, MK and Joas, E and Kern, S and Kuller, LH and Launer, L and Lopez, O and Matthews, FE and McRae-McKee, K and Meirelles, O and Mosley, TH and Pase, MP and Psaty, BM and Satizabal, CL and Seshadri, S and Skoog, I and Stephan, BC and Wetterberg, H and Wong, MM and Zettergren, A and Hofman, A}, title = {27-year time trends in dementia incidence in Europe and the US: the Alzheimer Cohorts Consortium.}, journal = {Neurology}, volume = {}, number = {}, pages = {}, doi = {10.1212/WNL.0000000000010022}, pmid = {32611641}, issn = {1526-632X}, abstract = {OBJECTIVE: To determine changes in the incidence of dementia between 1988 and 2015.

METHODS: This analysis was performed in aggregated data from individuals >65 years in seven population-based cohort studies in the United States and Europe from the Alzheimer Cohort Consortium. First, we calculated age- and sex-specific incidence rates for all-cause dementia, and then defined non-overlapping 5-year epochs within each study to determine trends in incidence. Estimates of change per 10-year interval were pooled and results are presented combined and stratified by sex.

RESULTS: Of 49,202 individuals, 4,253 (8.6%) developed dementia. The incidence rate of dementia increased with age, similarly for women and men, ranging from about 4 per 1,000 person years in individuals aged 65-69 years, to 65 per 1,000 person years for those aged 85-89 years. The incidence rate of dementia declined by 13% per calendar decade (95% CI: 7%-19%), consistently across studies, and somewhat more pronouncedly in men than in women (24% [95% CI 14%-32%] versus 8% [0%-15%]).

CONCLUSION: The incidence rate of dementia in Europe and North America has declined by 13% per decade over the past 25 years, consistently across studies. Incidence is similar for men and women, although declines were somewhat more profound in men. These observations call for sustained efforts to finding the causes for this decline, as well as determining their validity in geographically and ethnically diverse populations.}, } @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 = {}, number = {}, pages = {}, doi = {10.1001/jamapsychiatry.2020.1807}, pmid = {32609320}, issn = {2168-6238}, 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 {pmid32608133, year = {2020}, author = {Tzeng, NS and Chien, WC and Chung, CH and Chang, HA and Kao, YC and Liu, YP}, title = {Association between amphetamine-related disorders and dementia-a nationwide cohort study in Taiwan.}, journal = {Annals of clinical and translational neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/acn3.51113}, pmid = {32608133}, issn = {2328-9503}, support = {CH-NDMC-108-9//Cheng Hsin General Hospital Foundation/ ; CH-NDMC-109-7//Cheng Hsin General Hospital Foundation/ ; TSGH-C108-003//Tri-Service General Hospital Research Foundation/ ; TSGH-C108-151//Tri-Service General Hospital Research Foundation/ ; TSGH-B-109-010//Tri-Service General Hospital Research Foundation/ ; MAB-107-084//Medical Affairs Bureau, Ministry of Defense of Taiwan/ ; }, abstract = {OBJECTIVE: We have conducted a study to clarify the association between amphetamine-related disorders (ARD) and the risk of developing dementia.

METHODS: This study used a retrospective cohort design by using Taiwan's National Health Research Institute Database. A random sample of 68,300 subjects between January 1, 2000, and December 31, 2015, was obtained, comprising of 17,075 patients with ARD, and 51,225 controls without ARD (1:3), matched for gender and age group. After adjusting for covariates, a Fine and Gray's survival analysis (competing with mortality) was used to compare the risk of dementia during a 15-year follow-up period.

RESULTS: In the present study, 1,751 of 17,075 patients with ARD and 2,147 of 51,225 in the control group without ARD (883.10 vs 342.83 per 100,000 person-years) developed dementia. ARD cohort was more likely to develop dementia (hazard ratio = 4.936 [95% CI: 4.609-5.285, P < 0.001). After adjusting for gender, age groups, education, monthly insured premiums, urbanization level, geographic region, comorbidities, the hazard ratio for ARD patients was 5.034 (95% CI: 4.701-5.391, P < 0.001). ARD has been associated with overall dementia, Alzheimer dementia, vascular dementia, and other dementia. Both the amphetamine use disorder and amphetamine-induced psychotic disorders were associated with the risk of overall dementia, Alzheimer dementia, vascular dementia, and other dementia.

INTERPRETATION: This study shows that patients with ARD, both the amphetamine use disorder and the amphetamine-induced psychotic disorder, may have a nearly fivefold risk of developing dementia, including Alzheimer dementia and other types of dementia.}, } @article {pmid32607419, year = {2020}, author = {Rondal, JA}, title = {Down syndrome: A curative prospect?.}, journal = {AIMS neuroscience}, volume = {7}, number = {2}, pages = {168-193}, doi = {10.3934/Neuroscience.2020012}, pmid = {32607419}, issn = {2373-7972}, abstract = {Experimental work regarding corrective actions on chromosomes and genes, and control of gene products is yielding promising results. It opens the way to advances in dealing with the etiological aspects of Down syndrome and may lead to important changes in the life of individuals affected with this condition. A small number of molecules are being investigated in pharmacological research that may have positive effects on intellectual functioning. Studies of the pathological consequences of the amyloid cascade and the TAU pathology in the etiology of Alzheimer disease (AD), which is more frequent and occuring earlier in life in persons with Down syndrome (DS), are presented. The search for biological markers of AD and ways for constrasting its early manifestations are also discussed.}, } @article {pmid32603732, year = {2020}, author = {Ameri, M and Shabaninejad, Z and Movahedpour, A and Sahebkar, A and Mohammadi, S and Hosseindoost, S and Ebrahimi, MS and Savardashtaki, A and Karimipour, M and Mirzaei, H}, title = {Biosensors for detection of Tau protein as an Alzheimer's disease marker.}, journal = {International journal of biological macromolecules}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ijbiomac.2020.06.239}, pmid = {32603732}, issn = {1879-0003}, abstract = {Known as a main neural MAP (microtubule associated protein), tau protein contributes to stabilizing microtubules involved in cellular transmission. Tau dysfunction is mainly associated with neurodegenerative diseases, particularly Alzheimer's disease (AD). In these patients, all the six tau isoforms, which are in hyperphosphorylated form, are first aggregated and then polymerized into neurofibrillary tangles inside the brain. Tau protein detected in cerebrospinal fluid (CSF) is significantly correlated with AD and is well recognized as a hallmark of the disease. Served for detection of analytes of interest, biosensor device comprises a physical transducer and a keen biological recognition component. Qualitative and quantitative evaluations may be performed through analyzation of the data, which is gathered by measurable signals converted from biological reaction. Antibodies, receptors, microorganisms, nucleic acids, enzymes, cells and tissues, as well as some biomimetic structures, normally constitute the biosensor biological recognition part. Production of nanobiosensor, which was made possible through several accomplishments in nano- and fabrication technology, opens up new biotechnological horizons in diagnosis of multiple diseases. In recent years, many researches have been focused on developing novel and effective tau protein biosensors for rapid and accurate detection of AD. In this review, tau protein function and correlation with AD as well as the eminent research on developing nanobiosensor based on optical, electrochemical and piezoelectric approaches will be highlighted.}, } @article {pmid32602825, year = {2020}, author = {Damulina, A and Pirpamer, L and Soellradl, M and Sackl, M and Tinauer, C and Hofer, E and Enzinger, C and Gesierich, B and Duering, M and Ropele, S and Schmidt, R and Langkammer, C}, title = {Cross-sectional and Longitudinal Assessment of Brain Iron Level in Alzheimer Disease Using 3-T MRI.}, journal = {Radiology}, volume = {}, number = {}, pages = {192541}, doi = {10.1148/radiol.2020192541}, pmid = {32602825}, issn = {1527-1315}, abstract = {Background Deep gray matter structures in patients with Alzheimer disease (AD) contain higher brain iron concentrations. However, few studies have included neocortical areas, which are challenging to assess with MRI. Purpose To investigate baseline and change in brain iron levels using MRI at 3 T with R2* relaxation rate mapping in individuals with AD compared with healthy control (HC) participants. Materials and Methods In this prospective study, participants with AD recruited between 2010 and 2016 and age-matched HC participants selected from 2010 to 2014 were evaluated. Of 100 participants with AD, 56 underwent subsequent neuropsychological testing and brain MRI at a mean follow-up of 17 months. All participants underwent 3-T MRI, including R2* mapping corrected for macroscopic B0 field inhomogeneities. Anatomic structures were segmented, and median R2* values were calculated in the neocortex and cortical lobes, basal ganglia (BG), hippocampi, and thalami. Multivariable linear regression analysis was applied to study the difference in R2* levels between groups and the association between longitudinal changes in R2* values and cognition in the AD group. Results A total of 100 participants with AD (mean age, 73 years ± 9 [standard deviation]; 58 women) and 100 age-matched HC participants (mean age, 73 years ± 9; 60 women) were evaluated. Median R2* levels were higher in the AD group than in the HC group in the BG (HC, 29.0 sec-1; AD, 30.2 sec-1; P = .01) and total neocortex (HC, 17.0 sec-1; AD, 17.4 sec-1; P < .001) and regionally in the occipital (HC, 19.6 sec-1; AD, 20.2 sec-1; P = .007) and temporal (HC, 16.4 sec-1; AD, 18.1 sec-1; P < .001) lobes. R2* values in the temporal lobe were associated with longitudinal changes in Consortium to Establish a Registry for Alzheimer's Disease total score (β = -3.23 score/sec-1, P = .003) in participants with AD independent of longitudinal changes in brain volume. Conclusion Iron concentration in the deep gray matter and neocortical regions was higher in patients with Alzheimer disease than in healthy control participants. Change in iron levels over time in the temporal lobe was associated with cognitive decline in individuals with Alzheimer disease. © RSNA, 2020 Online supplemental material is available for this article.}, } @article {pmid32602403, year = {2020}, 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 = {}, number = {}, pages = {891988720933351}, 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}, doi = {10.12779/dnd.2020.19.2.39}, 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 = {2020}, 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 = {}, number = {}, pages = {}, doi = {10.1007/s10571-020-00912-4}, 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 {pmid32601397, year = {2020}, author = {Saez-Atienzar, S and Masliah, E}, title = {Cellular senescence and Alzheimer disease: the egg and the chicken scenario.}, journal = {Nature reviews. Neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41583-020-0325-z}, pmid = {32601397}, issn = {1471-0048}, abstract = {Globally, 50 million people live with dementia, with Alzheimer disease (AD) being responsible for two-thirds of the total cases. As ageing is the main risk factor for dementia-related neurodegeneration, changes in the timing or nature of the cellular hallmarks of normal ageing might be key to understanding the events that convert normal ageing into neurodegeneration. Cellular senescence is a candidate mechanism that might be important for this conversion. Under persistent stress, as occurs in ageing, both postmitotic cells - including neurons - and proliferative cells - such as astrocytes and microglia, among others - can engender a state of chronic cellular senescence that is characterized by the secretion of pro-inflammatory molecules that promote the functional decline of tissues and organs. Ablation of senescent cells has been postulated as a promising therapeutic venue to target the ageing phenotype and, thus, prevent or mitigate ageing-related diseases. However, owing to a lack of evidence, it is not possible to label cellular senescence as a cause or a consequence of neurodegeneration. This Review examines cellular senescence in the context of ageing and AD, and discusses which of the processes - cellular senescence or AD - might come first.}, } @article {pmid32597941, year = {2020}, author = {Oveisgharan, S and Wilson, RS and Yu, L and Schneider, JA and Bennett, DA}, title = {Association of Early-Life Cognitive Enrichment With Alzheimer Disease Pathological Changes and Cognitive Decline.}, journal = {JAMA neurology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaneurol.2020.1941}, pmid = {32597941}, issn = {2168-6157}, abstract = {Importance: Indicators of early-life cognitive enrichment (ELCE) have been associated with slower cognitive decline and decreased dementia in late life. However, the mechanisms underlying this association have not been elucidated.

Objective: To examine the association of ELCE with late-life Alzheimer disease (AD) and other common dementia-related pathological changes.

This clinical-pathological community-based cohort study, the Rush Memory and Aging Project, followed up participants before death for a mean (SD) of 7.0 (3.8) years with annual cognitive and clinical assessments. From January 1, 1997, through June 30, 2019, 2044 participants enrolled, of whom 1018 died. Postmortem data were leveraged from 813 participants. Data were analyzed from April 12, 2019, to February 20, 2020.

Exposures: Four indicators of ELCE (early-life socioeconomic status, availability of cognitive resources at 12 years of age, frequency of participation in cognitively stimulating activities, and early-life foreign language instruction) were obtained by self-report at the study baseline, from which a composite measure of ELCE was derived.

Main Outcomes and Measures: A continuous global AD pathology score derived from counts of diffuse plaques, neuritic plaques, and neurofibrillary tangles.

Results: The 813 participants included in the analysis had a mean (SD) age of 90.1 (6.3) years at the time of death, and 562 (69%) were women. In a linear regression model controlled for age at death, sex, and educational level, a higher level of ELCE was associated with a lower global AD pathology score (estimate, -0.057; standard error, 0.022; P = .01). However, ELCE was not associated with any other dementia-related pathological changes. In addition, a higher level of ELCE was associated with less cognitive decline (mean [SD], -0.13 [0.19] units per year; range, -1.74 to 0.85). An indirect effect through AD pathological changes constituted 20% of the association between ELCE and the rate of late-life cognitive decline, and 80% was a direct association.

Conclusions and Relevance: These findings suggest that ELCE was associated with better late-life cognitive health, in part through an association with fewer AD pathological changes.}, } @article {pmid32597936, year = {2020}, author = {Hohman, TJ and Kaczorowski, CC}, title = {Modifiable Lifestyle Factors in Alzheimer Disease: An Opportunity to Transform the Therapeutic Landscape Through Transdisciplinary Collaboration.}, journal = {JAMA neurology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaneurol.2020.1114}, pmid = {32597936}, issn = {2168-6157}, } @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 = {}, number = {}, pages = {}, doi = {10.1093/advances/nmaa073}, pmid = {32597927}, issn = {2156-5376}, 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 {pmid32597776, year = {2020}, author = {Schuch, LF and Rocha, MI and Matias, MP and Cintra, MT and Ferreira, RC and Aguiar, MC}, title = {Denture-related oral mucosal lesions in Alzheimer disease: a case-control study.}, journal = {General dentistry}, volume = {68}, number = {4}, pages = {36-41}, pmid = {32597776}, issn = {0363-6771}, abstract = {The aim of this case-control study was to evaluate the association between denture-related oral mucosal lesions and Alzheimer disease (AD) in older adults (60 years and older). Seventy elderly adults (35 with AD and 35 classified as mentally healthy) were included in this study, which was carried out in a Brazilian medical center. Clinical data on oral lesions and mucosal findings were recorded, including alterations in the color or appearance of any lesions, if present. The influence of possible confounding factors, including sex, age, race, education level, health conditions, harmful habits, gait speed, and oral status (use of removable prostheses and denture hygiene), was analyzed. There was no statistically significant difference between groups in the frequency of denture-related oral mucosal lesions. Logistic regression analysis showed a higher prevalence of AD among individuals aged 80 years and older, those who were illiterate, users of tobacco, and patients with a slower gait. These results suggest that AD is not a risk factor for denture-related oral mucosal lesions.}, } @article {pmid32597493, year = {2020}, author = {Chan, LKM and Braidy, N and Ng, W and Xu, YH and Chen, J and McDonald, R and Chan, DKY}, title = {Re-pigmentation of hair after prolonged cholinesterase inhibitor therapy in a Chinese population.}, journal = {The Australasian journal of dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1111/ajd.13356}, pmid = {32597493}, issn = {1440-0960}, abstract = {Eighty consecutive Chinese patients diagnosed with Alzheimer disease were assessed for darkening of grey hair. Of the 62 eligible patients (mean age = 79.3 ± 7.9 years; male: female = 1:1.48), 24/62 (38.7%, 95%CI: 26.6 - 51.9) reported hair darkening after prolonged usage of cholinesterase inhibitor for at least 6 months. Of the 24 patients with hair darkening, 17 (70.9%) experienced hair darkening in the occipital region, 3 (12.5%) in the parietal region, 2 (8.3%) patients in the frontal region and 2 (8.3%) patients experienced hair darkening in multiple regions. Analysis of melanin concentration showed no significant difference between darkened hair of patients after prolonged drug use and the dark hair of controls (P = 0.381).}, } @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 = {}, doi = {10.1111/cns.13429}, 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 {pmid32595884, year = {2020}, author = {Moura, FP and Hamdan, AC}, title = {Relations between subjective well-being and Alzheimer's disease: A systematic review.}, journal = {Dementia & neuropsychologia}, volume = {14}, number = {2}, pages = {153-158}, pmid = {32595884}, issn = {1980-5764}, abstract = {Subjective Well-Being (SWB) is determined by the degree of satisfaction with one's own life and the intensity/frequency with which we experience negative and positive emotions. Current studies indicate that SWB is beneficial for health.

Objective: The aim of this systematic review was to analyze the methodological quality of published articles on SWB in people with Alzheimer's disease (AD).

Methods: The keywords "Well-Being" and "Alzheimer" were used. Inclusion criteria were a) articles with a sample of the elderly population; b) empirical articles; c) articles published between 2014 and 2019. Analysis of the selected articles was performed using the Downs and Black Checklist.

Results: 13 articles were selected for further analysis. The results showed that only one of the articles reached a high methodological quality level. The other articles had an average level, ranging from 46% to 67%, of total protocol compliance.

Conclusion: The studies analyzed had a medium level of methodological quality. It is important to improve the methodological quality of studies on SWB in people with AD.}, } @article {pmid32595465, year = {2020}, author = {Castellazzi, G and Cuzzoni, MG and Cotta Ramusino, M and Martinelli, D and Denaro, F and Ricciardi, A and Vitali, P and Anzalone, N and Bernini, S and Palesi, F and Sinforiani, E and Costa, A and Micieli, G and D'Angelo, E and Magenes, G and Gandini Wheeler-Kingshott, CAM}, title = {A Machine Learning Approach for the Differential Diagnosis of Alzheimer and Vascular Dementia Fed by MRI Selected Features.}, journal = {Frontiers in neuroinformatics}, volume = {14}, number = {}, pages = {25}, pmid = {32595465}, issn = {1662-5196}, abstract = {Among dementia-like diseases, Alzheimer disease (AD) and vascular dementia (VD) are two of the most frequent. AD and VD may share multiple neurological symptoms that may lead to controversial diagnoses when using conventional clinical and MRI criteria. Therefore, other approaches are needed to overcome this issue. Machine learning (ML) combined with magnetic resonance imaging (MRI) has been shown to improve the diagnostic accuracy of several neurodegenerative diseases, including dementia. To this end, in this study, we investigated, first, whether different kinds of ML algorithms, combined with advanced MRI features, could be supportive in classifying VD from AD and, second, whether the developed approach might help in predicting the prevalent disease in subjects with an unclear profile of AD or VD. Three ML categories of algorithms were tested: artificial neural network (ANN), support vector machine (SVM), and adaptive neuro-fuzzy inference system (ANFIS). Multiple regional metrics from resting-state fMRI (rs-fMRI) and diffusion tensor imaging (DTI) of 60 subjects (33 AD, 27 VD) were used as input features to train the algorithms and find the best feature pattern to classify VD from AD. We then used the identified VD-AD discriminant feature pattern as input for the most performant ML algorithm to predict the disease prevalence in 15 dementia patients with a "mixed VD-AD dementia" (MXD) clinical profile using their baseline MRI data. ML predictions were compared with the diagnosis evidence from a 3-year clinical follow-up. ANFIS emerged as the most efficient algorithm in discriminating AD from VD, reaching a classification accuracy greater than 84% using a small feature pattern. Moreover, ANFIS showed improved classification accuracy when trained with a multimodal input feature data set (e.g., DTI + rs-fMRI metrics) rather than a unimodal feature data set. When applying the best discriminant pattern to the MXD group, ANFIS achieved a correct prediction rate of 77.33%. Overall, results showed that our approach has a high discriminant power to classify AD and VD profiles. Moreover, the same approach also showed potential in predicting earlier the prevalent underlying disease in dementia patients whose clinical profile is uncertain between AD and VD, therefore suggesting its usefulness in supporting physicians' diagnostic evaluations.}, } @article {pmid32595443, year = {2020}, author = {Sackmann, C and Sackmann, V and Hallbeck, M}, title = {TDP-43 Is Efficiently Transferred Between Neuron-Like Cells in a Manner Enhanced by Preservation of Its N-Terminus but Independent of Extracellular Vesicles.}, journal = {Frontiers in neuroscience}, volume = {14}, number = {}, pages = {540}, pmid = {32595443}, issn = {1662-4548}, abstract = {The misfolding of transactive response DNA-binding protein (TDP-43) is a major contributor to the pathogenesis of TDP-43 proteinopathies, including amyotrophic lateral sclerosis and frontotemporal lobar degeneration with TDP-43 inclusions, but also plays a role in other neurodegenerative diseases including Alzheimer disease. It is thought that different truncations at the N- and C-termini of TDP-43 contribute to its misfolding and aggregation in the brain, and that these aberrant TDP-43 fragments contribute to disease. Despite this, little is known about whether different truncation events influence the protein's transmissibility between cells and how this cell-to-cell transfer occurs. In this study, we use a well-established cellular model to study the efficiency by which full-length and truncated TDP-43 fragments are transferred between neuron-like cells. We demonstrate that preservation of the N-terminus of TDP-43 enhances its transmissibility between cells and that this protein transmission occurs in a manner exclusive of extracellular vesicles, instead requiring cellular proximity for efficient propagation. These data indicate that the N-terminus of TDP-43 might be a useful target in the generation of therapeutics to limit the spread of TDP-43 pathology.}, } @article {pmid32594811, year = {2020}, author = {Salimi, A and Gobadian, H and Sharif Makhmal Zadeh, B}, title = {Dermal Pharmacokinetics of rivastigmine-loaded liposomes: an Ex vivo- in vivo correlation study.}, journal = {Journal of liposome research}, volume = {}, number = {}, pages = {1-34}, doi = {10.1080/08982104.2020.1787440}, pmid = {32594811}, issn = {1532-2394}, abstract = {The aim of the present study was to develop a topical liposomal formulation as a transdermal delivery of rivastigmine for the treatment of Alzheimer disease as an alternative to the oral dosage form and to achieve smooth continuous drug delivery and maintain plasma levels within the therapeutic window. Rivastigmine-loaded liposomes were prepared by a thin layer hydration technique that was applied in Ex vivo- in vivo correlation study. Permeability parameters through rat skin in Ex vivo study and pharmacokinetic parameters in the in-vivo study were evaluated. The Ex vivo permeation study showed that liposomes provided steady-state flux 0.11 ± 0.01 mg/cm.h that was more than 2-fold the aqueous control. In the in vivo experiments, after topical application of optimized rivastigmine liposomes, the Cmax 208 ng/ml and AUC0-24 3605 (ng.h/ml) were also significantly higher than the control group (both P < 0.01). A point-to-point significant linear correlation was found between ex vivo- in vivo parameters, meaning in vivo pharmacokinetic parameters can be predicted by Ex vivo permeation parameters. These data suggest that a liposomal formulation could be an effective carrier to enhance rivastigmine permeation through the skin and maintain plasma levels within the therapeutic window.}, } @article {pmid32594361, year = {2020}, author = {Seliverstov, Y and Kanivets, I and Illarioshkin, S}, title = {Spinocerebellar Ataxia-Like Presentation of the M233V PSEN1 Mutation.}, journal = {Cerebellum (London, England)}, volume = {}, number = {}, pages = {}, doi = {10.1007/s12311-020-01161-3}, pmid = {32594361}, issn = {1473-4230}, abstract = {PSEN1 gene is considered to be the most common gene, which is responsible for the development of an autosomal dominant Alzheimer disease with early onset and sometimes broad phenotype. We present a patient with a spinocerebellar ataxia (SCA)-like phenotype who was found to carry an M233V mutation. General and neurological exam was carried out. Brain MRI as well as genetic testing for SCAs 1, 2, 3, 6, and 17 were performed. The patient was then referred for a next-generation sequencing-based gene panel test with 723 genes included. A 26-year-old man of an Azerbaijani origin presented with a progressive impairment of coordination followed by memory impairment. Family history was positive for a similar disorder suggesting autosomal dominant inheritance. Brain MRI showed bilateral hippocampal atrophy (more pronounced in the left), as well as mild atrophy of the left temporoparietal cortex. Tests for SCAs 1, 2, 3, 6, and 17 came negative. Gene panel test showed c.697A > G heterozygous variant in the PSEN1 gene leading to a M233V amino acid change, which was validated by a Sanger sequencing. So far, M233V mutation has not been associated with a combination of cerebellar and cognitive features at onset. Our case contributes to a better characterization of the PSEN1 mutations and expands the phenotype of the M233V carriers. We propose to consider PSEN1 mutations in patients presenting with an SCA-like phenotype but negative for common types of SCA.}, } @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}, 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}, 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 {pmid32593000, year = {2020}, author = {Hijazi, S and Heistek, TS and van der Loo, R and Mansvelder, HD and Smit, AB and van Kesteren, RE}, title = {Hyperexcitable Parvalbumin Interneurons Render Hippocampal Circuitry Vulnerable to Amyloid Beta.}, journal = {iScience}, volume = {23}, number = {7}, pages = {101271}, doi = {10.1016/j.isci.2020.101271}, pmid = {32593000}, issn = {2589-0042}, abstract = {Parvalbumin (PV) interneuron dysfunction is associated with various brain disorders, including Alzheimer disease (AD). Here, we asked whether early PV neuron hyperexcitability primes the hippocampus for amyloid beta-induced functional impairment. We show that prolonged chemogenetic activation of PV neurons induces long-term hyperexcitability of these cells, disrupts synaptic transmission, and causes spatial memory deficits on the short-term. On the long-term, pyramidal cells also become hyperexcitable, and synaptic transmission and spatial memory are restored. However, under these conditions of increased excitability of both PV and pyramidal cells, a single low-dose injection of amyloid beta directly into the hippocampus significantly impairs PV neuron function, increases pyramidal neuron excitability, and reduces synaptic transmission, resulting in significant spatial memory deficits. Taken together, our data show that an initial hyperexcitable state of PV neurons renders hippocampal function vulnerable to amyloid beta and may contribute to an increased risk for developing AD.}, } @article {pmid32591471, year = {2020}, author = {Van Harten, AC and Wiste, HJ and Weigand, SD and Mielke, MM and Kremers, WK and Eichenlaub, U and Batrla-Utermann, R and Dyer, RB and Algeciras-Schimnich, A and Knopman, DS and Jack, CR and Petersen, RC}, title = {CSF biomarkers in Olmsted County: Evidence of 2 subclasses and associations with demographics.}, journal = {Neurology}, volume = {}, number = {}, pages = {}, doi = {10.1212/WNL.0000000000009874}, pmid = {32591471}, issn = {1526-632X}, abstract = {OBJECTIVE: We studied interrelationships between CSF biomarkers and associations with APOE ε4 genotype, demographic variables, vascular variables, and clinical diagnosis in Olmsted County, Minnesota.

METHODS: We included 774 Mayo Clinic Study of Aging participants (693 cognitively unimpaired [CU]; 71 with mild cognitive impairment [MCI]). CSF β-amyloid 42 (Aβ42), total tau (t-tau), and hyperphosphorylated tau (p-tau) were analyzed using Aβ42 CSF, t-tau CSF, and p-tau (181P) CSF electrochemiluminescence immunoassays. Bivariate mixture models were used to evaluate latent classes. We used linear regression models to evaluate independent associations of APOE ε4, demographic factors, cardiovascular risk, and diagnosis with CSF biomarker levels. Results were weighted back to the Olmsted County population.

RESULTS: Interrelationships between CSF Aβ42 and p-tau/t-tau were consistent with 2 latent classes in the general population. In subgroup 1 (n = 547 [71%]), we found a strong positive correlation between Aβ42 and p-tau (ρ = 0.81), while the correlation was much smaller in group 2 (ρ = 0.26, n = 227 [29%]). Group 2 was associated with older age, APOE ε4 genotype, a diagnosis of MCI, and elevated amyloid PET. Overall, APOE ε4 genotype and MCI were associated with Aβ42, while age was associated with p-tau/t-tau. There were no associations with sex, education, or vascular risk.

CONCLUSION: We hypothesize the population without dementia can be subdivided into participants with and without biological Alzheimer disease (AD) based on the combination of CSF Aβ42 and p-tau/t-tau (represented also by the p-tau/t-tau/Aβ42 ratio). In those without biological AD, common factors such as CSF dynamics may cause a positive correlation between CSF Aβ42 and p-tau/t-tau, while AD leads to dissociation of these proteins.}, } @article {pmid32591186, year = {2020}, author = {Khedr, EM and Ahmed, OG and Sayed, HM and Abo-Elfetoh, N and Ali, AM and Gomaa, AM}, title = {Electrophysiological differences in cortical excitability in different forms of dementia: A transcranial magnetic stimulation and laboratory biomarkers study.}, journal = {Neurophysiologie clinique = Clinical neurophysiology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neucli.2020.05.001}, pmid = {32591186}, issn = {1769-7131}, abstract = {BACKGROUND: The aim of the present study was to identify neurophysiologic markers to differentiate between Alzheimer dementia (AD), Vascular dementia (VaD), and Parkinson's disease dementia (PDD), and to examine their relationship to levels of transforming growth factor β1 (TGFβ1).

METHODS: The study included 15 patients with each type of dementia (AD, VaD, PDD) and 25 control subjects. Dementia patients were diagnosed according to the DiagnosticandStatisticalManualofMentalDisorders4thedition-revised(DSM-IV-R). Modified Mini Mental State Examination (MMMSE), motor cortex excitability including resting and active motor thresholds (rMT, aMT), input-output (I/O) curve, contralateral and ipsilateral silent periods (cSP, iSP), short-interval intracortical inhibition (SICI) at 1,2 and 4ms, and serum levels of TGFβ1 were examined.

RESULTS: There were no significant differences between groups with regards to age, sex, education or socioeconomic level. There was significant neuronal hyperexcitability in the form of reduced rMT and aMT and a shallower I/O curve in all three groups of dementia compared with the control group. The durations of cSP and iSP were longer in AD and PDD groups compared with the control group, whereas there were no significant differences in VaD. SICI was less effective in the three dementia groups than in the control group at intervals of 4ms. Serum levels of TGFβ1 were significantly elevated in all dementia groups in comparison with the control group. There was a significant negative correlation between serum level of TGFβ1 and cSP, iSP, and SICI across all patients and a significant negative correlation between serum level of TGFβ1 and iSP duration in AD.

CONCLUSION: Although motor thresholds were reduced in all patients, measures of SICI, cSP and iSP could distinguish between dementia groups. Serum level of TGFβ1 negatively correlated with iSP specifically in the AD group. This suggests that levels of TGFβ1 may relate to GABAergic dysfunction in dementia.}, } @article {pmid32589876, year = {2020}, author = {Pomeshchik, Y and Klementieva, O and Gil, J and Martinsson, I and Hansen, MG and de Vries, T and Sancho-Balsells, A and Russ, K and Savchenko, E and Collin, A and Vaz, AR and Bagnoli, S and Nacmias, B and Rampon, C and Sorbi, S and Brites, D and Marko-Varga, G and Kokaia, Z and Rezeli, M and Gouras, GK and Roybon, L}, title = {Human iPSC-Derived Hippocampal Spheroids: An Innovative Tool for Stratifying Alzheimer Disease Patient-Specific Cellular Phenotypes and Developing Therapies.}, journal = {Stem cell reports}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.stemcr.2020.06.001}, pmid = {32589876}, issn = {2213-6711}, abstract = {The hippocampus is important for memory formation and is severely affected in the brain with Alzheimer disease (AD). Our understanding of early pathogenic processes occurring in hippocampi in AD is limited due to tissue unavailability. Here, we report a chemical approach to rapidly generate free-floating hippocampal spheroids (HSs), from human induced pluripotent stem cells. When used to model AD, both APP and atypical PS1 variant HSs displayed increased Aβ42/Aβ40 peptide ratios and decreased synaptic protein levels, which are common features of AD. However, the two variants differed in tau hyperphosphorylation, protein aggregation, and protein network alterations. NeuroD1-mediated gene therapy in HSs-derived progenitors resulted in modulation of expression of numerous genes, including those involved in synaptic transmission. Thus, HSs can be harnessed to unravel the mechanisms underlying early pathogenic changes in the hippocampi of AD patients, and provide a robust platform for the development of therapeutic strategies targeting early stage AD.}, } @article {pmid32589558, year = {2020}, author = {Dos Santos, TTBA and de Carvalho, RLS and Nogueira, M and Baptista, MAT and Kimura, N and Lacerda, IB and Dourado, MCN}, title = {The Relationship between Social Cognition and Executive Functions in Alzheimer's Disease: A Systematic Review.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/1567205017666200626205154}, pmid = {32589558}, issn = {1875-5828}, abstract = {INTRODUCTION: Social cognition (SC) is a complex construct that reflects a wide variety of implicit and explicit cognitive processes. Many neurocognitive domains are associated with SC and the executive function (EF) is the most representative one. We conducted a systematic review aiming at clarifying whether SC impairments are associated with dysfunction on EF in people with Alzheimer Disease (AD).

METHODS: The search, based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), was undertaken between January 2007 and December 2019 using Pubmed, SciELO, BIREME and Thomson Reuters Web of Science electronic databases. The keywords were SC, AD, EF, Neuropsychological functioning and Executive Disorder.

RESULTS: One hundred thirty-six articles were identified and fifteen were included. These studies are not in agreement about the extent of SC deficits in AD, mainly in the mild stage of the disease. EF deficits, specifically inhibition and the ability to manipulate verbal information, are associated with the impairment in SC in AD. SC decreases with the disease progression, a relationship explained by global cognition impairment and SC specific symptoms.

CONCLUSION: SC impairment is associated with disease progression, mainly because of the decline in EF. Studies on SC components are unequal, contributing to a frequent generalization of Theory of Mind results, and often hampering the investigation of other components, mainly empathy. More precise knowledge about SC functioning in AD may contribute to a better understanding of the behavioral changes and interpersonal interactions.}, } @article {pmid32589158, year = {2020}, author = {Peterson, CM and Mikal, JP and McCarron, HR and Finlay, JM and Mitchell, LL and Gaugler, JE}, title = {The Feasibility and Utility of a Personal Health Record for Persons With Dementia and Their Family Caregivers for Web-Based Care Coordination: Mixed Methods Study.}, journal = {JMIR aging}, volume = {3}, number = {1}, pages = {e17769}, doi = {10.2196/17769}, pmid = {32589158}, issn = {2561-7605}, abstract = {BACKGROUND: Managing the complex and long-term care needs of persons living with Alzheimer disease and related dementias (ADRD) can adversely impact the health of informal caregivers and their care recipients. Web-based personal health records (PHRs) are one way to potentially alleviate a caregiver's burden by simplifying ADRD health care management.

OBJECTIVE: This study aimed to evaluate Personal Health Record for Persons with Dementia and Their Family Caregivers (PHR-ADRD), a free web-based information exchange tool, using a multiphase mixed methods approach.

METHODS: Dementia caregivers (N=34) were surveyed for their well-being and perceptions of PHR-ADRD feasibility and utility at 6 and 12 months using close- and open-ended questions as well as a semistructured interview (n=8). Exploratory analyses compared participants' characteristics as well as PHR-ADRD use and experiences based on overall favorability status.

RESULTS: Feasibility and utility scores decreased over time, but a subset of participants indicated that the system was helpful. Quantitative comparisons could not explain why some participants indicated favorable, neutral, or unfavorable views of the system overall or had not engaged with PHR-ADRD. Qualitative findings suggested that technology literacy and primary care provider buy-in were barriers. Both qualitative and qualitative findings indicated that time constraints to learn and use the system affected most participants.

CONCLUSIONS: Development and dissemination of PHRs for family caregivers of persons with ADRD should aim to make systems user-friendly for persons with limited time and technological literacy. Establishing health care provider buy-in may be essential to the future success of any PHR system.}, } @article {pmid32588397, year = {2020}, author = {Gamboa, CJ and Julion, WA}, title = {Proactive Recruitment of Older African-Americans for Alzheimer's Research with Brain Donation: a Cohort Case Study of Success.}, journal = {Journal of racial and ethnic health disparities}, volume = {}, number = {}, pages = {}, doi = {10.1007/s40615-020-00803-w}, pmid = {32588397}, issn = {2196-8837}, support = {R01AG22018/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: Older African-American adults are under-recruited for Alzheimer's-related research that includes brain donation.

OBJECTIVE: This article describes the Minority Aging Research Study's brain donation challenges, processes, and successful procurement with older African-American adults (65 years and older).

DESIGN AND METHODS: The recruitment and retention strategy of the Minority Aging Research Study Brain Gifting Program was developed in accordance with Peplau's theory of interpersonal relationship and Swanson's middle-range theory of caring.

RESULTS: At the time of this submission, approximately 345 of 755 older African-American adults in the Minority Aging Research Study consented to brain donation to be completed at the time of death. Furthermore, the Minority Aging Research Study has had 33 successful brain donations with family amenability.

DISCUSSION: Tailored caring behaviors are effective to achieve high donation rates with older African-American adults who have consented to brain donation within an Alzheimer Research Study.

IMPLICATIONS: Changes in funding policy are needed to meet tailored active recruitment that is required to close the gaps in older African-American adults' participation in Alzheimer's-related research studies.}, } @article {pmid32587883, year = {2020}, author = {Aschenbrenner, AJ and Petros, J and McDade, E and Wang, G and Balota, DA and Benzinger, TL and Cruchaga, C and Goate, A and Xiong, C and Perrin, R and Fagan, AM and Graff-Radford, N and Ghetti, B and Levin, J and Weidinger, E and Schofield, P and Gräber, S and Lee, JH and Chhatwal, JP and Morris, JC and Bateman, R and Hassenstab, J and , }, title = {Relationships between big-five personality factors and Alzheimer's disease pathology in autosomal dominant Alzheimer's disease.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {12}, number = {1}, pages = {e12038}, doi = {10.1002/dad2.12038}, pmid = {32587883}, issn = {2352-8729}, abstract = {Introduction: Changes in personality characteristics are associated with the onset of symptoms in Alzheimer's disease (AD) and may even precede clinical diagnosis. However, personality changes caused by disease progression can be difficult to separate from changes that occur with normal aging. The Dominantly Inherited Alzheimer Network (DIAN) provides a unique cohort in which to relate measures of personality traits to in vivo markers of disease in a much younger sample than in typical late onset AD.

Methods: Personality traits measured with the International Personality Item Pool at baseline from DIAN participants were analyzed as a function of estimated years to onset of clinical symptoms and well-established AD biomarkers.

Results: Both neuroticism and conscientiousness were correlated with years to symptom onset and markers of tau pathology in the cerebrospinal fluid. Self-reported conscientiousness and both neuroticism and conscientiousness ratings from a collateral source were correlated with longitudinal rates of cognitive decline such that participants who were rated as higher on neuroticism and lower on conscientiousness exhibited accelerated rates of cognitive decline.

Discussion: Personality traits are correlated with the accumulation of AD pathology and time to symptom onset, suggesting that AD progression can influence an individual's personality characteristics. Together these findings suggest that measuring neuroticism and conscientiousness may hold utility in tracking disease progression in AD.}, } @article {pmid32587611, year = {2020}, author = {Li, Y and Kang, M and Sheng, C and Chen, G and Li, T and Wang, J and Cai, Y and Wang, R and Han, Y}, title = {Relationship between Urinary Alzheimer-Associated Neuronal Thread Protein and Apolipoprotein Epsilon 4 Allele in the Cognitively Normal Population.}, journal = {Neural plasticity}, volume = {2020}, number = {}, pages = {9742138}, doi = {10.1155/2020/9742138}, pmid = {32587611}, issn = {1687-5443}, abstract = {We investigated the relationship between urinary Alzheimer-associated neuronal thread protein (AD7c-NTP) levels and apolipoprotein epsilon 4 (ApoE ɛ4) alleles, as well as other factors that cause cognitive decline, in the cognitively normal population. We recruited 329 cognitively normal right-handed Han Chinese subjects who completed ApoE gene testing and urinary AD7c-NTP testing. There was no significant difference in urinary AD7c-NTP levels between the normal control and subjective cognitive decline groups. Urinary AD7c-NTP levels were significantly higher in subjects with ApoE ɛ3/4 and 4/4 [0.6074 (0.6541) ng/mL] than in subjects without ApoE ɛ4 [0.4368 (0.3392) ng/mL and 0.5287 (0.3656) ng/mL], and urinary AD7c-NTP levels positively correlated with ApoE genotype grade (r = 0.165, p = 0.003). There were significant differences in urinary AD7c-NTP levels between subjects with and without a history of coronary heart disease or diabetes. Urinary AD7c-NTP levels were not related to years of education, nature of work, family history of dementia, a history of hypertension, stroke, anemia, or thyroid dysfunction. Urinary AD7c-NTP levels were positively correlated with ApoE grade in the cognitively normal population. The relationship between risk factors of cognitive decline and urinary AD7c-NTP levels provides a new way for us to understand AD and urinary AD7c-NTP.}, } @article {pmid32587315, year = {2020}, author = {Frost, GR and Longo, V and Li, T and Jonas, LA and Judenhofer, M and Cherry, S and Koutcher, J and Lekaye, C and Zanzonico, P and Li, YM}, title = {Hybrid PET/MRI enables high-spatial resolution, quantitative imaging of amyloid plaques in an Alzheimer's disease mouse model.}, journal = {Scientific reports}, volume = {10}, number = {1}, pages = {10379}, doi = {10.1038/s41598-020-67284-z}, pmid = {32587315}, issn = {2045-2322}, abstract = {The emergence of PET probes for amyloid plaques and neurofibrillary tangles, hallmarks of Alzheimer disease (AD), enables monitoring of pathology in AD mouse models. However, small-animal PET imaging is limited by coarse spatial resolution. We have installed a custom-fabricated PET insert into our small-animal MRI instrument and used PET/MRI hybrid imaging to define regions of amyloid vulnerability in 5xFAD mice. We compared fluorine-18 [18F]-Florbetapir uptake in the 5xFAD brain by dedicated small-animal PET/MRI and PET/CT to validate the quantitative measurement of PET/MRI. Next, we used PET/MRI to define uptake in six brain regions. As expected, uptake was comparable to wild-type in the cerebellum and elevated in the cortex and hippocampus, regions implicated in AD. Interestingly, uptake was highest in the thalamus, a region often overlooked in AD studies. Development of small-animal PET/MRI enables tracking of brain region-specific pathology in mouse models, which may prove invaluable to understanding AD progression and therapeutic development.}, } @article {pmid32586758, year = {2020}, author = {González-Sánchez, M and Bartolome, F and Antequera, D and Puertas-Martín, V and González, P and Gómez-Grande, A and Llamas-Velasco, S and Herrero-San Martín, A and Pérez-Martínez, D and Villarejo-Galende, A and Atienza, M and Palomar-Bonet, M and Cantero, JL and Perry, G and Orive, G and Ibañez, B and Bueno, H and Fuster, V and Carro, E}, title = {Decreased salivary lactoferrin levels are specific to Alzheimer's disease.}, journal = {EBioMedicine}, volume = {}, number = {}, pages = {102834}, doi = {10.1016/j.ebiom.2020.102834}, pmid = {32586758}, issn = {2352-3964}, abstract = {BACKGROUND: Evidences of infectious pathogens in Alzheimer's disease (AD) brains may suggest a deteriorated innate immune system in AD pathophysiology. We previously demonstrated reduced salivary lactoferrin (Lf) levels, one of the major antimicrobial proteins, in AD patients.

METHODS: To assess the clinical utility of salivary Lf for AD diagnosis, we examine the relationship between salivary Lf and cerebral amyloid-β (Aβ) load using amyloid-Positron-Emission Tomography (PET) neuroimaging, in two different cross-sectional cohorts including patients with different neurodegenerative disorders.

FINDINGS: The diagnostic performance of salivary Lf in the cohort 1 had an area under the curve [AUC] of 0•95 (0•911-0•992) for the differentiation of the prodromal AD/AD group positive for amyloid-PET (PET+) versus healthy group, and 0•97 (0•924-1) versus the frontotemporal dementia (FTD) group. In the cohort 2, salivary Lf had also an excellent diagnostic performance in the health control group versus prodromal AD comparison: AUC 0•93 (0•876-0•989). Salivary Lf detected prodromal AD and AD dementia distinguishing them from FTD with over 87% sensitivity and 91% specificity.

INTERPRETATION: Salivary Lf seems to have a very good diagnostic performance to detect AD. Our findings support the possible utility of salivary Lf as a new non-invasive and cost-effective AD biomarker.

FUNDING: Instituto de Salud Carlos III (FIS15/00780, FIS18/00118), FEDER, Comunidad de Madrid (S2017/BMD-3700; NEUROMETAB-CM), and CIBERNED (PI2016/01) to E.C.; Spanish Ministry of Economy and Competitiveness (SAF2017-85310-R) to J.L.C., and (PSI2017-85311-P) to M.A.; International Centre on ageing CENIE-POCTEP (0348_CIE_6_E) to M.A.; Instituto de Salud Carlos III (PIE16/00021, PI17/01799), to H.B.}, } @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}, 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 {pmid32584440, year = {2020}, author = {García-Alberca, JM and Mendoza, S and Gris, E and Royo, JL and Cruz-Gamero, JM and García-Casares, N}, title = {White matter lesions and temporal atrophy are associated with cognitive and neuropsychiatric symptoms in patients with hypertension and alzheimer´s disease.}, journal = {International journal of geriatric psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1002/gps.5366}, pmid = {32584440}, issn = {1099-1166}, abstract = {OBJECTIVES: An increasing evidence suggests hypertension (HTN) could be linked to cognitive impairment and incident Alzheimer disease (AD). The precise mechanisms linking HTN and AD are not well known. The aim of this study was to assess the putative association between HTN and AD.

METHODS: We assessed in patients with AD associations between HTN and demographic and clinical data, vascular risk factors, treatments, APOE genotypes, brain white matter hyperintensities (WMH), and medial temporal atrophy (MTA) in multivariate analysis of covariance.

RESULTS: We studied 92 patients with AD (mean ± standard deviation age: 72.12±6.91; women: 66.30%). Patients with HTN had significantly worse cognitive and functional status and higher frequency and severity of neuropsychiatric symptoms (P=.010). MRI analyses showed significant increases in WMH (P=.018) and in MTA (P=.012) in patients with AD with HTN compared with those without HTN.

CONCLUSIONS: Neuroimaging burden (MTA and higher degree of severity of WMH) among patients with AD and HTN are associated with the impaired cognitive function and neuropsychiatric symtoms. This article is protected by copyright. All rights reserved.}, } @article {pmid32584265, year = {2020}, author = {Zhou, F and Xiong, X and Li, S and Liang, J and Zhang, X and Tian, M and Li, X and Gao, M and Tang, L and Li, Y}, title = {Enhanced autophagic retrograde axonal transport by dynein intermediate chain upregulation improves Aβ clearance and cognitive function in APP/PS1 double transgenic mice.}, journal = {Aging}, volume = {12}, number = {}, pages = {}, doi = {10.18632/aging.103382}, pmid = {32584265}, issn = {1945-4589}, abstract = {Autophagosome accumulation is observed in the distal axons of Alzheimer disease (AD) patients and AD animal models, suggesting that deficient retrograde transport and impaired autophagic clearance of beta-amyloid (A β) contribute to AD pathogenesis. Expression of the retrograde axonal transport-related protein dynein intermediate chain (DIC) is also reduced in AD patients, but the contributions of DIC to AD pathology remain elusive. This study investigated the effects of DIC expression levels on cognitive function, autophagosome axonal transport, and A β clearance in the APP/PS1 double transgenic mouse model of AD. Autophagic activity was enhanced in the hippocampus of young (3-month-old) AD mice, as evidenced by greater expression of autophagosome markers, lysosome markers, axonal transport motors (including DIC), and dynein regulatory proteins. The expression levels of autophagosome markers remained elevated, whereas those of autophagic and axonal transport proteins decreased progressively with age, accompanied by spatial learning and memory deficits, axonal autophagosome accumulation, and A β deposition. Knockdown of DIC exacerbated while overexpression improved axonal transport, autophagosome maturation, Aβ clearance, and spatial learning and memory in aged AD mice. Our study provides evidence that age-dependent failure of axonal autophagic flux contributes to AD-associated neuropathology and cognitive deficits, suggesting DIC as a potential therapeutic target for AD.}, } @article {pmid32583410, year = {2020}, author = {Montoya-Pedrón, A and Ocaña-Montoya, CM and Bolaño-Díaz, GA}, title = {[P300 cognitive event-related potentials in the diagnosis and classification of possible Alzheimer-type neurocognitive disorders].}, journal = {Revista de neurologia}, volume = {71}, number = {1}, pages = {11-18}, doi = {10.33588/rn.7101.2019341}, pmid = {32583410}, issn = {1576-6578}, abstract = {INTRODUCTION: The value of the P300 cognitive event-related potential in the diagnosis of Alzheimer subtype neurocognitive disorders is still incipient. Recent studies suggest that combining it with neuropsychological tests by cognitive domains would allow an objective and early characterisation of the cognitive impairment in its initial stages.

AIMS: To characterise the electrophysiological patterns in the P300 potential that obtain a discriminatory value for the diagnosis and classification of the neurocognitive disorders with a possible Alzheimer-type aetiology.

SUBJECTS AND METHODS: This study examines 39 patients classified, according to the DSM-5, with possible Alzheimer-type minor and major neurocognitive disorders, aged between 50 and 85 years, and 53 control subjects with normal cognitive functions. The P300 potential is registered in the auditory mode, oddball paradigm and centroparietal recording.

RESULTS: P300 latency is significantly prolonged in subjects with neurocognitive disorder; there are significant differences in the mean values and confidence intervals between healthy controls and patients. No significant differences are obtained in P300 latency between groups with minor and major neurocognitive disorder. The mean amplitude value decreases in neurocognitive disorder, and the P300 amplitude logarithm of the control groups and those with minor and major neurocognitive disorder reaches significantly different mean values and confidence intervals.

CONCLUSIONS: The parameters quantified in the P300 potential can be used as complementary biomarkers to classify the presence and level of cognitive dysfunction with a possible Alzheimer-type aetiology.}, } @article {pmid32582835, year = {2020}, author = {Tsoy, E and Erlhoff, SJ and Goode, CA and Dorsman, KA and Kanjanapong, S and Lindbergh, CA and La Joie, R and Strom, A and Rabinovici, GD and Lanata, SC and Miller, BL and Tomaszewski Farias, SE and Kramer, JH and Rankin, KP and Possin, KL}, title = {BHA-CS: A novel cognitive composite for Alzheimer's disease and related disorders.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {12}, number = {1}, pages = {e12042}, doi = {10.1002/dad2.12042}, pmid = {32582835}, issn = {2352-8729}, abstract = {Introduction: Composite scores based on psychometrically rigorous cognitive assessments are well suited for early diagnosis and disease monitoring.

Methods: We developed and cross-validated the Brain Health Assessment-Cognitive Score (BHA-CS), based on a brief computerized battery, in 451 cognitively normal (CN) and 399 cognitively impaired (mild cognitive impairment [MCI] or dementia) older adults. We investigated its long-term reliability and reliable change indices at longitudinal follow-up (N = 340), and the association with amyloid beta (Aβ) burden in the CN subgroup with Aβ positron emission tomography (N = 119).

Results: The BHA-CS was accurate at detecting cognitive impairment and exhibited excellent long-term stability. Reliable decline over one year was detected in 75% of participants with dementia, 44% with MCI, and 3% of CN. Among CN, the Aβ-positive group showed worse longitudinal performance on the BHA-CS compared to the Aβ-negative group.

Discussion: The BHA-CS is sensitive to cognitive decline in preclinical and prodromal neurodegenerative disease.}, } @article {pmid32582762, year = {2020}, author = {Milordini, G and Zacco, E and Percival, M and Puglisi, R and Dal Piaz, F and Temussi, P and Pastore, A}, title = {The Role of Glycation on the Aggregation Properties of IAPP.}, journal = {Frontiers in molecular biosciences}, volume = {7}, number = {}, pages = {104}, doi = {10.3389/fmolb.2020.00104}, pmid = {32582762}, issn = {2296-889X}, abstract = {Epidemiological evidence shows an increased risk for developing Alzheimer's disease in people affected by diabetes, a pathology associated with increased hyperglycemia. A potential factor that could explain this link could be the role that sugars may play in both diseases under the form of glycation. Contrary to glycosylation, glycation is an enzyme-free reaction that leads to formation of toxic advanced glycation end-products (AGEs). In diabetes, the islet amyloid polypeptide (IAPP or amylin) is found to be heavily glycated and to form toxic amyloid-like aggregates, similar to those observed for the Aβ peptides, often also heavily glycated, observed in Alzheimer patients. Here, we studied the effects of glycation on the structure and aggregation properties of IAPP with several biophysical techniques ranging from fluorescence to circular dichroism, mass spectrometry and atomic force microscopy. We demonstrate that glycation occurs exclusively on the N-terminal lysine leaving the only arginine (Arg11) unmodified. At variance with recent studies, we show that the dynamical interplay between glycation and aggregation affects the structure of the peptide, slows down the aggregation process and influences the aggregate morphology.}, } @article {pmid32582013, year = {2020}, author = {Turner, RS and Stubbs, T and Davies, DA and Albensi, BC}, title = {Potential New Approaches for Diagnosis of Alzheimer's Disease and Related Dementias.}, journal = {Frontiers in neurology}, volume = {11}, number = {}, pages = {496}, doi = {10.3389/fneur.2020.00496}, pmid = {32582013}, issn = {1664-2295}, abstract = {Dementia is an umbrella term-caused by a large number of specific diagnoses, including several neurodegenerative disorders. Alzheimer's disease (AD) is now the most common cause of dementia in advanced countries, while dementia due to neurosyphilis was the leading cause a century ago. Many challenges remain for diagnosing dementia definitively. Some of these include variability of early symptoms and overlap with similar disorders, as well as the possibility of combined, or mixed, etiologies in some cases. Newer technologies, including the incorporation of PET neuroimaging and other biomarkers (genomics and proteomics), are being incorporated into revised diagnostic criteria. However, the application of novel diagnostic methods at clinical sites is plagued by many caveats including availability and access. This review surveys new diagnostic methods as well as remaining challenges-for clinical care and clinical research.}, } @article {pmid32581770, year = {2020}, author = {Kim, JW and Byun, MS and Yi, D and Lee, JH and Jeon, SY and Ko, K and Jung, G and Lee, HN and Lee, JY and Sohn, CH and Lee, YS and Shin, SA and Kim, YK and Lee, DY and , }, title = {Serum Uric Acid, Alzheimer-Related Brain Changes, and Cognitive Impairment.}, journal = {Frontiers in aging neuroscience}, volume = {12}, number = {}, pages = {160}, doi = {10.3389/fnagi.2020.00160}, pmid = {32581770}, issn = {1663-4365}, abstract = {Background: Despite known associations of lower serum uric acid (UA) with Alzheimer's disease (AD) dementia or AD-related cognitive impairment, little is known regarding the underlying patho-mechanisms. We aimed to examine the relationships of serum UA with in vivo AD pathologies including cerebral beta-amyloid (Aβ) and tau deposition, AD-signature region cerebral glucose metabolism (AD-CM), and white matter hyperintensities (WMH). We also investigated the association between serum UA and cognitive performance, and then assessed whether such an association is mediated by the brain pathologies.

Methods: A total of 430 non-demented older adults underwent comprehensive clinical assessments, measurement of serum UA level, and multimodal brain imaging, including Pittsburgh compound B-positron emission tomography (PET), AV-1451 PET, fluorodeoxyglucose (FDG)-PET, and magnetic resonance imaging scans. Mini-Mental State Examination (MMSE) and word list recall (WLR) test scores were used to measure cognitive performance.

Results: Serum UA level was significantly associated with AD-CM, but not with Aβ deposition, tau deposition, or WMH volume. Serum UA levels also had significant association with WLR and marginal association with MMSE; such associations disappeared when AD-CM was controlled as a covariate, indicating that AD-CM has a mediating effect.

Conclusion: The findings of the present study indicate that there is an association of low serum UA with AD-related cerebral hypometabolism, and whether this represents a causal relationship remains to be determined.}, } @article {pmid32580974, year = {2020}, author = {Rahman, A and Schelbaum, E and Hoffman, K and Diaz, I and Hristov, H and Andrews, R and Jett, S and Jackson, H and Lee, A and Sarva, H and Pahlajani, S and Matthews, D and Dyke, J and de Leon, MJ and Isaacson, RS and Brinton, RD and Mosconi, L}, title = {Sex-driven modifiers of Alzheimer risk: A multimodality brain imaging study.}, journal = {Neurology}, volume = {}, number = {}, pages = {}, doi = {10.1212/WNL.0000000000009781}, pmid = {32580974}, issn = {1526-632X}, abstract = {OBJECTIVE: To investigate sex differences in late-onset Alzheimer disease (AD) risks by means of multimodality brain biomarkers (β-amyloid load via 11C-Pittsburgh compound B [PiB] PET, neurodegeneration via 18F-fluorodeoxyglucose [FDG] PET and structural MRI).

METHODS: We examined 121 cognitively normal participants (85 women and 36 men) 40 to 65 years of age with clinical, laboratory, neuropsychological, lifestyle, MRI, FDG- and PiB-PET examinations. Several clinical (e.g., age, education, APOE status, family history), medical (e.g., depression, diabetes mellitus, hyperlipidemia), hormonal (e.g., thyroid disease, menopause), and lifestyle AD risk factors (e.g., smoking, diet, exercise, intellectual activity) were assessed. Statistical parametric mapping and least absolute shrinkage and selection operator regressions were used to compare AD biomarkers between men and women and to identify the risk factors associated with sex-related differences.

RESULTS: Groups were comparable on clinical and cognitive measures. After adjustment for each modality-specific confounders, the female group showed higher PiB β-amyloid deposition, lower FDG glucose metabolism, and lower MRI gray and white matter volumes compared to the male group (p < 0.05, family-wise error corrected for multiple comparisons). The male group did not show biomarker abnormalities compared to the female group. Results were independent of age and remained significant with the use of age-matched groups. Second to female sex, menopausal status was the predictor most consistently and strongly associated with the observed brain biomarker differences, followed by hormone therapy, hysterectomy status, and thyroid disease.

CONCLUSION: Hormonal risk factors, in particular menopause, predict AD endophenotype in middle-aged women. These findings suggest that the window of opportunity for AD preventive interventions in women is early in the endocrine aging process.}, } @article {pmid32580164, year = {2020}, author = {Dillon, K and Prapavessis, H}, title = {REducing SEDENTary Behavior Among Mild to Moderate Cognitively Impaired Assisted Living Residents: A Pilot Randomized Controlled Trial (RESEDENT Study).}, journal = {Journal of aging and physical activity}, volume = {}, number = {}, pages = {1-9}, doi = {10.1123/japa.2019-0440}, pmid = {32580164}, issn = {1543-267X}, abstract = {Older adults in assisted living spend most of their day in sedentary behaviors, which may be detrimental to cognitive function. The primary purpose of this pilot study was to assess the feasibility of using a prompting device to reduce sitting time with light walking among older adults with mild to moderate cognitive impairment residing in an assisted living setting. A secondary purpose was to examine the effectiveness of the intervention on the residents' cognitive function, physical function, and quality of life. The participants (n = 25, mean age = 86.7 [5.3] years) were assigned in clusters into a two-arm 10-week single-site pilot randomized controlled trial. The intervention group was prompted with a watch to interrupt sedentary behaviors and partake in 10 min of light physical activity (i.e., walking) three times a day after a meal. The assessments included hip-worn accelerometers (Actical) and diaries, the Alzheimer's disease assessment scale-cognitive, Timed Up and Go, and the short-form 36 health survey. Adherence was high, as there were no dropouts, and over 70% of the participants completed over 80% of the prescribed physical activity bouts. Significant effects favoring the intervention were shown for all outcomes.}, } @article {pmid32579923, year = {2020}, author = {Socodato, R and Portugal, CC and Canedo, T and Rodrigues, A and Almeida, TO and Henriques, JF and Vaz, SH and Magalhães, J and Silva, CM and Baptista, FI and Alves, RL and Coelho-Santos, V and Silva, AP and Paes-de-Carvalho, R and Magalhães, A and Brakebusch, C and Sebastião, AM and Summavielle, T and Ambrósio, AF and Relvas, JB}, title = {Microglia Dysfunction Caused by the Loss of Rhoa Disrupts Neuronal Physiology and Leads to Neurodegeneration.}, journal = {Cell reports}, volume = {31}, number = {12}, pages = {107796}, doi = {10.1016/j.celrep.2020.107796}, pmid = {32579923}, issn = {2211-1247}, abstract = {Nervous tissue homeostasis requires the regulation of microglia activity. Using conditional gene targeting in mice, we demonstrate that genetic ablation of the small GTPase Rhoa in adult microglia is sufficient to trigger spontaneous microglia activation, producing a neurological phenotype (including synapse and neuron loss, impairment of long-term potentiation [LTP], formation of β-amyloid plaques, and memory deficits). Mechanistically, loss of Rhoa in microglia triggers Src activation and Src-mediated tumor necrosis factor (TNF) production, leading to excitotoxic glutamate secretion. Inhibiting Src in microglia Rhoa-deficient mice attenuates microglia dysregulation and the ensuing neurological phenotype. We also find that the Rhoa/Src signaling pathway is disrupted in microglia of the APP/PS1 mouse model of Alzheimer disease and that low doses of Aβ oligomers trigger microglia neurotoxic polarization through the disruption of Rhoa-to-Src signaling. Overall, our results indicate that disturbing Rho GTPase signaling in microglia can directly cause neurodegeneration.}, } @article {pmid32579270, year = {2020}, author = {Bres, EE and Safina, D and Müller, J and Bedner, P and Yang, H and Helluy, X and Shchyglo, O and Jansen, S and Mark, MD and Esser, A and Steinhäuser, C and Herlitze, S and Pietrzik, CU and Sirko, S and Manahan-Vaughan, D and Faissner, A}, title = {Lipoprotein receptor loss in forebrain radial glia results in neurological deficits and severe seizures.}, journal = {Glia}, volume = {}, number = {}, pages = {}, doi = {10.1002/glia.23869}, pmid = {32579270}, issn = {1098-1136}, support = {MA 5806/1-2//Deutsche Forschungsgemeinschaft/ ; MA 5806/2-1//Deutsche Forschungsgemeinschaft/ ; PI 379/8-1//Deutsche Forschungsgemeinschaft/ ; SFB 1280/A04//Deutsche Forschungsgemeinschaft/ ; SFB 874/B10//Deutsche Forschungsgemeinschaft/ ; SPP 1757 Fa 159/20-1-2//Deutsche Forschungsgemeinschaft/ ; //European Commission: ERA NET Neuron, H2020-MSCA-ITN EU-Glia-PhD./ ; }, abstract = {The Alzheimer disease-associated multifunctional low-density lipoprotein receptor-related protein-1 is expressed in the brain. Recent studies uncovered a role of this receptor for the appropriate functioning of neural stem cells, oligodendrocytes, and neurons. The constitutive knock-out (KO) of the receptor is embryonically lethal. To unravel the receptors' role in the developing brain we generated a mouse mutant by specifically targeting radial glia stem cells of the dorsal telencephalon. The low-density lipoprotein receptor-related protein-1 lineage-restricted KO female and male mice, in contrast to available models, developed a severe neurological phenotype with generalized seizures during early postnatal development. The mechanism leading to a buildup of hyperexcitability and emergence of seizures was traced to a failure in adequate astrocyte development and deteriorated postsynaptic density integrity. The detected impairments in the astrocytic lineage: precocious maturation, reactive gliosis, abolished tissue plasminogen activator uptake, and loss of functionality emphasize the importance of this glial cell type for synaptic signaling in the developing brain. Together, the obtained results highlight the relevance of astrocytic low-density lipoprotein receptor-related protein-1 for glutamatergic signaling in the context of neuron-glia interactions and stage this receptor as a contributing factor for epilepsy.}, } @article {pmid32579116, year = {2020}, author = {Ren, S and Yao, W and Tambini, MD and Yin, T and Norris, KA and D'Adamio, L}, title = {Microglia TREM2R47H Alzheimer-linked variant enhances excitatory transmission and reduces LTP via increased TNF-α levels.}, journal = {eLife}, volume = {9}, number = {}, pages = {}, doi = {10.7554/eLife.57513}, pmid = {32579116}, issn = {2050-084X}, support = {R01AG063407/AG/NIA NIH HHS/United States ; RF1AG064821/AG/NIA NIH HHS/United States ; }, abstract = {To study the mechanisms by which the p.R47H variant of the microglia gene and Alzheimer's disease (AD) risk factor TREM2 increases dementia risk, we created Trem2R47H KI rats. Trem2R47H rats were engineered to produce human Aβ to define human-Aβ-dependent and -independent pathogenic mechanisms triggered by this variant. Interestingly, pre- and peri-adolescent Trem2R47H rats present increased brain concentrations of TNF-α, augmented glutamatergic transmission, suppression of Long-term-Potentiation (LTP), an electrophysiological surrogate of learning and memory, but normal Ab levels. Acute reduction of TNF-α activity with a neutralizing anti-TNF-α antibody occludes the boost in amplitude of glutamatergic transmission and LTP suppression observed in young Trem2R47H/R47H rats. Thus, the microglia-specific pathogenic Trem2 variant boosts glutamatergic neuronal transmission and suppresses LTP by increasing brain TNF-α concentrations, directly linking microglia to neuronal dysfunction. Future studies will determine whether this phenomenon represents an early, Aβ-independent pathway that facilitates dementia pathogenesis in humans.}, } @article {pmid32576807, year = {2020}, author = {Yasen, AL and Eick, GN and Sterner, KN and Christie, AD}, title = {Motor Cortex Function in APOE4 Carriers and Noncarriers.}, journal = {Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society}, volume = {}, number = {}, pages = {}, doi = {10.1097/WNP.0000000000000738}, pmid = {32576807}, issn = {1537-1603}, abstract = {PURPOSE: The ε4 allele of the apolipoprotein-E gene has been associated with disease activity including Alzheimer disease, multiple sclerosis, and cardiovascular disease. Individuals who possess the ε4 variant of this gene (ε4 carriers) also demonstrate higher levels of cognitive impairment and lower motor scores compared with noncarriers. The purpose of this study was to establish whether there is a difference in motor cortex function between apoε4 carriers and noncarriers. We hypothesized that carriers would have lower levels of excitability and excitatory transmitter (glutamate) and similar levels of intracortical inhibition and inhibitory neurotransmitter (gamma-aminobutyric acid) than noncarriers.

METHODS: Fifty-two participants provided saliva samples to determine apoε4 carrier status. Measures of motor cortex excitability and inhibition were obtained using transcranial magnetic stimulation, and measures of glutamate and gamma-aminobutyric acid concentrations were obtained using proton magnetic resonance spectroscopy.

RESULTS: No significant differences in transcranial magnetic stimulation (P ≥ 0.19) or proton magnetic resonance spectroscopy measures (P ≥ 0.90) were found between carriers and noncarriers.

CONCLUSIONS: The results from this study suggest that motor cortex function, as assessed by transcranial magnetic stimulation measures of excitability and inhibition, and MRS measures of excitatory and inhibitory neurotransmitter are similar in those who possess an apoε4 allele and those who do not.}, } @article {pmid32576542, year = {2020}, author = {Van Overloop, R and Campserveux, L and Arlotto, S}, title = {Psychotropic drugs use in cognitive behavioral specialized care unit.}, journal = {Geriatrie et psychologie neuropsychiatrie du vieillissement}, volume = {}, number = {}, pages = {}, doi = {10.1684/pnv.2020.0851}, pmid = {32576542}, issn = {2115-7863}, abstract = {Behavioral and psychological symptoms of dementia (BPSD) are frequent and belong to the evolution of the disease. Cognitive behavioral units (unité cognitivo-comportementale) were created in France to improve care management. The main aim of the current study was to describe the progression of the psychotropic drugs use between admission to discharge. The second aim was to compare the prescriptions of two physicians.

METHOD: Descriptive, retrospective, monocentric study, between may 2016 and may 2018.

RESULTS: Psychotropic drugs use was constant regarding the 123 patients. Antipsychotic agents, acetylcholinesterase inhibitors and memantine use was lower at discharge (p <0.05), while hypnotic benzodiazepines and antidepressive agents use were higher (p <0.05). For both of physicians, prescriptions were similar except for antipsychotics association and benzodiazepines association.

CONCLUSION: To optimize psychotropic drugs use is an important aim in specialized cognitive behavioral units. Analysis and knowledge sharing shall be kep on going.}, } @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 = {}, doi = {10.3390/molecules25122837}, pmid = {32575531}, issn = {1420-3049}, 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 = {}, doi = {10.3390/jcm9061919}, 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}, 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 {pmid32570570, year = {2020}, author = {Almeida, JR and Monteiro, E and Silva, LB and Pazos, A and Oliveira, JL}, title = {A Recommender System Based on Cohorts' Similarity.}, journal = {Studies in health technology and informatics}, volume = {270}, number = {}, pages = {1183-1184}, doi = {10.3233/SHTI200353}, pmid = {32570570}, issn = {1879-8365}, abstract = {Aiming to better understand the genetic and environmental associations of Alzheimer's disease, many clinical trials and scientific studies have been conducted. However, these studies are often based on a small number of participants. To address this limitation, there is an increasing demand of multi-cohorts studies, which can provide higher statistical power and clinical evidence. However, this data integration implies dealing with the diversity of cohorts structures and the wide variability of concepts. Moreover, discovering similar cohorts to extend a running study is typically a demanding task. In this paper, we present a recommendation system to allow finding similar cohorts based on profile interests. The method uses collaborative filtering mixed with context-based retrieval techniques to find relevant cohorts on scientific literature about Alzheimer's diseases. The method was validated in a set of 62 cohorts.}, } @article {pmid32570553, year = {2020}, author = {Arief, M and Rissanen, S and Saranto, K}, title = {Effectiveness of Web Accessibility Policy Implementation in Online Healthcare Information.}, journal = {Studies in health technology and informatics}, volume = {270}, number = {}, pages = {1108-1112}, doi = {10.3233/SHTI200334}, pmid = {32570553}, issn = {1879-8365}, abstract = {UN have recommended the adoption of Web Content Accessibility Guidelines (WCAG) version 2.0 from W3C to guarantee that web content is more accessible to everyone. This study aims to evaluate the effectiveness of WCAG 2.0 implementation by comparing the country with and without WCAG2.0 policy adoption. The objective is to compare the impact of adopting the WCAG 2.0 standard in health information provision by analyzing the differences between countries that adopted the WCAG 2.0 standard and those that did not, specifically for health information related to the elderly. To this end, searches were performed on the Google search engine for online health websites with the keyword "Alzheimer" and the specific country settings for Indonesia and UK, in the local language of each country. Website evaluations were performed for ten websites found with this search by using the WCAG 2.0 measurement tool Axe. Statistical analysis using descriptive and Mann-Whitney analysis to measure the impact of the WCAG 2.0 showed a predominance of low violation occurrences in the UK with 40% from selected websites compared to 80% medium violation occurrences and no low violation occurrences in Indonesia. Although the country with WCAG 2.0 implementation had a lower frequency of violation, no significant differences were found between countries and the media type in WCAG 2.0 evaluation, implying the need to improve the effectiveness of policy implementation.}, } @article {pmid32568785, year = {2020}, author = {Lehrer, S and Rheinstein, PH}, title = {Alzheimer Gene BIN1 may Simultaneously Influence Dementia Risk and Androgen Deprivation Therapy Dosage in Prostate Cancer.}, journal = {American journal of clinical oncology}, volume = {}, number = {}, pages = {}, doi = {10.1097/COC.0000000000000727}, pmid = {32568785}, issn = {1537-453X}, abstract = {BACKGROUND: Androgen deprivation therapy (ADT) is extensively used in prostate cancer. Yet the risk of impaired cognition or Alzheimer disease (AD) in men with prostate cancer receiving ADT is uncertain. Some studies of prostate cancer and ADT suggest that the risk of AD is not increased. But other studies have found an increased risk of AD and cognitive impairment.

OBJECTIVES: As the uncertainty about ADT and dementia might relate to the genetics of prostate cancer and AD, the authors used the Cancer Genome Atlas (TCGA) to examine the relationship in men with prostate cancer between genes implicated in AD and genes implicated in prostate cancer.

METHODS: The authors examined the genomics of 492 prostate cancer cases in the Genomic Data Commons (GDC) TCGA Prostate Cancer (PRAD) data set. To access and analyze the data, 2 web-based interfaces were used: (1) the UCSC Xena browser, a web-based visual integration and exploration tool for TCGA data, including clinical and phenotypic annotations; and (2) cBioportal, a web-based interface that enables integrative analysis of complex cancer genomics and clinical profiles.

RESULTS: Co-occurrence analysis indicates that alterations in the prostate cancer gene Speckle-type POZ protein (SPOP) significantly co-occur with alterations in the AD gene BIN1 (P<0.001). The presence of somatic mutations (deleterious and missense/in frame) in SPOP deranges BIN1 gene expression. SPOP/BIN1 RNA gene expression in 492 prostate cancer specimens is significantly correlated (P<0.001). Increased expression of SPOP in 492 prostate cancers is associated with reduced survival (P=0.00275). Men receiving pharmacologic therapy had a tumor with a significantly higher Gleason score (P=0.023). Gleason score and BIN1 RNA gene expression, unit log2 (fragments per kilobase of transcript per million mapped reads upper quartile [FPKM-UQ]+1), in 499 prostate cancer specimens were significantly inversely correlated (P<0.001).

CONCLUSIONS: BIN1 forms part of a network that interacts with the MYC oncogene, activated at the earliest phases of prostate cancer and in its position on chr8q24 linked to disease aggressiveness. Dynamic regulation of the BIN1-Tau interaction is involved in AD. BIN1 loss in AD allows phosphorylated tau to be mis-sorted to synapses, which likely alters the integrity of the postsynapse, alongside reducing the functionally important release of physiological forms of tau. Alzheimer symptoms are usually preceded by a preclinical phase that may be 16 years long. The authors suggest that the ADT dosage reflects the severity of a process that is already underway. The severity is determined by the genetics of the tumor itself, at least in part by BIN1. ADT is not causing new cases of AD. The oncologist treats higher-grade prostate cancer with more ADT, which serves as a surrogate marker for disease severity. Our analysis of TCGA data does not support the idea that ADT causes AD or dementia.}, } @article {pmid32568700, year = {2020}, author = {Razzino, CA and Serafín, V and Gamella, M and Pedrero, M and Montero-Calle, A and Barderas, R and Calero, M and Lobo, AO and Yáñez-Sedeño, P and Campuzano, S and Pingarrón, JM}, title = {An electrochemical immunosensor using gold nanoparticles-PAMAM-nanostructured screen-printed carbon electrodes for tau protein determination in plasma and brain tissues from Alzheimer patients.}, journal = {Biosensors & bioelectronics}, volume = {163}, number = {}, pages = {112238}, doi = {10.1016/j.bios.2020.112238}, pmid = {32568700}, issn = {1873-4235}, abstract = {This work reports a new sensitive strategy for the determination of tau protein, a hallmark of Alzheimer's disease (AD), involving a sandwich immunoassay and amperometric detection at disposable screen-printed carbon electrodes (SPCEs) modified with a gold nanoparticles-poly(amidoamine) (PAMAM) dendrimer nanocomposite (3D-Au-PAMAM) covalently immobilized onto electrografted p-aminobenzoic acid (p-ABA). The capture antibody (CAb) was immobilized by crosslinking with glutaraldehyde (GA) on the amino groups of the 3D-Au-PAMAM-p-ABA-SPCE, where tau protein was sandwiched with a secondary antibody labeled with horseradish peroxidase (HRP-DAb). Amperometry at -200 mV (vs the Ag pseudo-reference electrode) upon the addition of hydroquinone (HQ) as electron transfer mediator and H2O2 as the enzyme substrate was used to detect the immunocomplex formation. The great analytical performance of the immunosensor in terms of selectivity and low limit of detection (LOD) (1.7 pg mL-1) allowed the direct determination of the target protein in raw plasma samples and in brain tissue extracts from healthy individuals and post mortem diagnosed AD patients, using a simple and fast protocol.}, } @article {pmid32568644, year = {2020}, author = {Tang, EYH and Price, CI and Robinson, L and Exley, C and Desmond, DW and Köhler, S and Staals, J and Yin Ka Lam, B and Wong, A and Mok, V and Bordet, R and Bordet, AM and Dondaine, T and Lo, JW and Sachdev, PS and Stephan, BCM and , }, title = {Assessing the Predictive Validity of Simple Dementia Risk Models in Harmonized Stroke Cohorts.}, journal = {Stroke}, volume = {51}, number = {7}, pages = {2095-2102}, doi = {10.1161/STROKEAHA.120.027473}, pmid = {32568644}, issn = {1524-4628}, abstract = {BACKGROUND AND PURPOSE: Stroke is associated with an increased risk of dementia. To assist in the early identification of individuals at high risk of future dementia, numerous prediction models have been developed for use in the general population. However, it is not known whether such models also provide accurate predictions among stroke patients. Therefore, the aim of this study was to determine whether existing dementia risk prediction models that were developed for use in the general population can also be applied to individuals with a history of stroke to predict poststroke dementia with equivalent predictive validity.

METHODS: Data were harmonized from 4 stroke studies (follow-up range, ≈12-18 months poststroke) from Hong Kong, the United States, the Netherlands, and France. Regression analysis was used to test 3 risk prediction models: the Cardiovascular Risk Factors, Aging and Dementia score, the Australian National University Alzheimer Disease Risk Index, and the Brief Dementia Screening Indicator. Model performance or discrimination accuracy was assessed using the C statistic or area under the curve. Calibration was tested using the Grønnesby and Borgan and the goodness-of-fit tests.

RESULTS: The predictive accuracy of the models varied but was generally low compared with the original development cohorts, with the Australian National University Alzheimer Disease Risk Index (C-statistic, 0.66) and the Brief Dementia Screening Indicator (C-statistic, 0.61) both performing better than the Cardiovascular Risk Factors, Aging and Dementia score (area under the curve, 0.53).

CONCLUSIONS: Dementia risk prediction models developed for the general population do not perform well in individuals with stroke. Their poor performance could have been due to the need for additional or different predictors related to stroke and vascular risk factors or methodological differences across studies (eg, length of follow-up, age distribution). Future work is needed to develop simple and cost-effective risk prediction models specific to poststroke 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 = {}, number = {}, pages = {}, doi = {10.1001/jamaneurol.2020.1840}, pmid = {32568367}, issn = {2168-6157}, 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 = {}, number = {}, pages = {}, doi = {10.1001/jamaneurol.2020.1760}, pmid = {32568366}, issn = {2168-6157}, 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 {pmid32568358, year = {2020}, author = {Karanth, S and Nelson, PT and Katsumata, Y and Kryscio, RJ and Schmitt, FA and Fardo, DW and Cykowski, MD and Jicha, GA and Van Eldik, LJ and Abner, EL}, title = {Prevalence and Clinical Phenotype of Quadruple Misfolded Proteins in Older Adults.}, journal = {JAMA neurology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaneurol.2020.1741}, pmid = {32568358}, issn = {2168-6157}, abstract = {Importance: Quadruple misfolded proteins (tau neurofibrillary tangles, amyloid-β [Aβ], α-synuclein, and transactive response DNA-binding protein 43 [TDP-43]) in the same brain are relatively common in aging. However, the clinical presentation, associated factors, frequency in community-based cohorts, genetic characteristics, and cognitive trajectories associated with the quadruple misfolded proteins phenotype are not well understood.

Objective: To describe the quadruple misfolded proteins phenotype, including the trajectories of global cognition, in an autopsy cohort.

This retrospective cohort study used brain autopsy data from the University of Kentucky Alzheimer Disease Center (UK-ADC) Brain Bank. Participants were deceased individuals who were enrolled in a longitudinal community-based cohort study of aging and dementia in central Kentucky conducted by the UK-ADC. Included participants were enrolled in the UK-ADC cohort between January 1, 1989, and December 31, 2017; aged 55 years or older at baseline; and followed up for a mean duration of 10.4 years. The participants had Alzheimer disease pathology (tau and Aβ), α-synuclein, and TDP-43 data, along with Braak neurofibrillary tangle stage I to VI. Data analysis was conducted between February 1, 2019, and September 30, 2019.

Main Outcomes and Measures: Frequency of quadruple misfolded proteins was estimated, and proteinopathy group characteristics and associations with global cognition were evaluated. Multinomial logistic regression was used to estimate the association of proteinopathy group with participant characteristics, including age at death, sex, and apolipoprotein ε4 (APOE ε4) allele. Generalized estimating equations were used to estimate the probability of obtaining Mini-Mental State Examination (MMSE) scores within the normal cognition (27-30 points) and severe impairment (≤13 points) ranges during the 12 years before death.

Results: The final sample included 375 individuals (mean [SD] age at death, 86.9 [8.0] years); 232 women [61.9%]). Quadruple misfolded proteins were detected in 41 of 214 individuals with dementia (19.2%). Overall, 46 individuals (12.3%) had quadruple misfolded proteins, whereas 143 individuals (38.1%) had 3 proteinopathies. Dementia frequency was highest among those with quadruple misfolded proteins (41 [89.1%]), and participants with quadruple misfolded proteins had the lowest final mean (SD) MMSE scores of 13.4 (9.8) points. Adjusting for age at death and sex, the APOE ε4 allele was associated with higher odds of quadruple misfolded proteins (adjusted odds ratio, 2.55; 95% CI, 1.16- 5.62; P = .02). The quadruple misfolded proteins group had both the lowest probability of obtaining MMSE scores in the normal cognition range, even 12 years before death, and the highest probability of having MMSE scores in the severe impairment range.

Conclusions and Relevance: Quadruple misfolded proteins appear to be a common substrate for cognitive impairment and to be associated with an aggressive course of disease that typically ends with severe dementia. The prevalence of comorbid α-synuclein and TDP-43 with Alzheimer disease pathology (tau and Aβ) may complicate efforts to identify therapies to treat and prevent Alzheimer disease.}, } @article {pmid32566943, year = {2020}, author = {Berto, S and Liu, Y and Konopka, G}, title = {Genomics at cellular resolution: insights into cognitive disorders and their evolution.}, journal = {Human molecular genetics}, volume = {}, number = {}, pages = {}, doi = {10.1093/hmg/ddaa117}, pmid = {32566943}, issn = {1460-2083}, abstract = {High-throughput genomic sequencing approaches have held the promise of understanding and ultimately leading to treatments for cognitive disorders such as autism spectrum disorders, schizophrenia, and Alzheimer disease. While significant progress has been made into identifying genetic variants associated with these diseases, these studies have also uncovered that these disorders are mostly genetically complex and thus challenging to model in non-human systems. Improvements in such models might benefit from understanding the evolution of the human genome and how such modifications have affected brain development and function. The intersection of genome-wide variant information with cell-type specific expression and epigenetic information will further assist in resolving the contribution of particular cell types in evolution or disease. For example, the role of non-neuronal cells in brain evolution and cognitive disorders has gone mostly underappreciated until the recent availability of single-cell transcriptomic approaches. In this review, we discuss recent studies that carry out cell type specific assessments of gene expression in brain tissue across primates and between healthy and disease populations. The emerging results from these studies are beginning to elucidate how specific cell types in the evolved human brain are contributing to cognitive disorders.}, } @article {pmid32565686, year = {2020}, author = {Almuhayawi, MS and Ramadan, WS and Harakeh, S and Al Jaouni, SK and Bharali, DJ and Mousa, SA and Almuhayawi, SM}, title = {The potential role of pomegranate and its nano-formulations on cerebral neurons in aluminum chloride induced Alzheimer rat model.}, journal = {Saudi journal of biological sciences}, volume = {27}, number = {7}, pages = {1710-1716}, doi = {10.1016/j.sjbs.2020.04.045}, pmid = {32565686}, issn = {1319-562X}, abstract = {The oxidative stress leading to degenerative changes in the brain of Alzheimer's disease (AD) is evident. Our aim was to evaluate the therapeutic and protective effects of pomegranate extract (PE) and pomegranate extract-loaded nanoparticles (PE nano) in an AlCl 3-induced AD rat model. Nanoparticles were synthesized with a PE load of 0.68% w/w, and 70 male Wistar rats were divided into 7 groups: Group I was the control, Group II received PE., Group III received PE nano for 2 weeks, Group IV received AlCl 3 (50 mg/kg) daily orally for 4 weeks, Group V received PE for 2 weeks, Group VI received PE nano for 2 weeks, and Groups V and VI were started after AlCl 3 administration was stopped. Group VII received PE for 2 weeks and was stopped before AlCl 3 was administered. The Results revealed that the discrimination index in the novel object recognition test was the least in AD rat model but increased in cases protected with PE treated with PE nano. Similar results were shown based on calculating the brain weight/body weight percent. The biomarkers of antioxidant activity (catalase, glutathione and total antioxidant activity) in brain homogenate were significantly increased in groups treated with either PE or PE nano. The thiobarbituric acid reactive substance measured to estimate lipid peroxidation was significantly increased in AD rat model and decreased in groups protected with PE or treated with PE nano. Histopathological studies using hematoxylin and eosin, cresyl violet, and silver stains revealed hyaline degeneration, chromatolysis, and hallmarks of AD; neurofibrillary tangles and the senile plaques in brains of AD rat model. Restoration of the histological architecture, Nissl granules, and minimal appearance of hallmarks of AD characterized brains treated with PE or PE nano. In conclusion, PE was more effective as a protectant than a therapeutic measure in alleviating the antioxidant, lipid peroxidative effects and histopathological hallmarks in AD brains. But, the therapeutic PE-loaded nanoparticles increased the efficacy of active components and produced similar results as the protective PE.}, } @article {pmid32564167, year = {2020}, author = {Di Lorenzo, F and Bonnì, S and Picazio, S and Motta, C and Caltagirone, C and Martorana, A and Koch, G}, title = {Effects of Cerebellar Theta Burst Stimulation on Contralateral Motor Cortex Excitability in Patients with Alzheimer's Disease.}, journal = {Brain topography}, volume = {}, number = {}, pages = {}, doi = {10.1007/s10548-020-00781-6}, pmid = {32564167}, issn = {1573-6792}, abstract = {Although the cerebellum is not among the most renowned brain structures affected in Alzheimer`s disease (AD), recent evidence suggest that it undergoes degenerative changes during the course of the disease. A main neurophysiological feature of AD patients is the remarkable impairment of long term potentiation (LTP)-like cortical plasticity assessed in the primary motor cortex (M1) using theta burst stimulation (TBS) protocols. In healthy conditions, continuous (cTBS) and intermittent TBS (iTBS) of the cerebellum induce respectively long term depression (LTD)-like and LTP-like after effects in the contralateral M1. Here we aimed at examining the effects of cerebellar TBS on contralateral M1 excitability in a sample of 15 AD patients and 12 healthy age matched controls (HS). Motor evoked potentials (MEPs) were obtained in the contralateral M1 before and after cerebellar cTBS and iTBS protocols. As compared to HS, AD patients showed an impairment of LTP-like cortical plasticity mechanisms following cerebellar iTBS. No difference was observed for the cTBS protocol, in which both populations exhibited the expected LTD-like after effect. This study shows that mechanisms of cerebellar-cortical plasticity are impaired in AD. Given its role in high order cognitive functions, new potential therapeutic strategies could be built up in the future to modulate neural activity in the cerebellum in AD.}, } @article {pmid32561678, year = {2020}, author = {Ferman, TJ and Aoki, N and Boeve, BF and Aakre, JA and Kantarci, K and Graff-Radford, J and Parisi, JE and Van Gerpen, JA and Graff-Radford, NR and Uitti, RJ and Pedraza, O and Murray, ME and Wszolek, ZK and Reichard, RR and Fields, JA and Ross, OA and Knopman, DS and Petersen, RC and Dickson, DW}, title = {Subtypes of dementia with Lewy bodies are associated with α-synuclein and tau distribution.}, journal = {Neurology}, volume = {}, number = {}, pages = {}, doi = {10.1212/WNL.0000000000009763}, pmid = {32561678}, issn = {1526-632X}, abstract = {OBJECTIVE: To determine whether Lewy body disease subgroups have different clinical profiles.

METHODS: Participants had dementia, autopsy-confirmed transitional or diffuse Lewy body disease (TLBD or DLBD) (n = 244), or Alzheimer disease (AD) (n = 210), and were seen at least twice (mean follow-up 6.2 ± 3.8 years). TLBD and DLBD groups were partitioned based on the presence or absence of neocortical neurofibrillary tangles using Braak staging. Four Lewy body disease subgroups and AD were compared on clinical features, dementia trajectory, and onset latency of probable dementia with Lewy bodies (DLB) or a DLB syndrome defined as probable DLB or dementia with one core feature of parkinsonism or probable REM sleep behavior disorder.

RESULTS: In TLBD and DLBD without neocortical tangles, diagnostic sensitivity was strong for probable DLB (87% TLBD, 96% DLBD) and the DLB syndrome (97% TLBD, 98% DLBD) with median latencies <1 year from cognitive onset, and worse baseline attention-visual processing but better memory-naming scores than AD. In DLBD with neocortical tangles, diagnostic sensitivity was 70% for probable DLB and 77% for the DLB syndrome with respective median latencies of 3.7 years and 2.7 years from cognitive onset, each associated with tangle distribution. This group had worse baseline attention-visual processing than AD, but comparable memory-naming impairment. TLBD with neocortical tangles had 48% diagnostic sensitivity for probable DLB and 52% for the DLB syndrome, with median latencies >6 years from cognitive onset, and were cognitively similar to AD. Dementia trajectory was slowest for TLBD without neocortical tangles, and fastest for DLBD with neocortical tangles.

CONCLUSIONS: The phenotypic expression of DLB was associated with the distribution of α-synuclein and tau pathology.}, } @article {pmid32561398, year = {2020}, author = {Fernandes, A and Tábuas-Pereira, M and Duro, D and Lima, M and Gens, H and Santiago, B and Durães, J and Almeida, MR and Leitão, MJ and Baldeiras, I and Santana, I}, title = {C-reactive protein as a predictor of mild cognitive impairment conversion into Alzheimer's disease dementia.}, journal = {Experimental gerontology}, volume = {}, number = {}, pages = {111004}, doi = {10.1016/j.exger.2020.111004}, pmid = {32561398}, issn = {1873-6815}, abstract = {BACKGROUND AND AIMS: Increasing evidence suggests that inflammation plays an important role in brain aging and neurodegeneration. Pathological studies demonstrate the presence of C-reactive protein (CRP) in the senile plaques and neurofibrillary tangles in Alzheimer's disease (AD) brain tissue suggesting that CRP may play a role in its neuropathological processes. Some findings suggest that midlife elevations of serum CRP are a risk factor for AD. However, others found lower CRP levels in mild or moderate AD than in controls, suggesting that CRP levels could be different in different stages of disease. We aimed to assess the role of CRP as a predictor of Mild cognitive impairment (MCI) conversion into AD dementia.

METHODS: We retrospectively reviewed the cohort of MCI patients followed at the Dementia Clinic, Neurology Department of University Hospital of Coimbra. We collected demographical, neuropsychological, genetic and laboratorial variables (including serum CRP measurements at the time of baseline laboratory tests). A Cox regression model was performed adjusted for the collected variables preconsidered to be predictors of dementia and the variable being studied (CRP) to assess for independent predictors of conversion.

RESULTS: We included 130 patients, 58.5% female, with a mean age of onset of 65.5 ± 9.1 years and age at first assessment of 69.3 ± 8.5 years. The mean CRP was 0.33 ± 0.58 mg/dl. At follow-up (mean, 36.9 ± 27.0 months) 42.3% of MCI patients converted to dementia. Lower CSF Aβ42 (HR = 0.999, 95%CI = [0.997, 1.000], p = 0.015), lower MMSE score (HR = 0.864, 95%CI = [0.510, 1.595], p = 0.008) and lower CRP quartile (HR = 0.597, 95%CI = [0.435, 0.819], p = 0.001) were independent predictors of conversion.

CONCLUSION: CRP may add information of risk of conversion in MCI patients. Patients with lower CRP levels appear to have a more rapid conversion to AD dementia.}, } @article {pmid32561284, year = {2020}, author = {Gupta, SD and Pan, CH}, title = {Recent update on discovery and development of Hsp90 inhibitors as senolytic agents.}, journal = {International journal of biological macromolecules}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ijbiomac.2020.06.115}, pmid = {32561284}, issn = {1879-0003}, 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 {pmid32559670, year = {2020}, author = {Wu, Y and Zhang, X and He, Y and Cui, J and Ge, X and Han, H and Luo, Y and Liu, L and Wang, X and Yu, H and , }, title = {Predicting Alzheimer's disease based on survival data and longitudinally measured performance on cognitive and functional scales.}, journal = {Psychiatry research}, volume = {291}, number = {}, pages = {113201}, doi = {10.1016/j.psychres.2020.113201}, pmid = {32559670}, issn = {1872-7123}, abstract = {This study assessed how well longitudinally taken cognitive and functional scales from people with mild cognitive impairment (MCI) predict conversion to Alzheimer's disease (AD). Participants were individuals with baseline MCI from the Alzheimer's Disease Neuroimaging Initiative. Scales included the Alzheimer Disease Assessment Scale-Cognitive (ADAS-Cog) 11 and 13, the Mini Mental State Examination (MMSE), and the Functional Assessment Questionnaire (FAQ). A joint modelling approach compared performance on the four scales for dynamic prediction of risk for AD. The goodness of fit measures included log likelihood, the Akaike Information Criterion (AIC) and the Bayesian Information Criterion (BIC). The area under the curve (AUC) of the receiver operating characteristic assessed predictive accuracy. The parameter α in the ADAS-Cog11, ADAS-Cog13, MMSE, and FAQ joint models was statistically significant. Joint MMSE and FAQ models had better goodness of fit. FAQ had the best predictive accuracy. Cognitive and functional impairment assessment scales are strong screening predictors when repeated measures are available. They could be useful for predicting risk for AD in primary healthcare.}, } @article {pmid32557144, year = {2020}, author = {Tang, Z and Liang, D and Cheng, M and Su, X and Liu, R and Zhang, Y and Wu, H}, title = {Effects of Porphyromonas gingivalis and Its Underlying Mechanisms on Alzheimer-Like Tau Hyperphosphorylation in Sprague-Dawley Rats.}, journal = {Journal of molecular neuroscience : MN}, volume = {}, number = {}, pages = {}, doi = {10.1007/s12031-020-01629-1}, pmid = {32557144}, issn = {1559-1166}, support = {2018SZ0163//Department of Science and Technology of Sichuan Province/ ; }, abstract = {Hyperphosphorylated tau is the main component of neurofibrillary tangles and involved in the pathogenesis of Alzheimer's disease (AD). Increasing evidences suggest close associations between Porphyromonas gingivalis (P. gingivalis) and AD, but the relationship between P. gingivalis and tau hyperphosphorylation is still unclear. In this study, we investigated whether peripheral infection with P. gingivalis caused tau hyperphosphorylation by using wild Sprague-Dawley (SD) rats and HT-22 cells. The rats were injected with P. gingivalis suspension or phosphate-buffered saline 3 times per week. After 4 weeks or 12 weeks, the rats were sacrificed for analyzing systemic inflammation, neuroinflammation, and tau hyperphosphorylation. The results showed that the severity of phosphorylated tau at the AD-related sites Thr181 and Thr231 and the number of activated astrocytes were notably greater in the hippocampus of rats with P. gingivalis injection. And the levels of the inflammatory cytokines interleukin (IL)-1β and IL-6 and tumor necrosis factor-α in serum and hippocampus were also increased in the rats with P. gingivalis injection. In addition, the activity of protein phosphatase 2A (PP2A) was significantly inhibited in the hippocampus of rats with P. gingivalis injection. In vitro, IL-1β induced tau hyperphosphorylation by inhibiting the activity of PP2A in HT-22 cells and application of the PP2A promoter efficiently attenuated IL-1β-induced tau hyperphosphorylation in HT-22 cells. These results indicated that P. gingivalis could induce tau hyperphosphorylation via, in part, attenuating the activity of PP2A through triggering systemic inflammation and neuroinflammation in wild-type SD rats.}, } @article {pmid32556236, year = {2020}, author = {Krüger, JF and Hillesheim, E and Pereira, ACSN and Camargo, CQ and Rabito, EI}, title = {Probiotics for dementia: a systematic review and meta-analysis of randomized controlled trials.}, journal = {Nutrition reviews}, volume = {}, number = {}, pages = {}, doi = {10.1093/nutrit/nuaa037}, pmid = {32556236}, issn = {1753-4887}, abstract = {CONTEXT: Dementia is the fifth leading cause of death in the world. Animal studies indicate that in addition to the aging process, intestinal microbiota may play an important role in the neurodegeneration process through the modulation of the gut-brain axis.

OBJECTIVE: A systematic review and meta-analysis was conducted to determine the effectiveness of probiotic and synbiotic supplementation on the cognitive function of individuals with dementia.

DATA SOURCES: MEDLINE, BVS, SciELO, CENTRAL, Embase, and grey literature were searched from their inception to January 2019.

STUDY SELECTION: We included data from randomized clinical trials (RCTs) that addressed dementias and assessed the following outcomes: cognitive function; inflammatory, oxidative stress, and metabolic markers; nutritional status; and intestinal microbiota composition.

DATA EXTRACTION: Data searches, article selection, data extraction, and risk-of-bias assessments were performed according to the Cochrane guidelines. Data were pooled by inverse-variance random-effects meta-analyses. GRADE (Grading of Recommendations Assessment, Development, and Evaluations) was used to assess the quality of evidence.

RESULTS: Data from 3 RCTs involving 161 individuals with Alzheimer's disease receiving Lactobacillus and Bifidobacterium strains showed no beneficial effect of probiotic supplementation on cognitive function (standardized mean difference, 0.56; 95%CI: -0.06 to 1.18), with very low certainty of evidence. However, probiotic supplementation improved plasma triglycerides, very-low-density lipoprotein cholesterol, insulin resistance, and plasma malondialdehyde. No RCTs included synbiotic supplementation or assessed microbiota composition.

CONCLUSION: Current evidence regarding the use of probiotics and synbiotics for individuals with dementia is insufficient to support their clinical application.

PROSPERO registration no: CRD42018116148.}, } @article {pmid32554763, year = {2020}, author = {Dhana, K and Evans, DA and Rajan, KB and Bennett, DA and Morris, MC}, title = {Healthy lifestyle and the risk of Alzheimer dementia: Findings from 2 longitudinal studies.}, journal = {Neurology}, volume = {}, number = {}, pages = {}, doi = {10.1212/WNL.0000000000009816}, pmid = {32554763}, issn = {1526-632X}, abstract = {OBJECTIVE: To quantify the impact of a healthy lifestyle on the risk of Alzheimer dementia.

METHODS: Using data from the Chicago Health and Aging Project (CHAP; n = 1,845) and the Rush Memory and Aging Project (MAP; n = 920), we defined a healthy lifestyle score on the basis of nonsmoking, ≥150 min/wk moderate/vigorous-intensity physical activity, light to moderate alcohol consumption, high-quality Mediterranean-DASH Diet Intervention for Neurodegenerative Delay diet (upper 40%), and engagement in late-life cognitive activities (upper 40%), giving an overall score ranging from 0 to 5. Cox proportional hazard models were used for each cohort to estimate the hazard ratio (HR) and 95% confidence interval (CI) of the lifestyle score with Alzheimer dementia, and a random-effect meta-analysis was used to pool the results.

RESULTS: During a median follow-up of 5.8 years in CHAP and 6.0 years in MAP, 379 and 229 participants, respectively, had incident Alzheimer dementia. In multivariable-adjusted models, the pooled HR (95% CI) of Alzheimer dementia across 2 cohorts was 0.73 (95% CI 0.66-0.80) per each additional healthy lifestyle factor. Compared to participants with 0 to 1 healthy lifestyle factor, the risk of Alzheimer dementia was 37% lower (pooled HR 0.63, 95% CI 0.47-0.84) in those with 2 to 3 healthy lifestyle factors and 60% lower (pooled HR 0.40, 95% CI 0.28-0.56) in those with 4 to 5 healthy lifestyle factors.

CONCLUSION: A healthy lifestyle as a composite score is associated with a substantially lower risk of Alzheimer's dementia.}, } @article {pmid32554350, year = {2020}, author = {Saba, M and Blanchet, S}, title = {Working memory training in normal and pathological aging: neurocognitive gains and generalization.}, journal = {Geriatrie et psychologie neuropsychiatrie du vieillissement}, volume = {18}, number = {2}, pages = {187-195}, doi = {10.1684/pnv.2020.0860}, pmid = {32554350}, issn = {2115-7863}, abstract = {Working memory is one of the cognitive functions that is the most sensitive to normal and pathological age-related effects. In older individuals with a mild cognitive impairment, deficits in working memory are frequent and can precede those of episodic memory, in addition to having a strong prognostic value of evolution toward a dementia of Alzheimer type. Because of its implication in numerous cognitive and cognitive-motor tasks, working memory is called upon in a wide range of daily life activities. Impairment in working memory therefore increases the risk of a loss of autonomy. In the current review, we present different working memory training programs. We show how these training programs are associated with specific effects and to near and far transfers towards other cognitive functions in older adults without cognitive impairment or with mild cognitive impairment, as well as in patients with dementia. We show that the benefits are confirmed by neuronal modifications, suggesting an improvement in the neuronal efficiency of the targeted or related trained processes. Finally, we consider the central question of the generalization of the cognitive gains of working memory training toward ecological situations.}, } @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 {pmid32546202, year = {2020}, author = {Watt, JA and Goodarzi, Z and Veroniki, AA and Nincic, V and Khan, PA and Ghassemi, M and Thompson, Y and Lai, Y and Treister, V and Tricco, AC and Straus, SE}, title = {Safety of pharmacologic interventions for neuropsychiatric symptoms in dementia: a systematic review and network meta-analysis.}, journal = {BMC geriatrics}, volume = {20}, number = {1}, pages = {212}, pmid = {32546202}, issn = {1471-2318}, abstract = {BACKGROUND: Prescribing trends suggest that pharmacologic alternatives to antipsychotics are gaining in popularity, but randomized trial (RCT) data of their comparative safety is scarce. Our objective was to describe the comparative safety of pharmacologic interventions for treating neuropsychiatric symptoms in dementia.

METHODS: We searched MEDLINE, EMBASE, CENTRAL, CINAHL, and PsycINFO, from inception to May 28, 2019, for studies of pharmacologic interventions used to treat neuropsychiatric symptoms in dementia. Dementia care partners selected fracture risk as our primary outcome. Pairs of reviewers, working independently, conducted all study screening, data abstraction, and risk of bias appraisal. We conducted Bayesian random-effects network meta-analyses (NMAs) using data from RCTs to derive odds ratios (ORs). In secondary analyses, we conducted frequentist random-effects NMAs using data from RCTs and Bayesian three-level hierarchical random-effects NMAs incorporating data from RCTs and non-randomized studies.

RESULTS: Our systematic review included 209 randomized and non-randomized studies (889,378 persons with dementia). In NMAs of data from randomized trials, there were no increased odds of fracture associated with any intervention in primary analyses; however, data were sparse. We found increased odds of cerebrovascular events associated with antipsychotics (odds ratio [OR] 2.12, 95% credible interval [CrI] 1.29 to 3.62; number needed to harm [NNH] = 99) and increased odds of falls associated with dextromethorphan-quinidine (OR 4.16, 95% CrI 1.47 to 14.22; NNH = 55) compared to placebo in persons with dementia. In a subgroup of persons with Alzheimer disease, antipsychotics were associated with increased odds of fracture compared to anticonvulsants (OR 54.1, 95% CrI 1.15 to 38,300; NNH = 18). In older persons (mean age ≥ 80 years) with dementia, anticonvulsants were associated with increased odds of death compared to placebo (OR 8.36, 95% CrI 1.17 to 203.4; NNH = 35) and antipsychotics were associated with increased odds of death compared to antidepressants (OR 5.28, 95% CrI 1.06 to 3.51; NNH = 47).

CONCLUSION: Although antipsychotics were associated with greater harm than antidepressants and anticonvulsants in subgroups of persons with dementia, medications used in lieu of antipsychotics for treating neuropsychiatric symptoms in dementia, such as anticonvulsants and dextromethorphan-quinidine, were also associated with harm. Decision-making concerning treatments prescribed in lieu of antipsychotics should include potential harms.

PROSPERO REGISTRATION: CRD42017050130.}, } @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 = {}, number = {}, pages = {119546}, doi = {10.1016/j.ijpharm.2020.119546}, pmid = {32544519}, issn = {1873-3476}, 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 {pmid32543313, year = {2020}, author = {Cai, CZ and Yang, C and Zhuang, XX and Yuan, NN and Wu, MY and Tan, JQ and Song, JX and Cheung, KH and Su, H and Wang, YT and Tang, BS and Behrends, C and Durairajan, SSK and Yue, Z and Li, M and Lu, JH}, title = {NRBF2 is a RAB7 effector required for autophagosome maturation and mediates the association of APP-CTFs with active form of RAB7 for degradation.}, journal = {Autophagy}, volume = {}, number = {}, pages = {1-19}, doi = {10.1080/15548627.2020.1760623}, pmid = {32543313}, issn = {1554-8635}, abstract = {NRBF2 is a component of the class III phosphatidylinositol 3-kinase (PtdIns3K) complex. Our previous study has revealed its role in regulating ATG14-associated PtdIns3K activity for autophagosome initiation. In this study, we revealed an unknown mechanism by which NRBF2 modulates autophagosome maturation and APP-C-terminal fragment (CTF) degradation. Our data showed that NRBF2 localized at autolysosomes, and loss of NRBF2 impaired autophagosome maturation. Mechanistically, NRBF2 colocalizes with RAB7 and is required for generation of GTP-bound RAB7 by interacting with RAB7 GEF CCZ1-MON1A and maintaining the GEF activity. Specifically, NRBF2 regulates CCZ1-MON1A interaction with PI3KC3/VPS34 and CCZ1-associated PI3KC3 kinase activity, which are required for CCZ1-MON1A GEF activity. Finally, we showed that NRBF2 is involved in APP-CTF degradation and amyloid beta peptide production by maintaining the interaction between APP and the CCZ1-MON1A-RAB7 module to facilitate the maturation of APP-containing vesicles. Overall, our study revealed a pivotal role of NRBF2 as a new RAB7 effector in modulating autophagosome maturation, providing insight into the molecular mechanism of NRBF2-PtdIns3K in regulating RAB7 activity for macroautophagy/autophagy maturation and Alzheimer disease-associated protein degradation.}, } @article {pmid32541930, year = {2020}, author = {Yoon, Y and Voloudakis, G and Doran, N and Zhang, E and Dimovasili, C and Chen, L and Shao, Z and Darmanis, S and Tang, C and Tang, J and Wang, VX and Hof, PR and Robakis, NK and Georgakopoulos, A}, title = {PS1 FAD mutants decrease ephrinB2-regulated angiogenic functions, ischemia-induced brain neovascularization and neuronal survival.}, journal = {Molecular psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41380-020-0812-7}, pmid = {32541930}, issn = {1476-5578}, support = {NS047229//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, abstract = {Microvascular pathology and ischemic lesions contribute substantially to neuronal dysfunction and loss that lead to Alzheimer disease (AD). To facilitate recovery, the brain stimulates neovascularization of damaged tissue via sprouting angiogenesis, a process regulated by endothelial cell (EC) sprouting and the EphB4/ephrinB2 system. Here, we show that in cultures of brain ECs, EphB4 stimulates the VE-cadherin/Rok-α angiogenic complexes known to mediate sprouting angiogenesis. Importantly, brain EC cultures expressing PS1 FAD mutants decrease the EphB4-stimulated γ-secretase cleavage of ephrinB2 and reduce production of the angiogenic peptide ephrinB2/CTF2, the VE-cadherin angiogenic complexes and EC sprouting and tube formation. These data suggest that FAD mutants may attenuate ischemia-induced brain angiogenesis. Supporting this hypothesis, ischemia-induced VE-cadherin angiogenic complexes, levels of neoangiogenesis marker Endoglin, vascular density, and cerebral blood flow recovery, are all decreased in brains of mouse models expressing PS1 FAD mutants. Ischemia-induced brain neuronal death and cognitive deficits also increase in these mice. Furthermore, a small peptide comprising the C-terminal sequence of peptide ephrinB2/CTF2 rescues angiogenic functions of brain ECs expressing PS1 FAD mutants. Together, our data show that PS1 FAD mutations impede the EphB4/ephrinB2-mediated angiogenic functions of ECs and impair brain neovascularization, neuronal survival and cognitive recovery following ischemia. Furthermore, our data reveal a novel brain angiogenic mechanism targeted by PS1 FAD mutants and a potential therapeutic target for ischemia-induced neurodegeneration. Importantly, FAD mutant effects occur in absence of neuropathological hallmarks of AD, supporting that such hallmarks may form downstream of mutant effects on neoangiogenesis and neuronal survival.}, } @article {pmid32540420, year = {2020}, author = {Broncel, A and Bocian, R and Kłos-Wojtczak, P and Konopacki, J}, title = {Effects of locus coeruleus activation and inactivation on hippocampal formation theta rhythm in anesthetized rats.}, journal = {Brain research bulletin}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.brainresbull.2020.05.017}, pmid = {32540420}, issn = {1873-2747}, abstract = {Previously obtained data suggests that noradrenaline (NE) released from the efferent locus coeruleus (LC) endings in hippocampal formation (HPC) may serve as an important modulating signal involved in the pharmacological mechanisms responsible for the production of type 2 theta rhythm in rats. Hence, two distinct hypotheses were tested in the present study: 1/ if the decrease in HPC level of NE is correlated with the desynchronization of HPC field potential, then the inhibition of LC would be expected to abolish HPC type 2 theta rhythm; 2/ if the increase in HPC NE level is correlated with synchronization of HPC field potential, then the stimulation of LC would be expected to produce type 2 theta. The experiments were performed using an experimental model of HPC type 2 theta rhythm recorded in urethanized rats. It was demonstrated that electrical stimulation of LC produced type 2 theta rhythm whereas procaine injection into LC, in contrast, reversibly abolished type 2 theta. The possible relation of type 2 theta rhythm with some disturbances of Alzheimer disease are addressed.}, } @article {pmid32535272, year = {2020}, author = {Ebrahimpour, S and Zakeri, M and Esmaeili, A}, title = {Crosstalk between Obesity, Diabetes, and Alzheimer's Disease: Introducing quercetin as an effective triple herbal medicine.}, journal = {Ageing research reviews}, volume = {}, number = {}, pages = {101095}, doi = {10.1016/j.arr.2020.101095}, pmid = {32535272}, issn = {1872-9649}, abstract = {Obesity and diabetes are the most common metabolic disorders, which are strongly related to Alzheimer's disease (AD) in aging. Diabetes and obesity can lead to the accumulation of amyloid plaques, neurofibrillary tangles, and other symptoms of AD through several pathways, including insulin resistance, hyperglycemia, hyperinsulinemia, chronic inflammation, oxidative stress, adipokines dysregulation, and vascular impairment. Currently, the use of polyphenols has been expanded in animal models and in-vitro studies because of their comparatively negligible adverse effects. Among them, quercetin (QT) is one of the most abundant polyphenolic flavonoids, which is present in fruits and vegetables and displays many biological, health-promoting effects in a wide range of diseases. The low bioavailability and poor solubility of QT have also led researchers to make various QT-involved nanoparticles (NPs) to overcome these limitations. In this paper, we review significant molecular mechanisms induced by diabetes and obesity that increase AD pathogenesis. Then, we summarize in vitro, in vivo, and clinical evidence regarding the anti-Alzheimer, anti-diabetic and anti-obesity effects of QT. Finally, QT in pure and combination form using NPs has been suggested as a promising therapeutic agent for future studies.}, } @article {pmid32532978, year = {2020}, author = {Caton, M and Ochoa, ELM and Barrantes, FJ}, title = {The role of nicotinic cholinergic neurotransmission in delusional thinking.}, journal = {NPJ schizophrenia}, volume = {6}, number = {1}, pages = {16}, pmid = {32532978}, issn = {2334-265X}, abstract = {Delusions are a difficult-to-treat and intellectually fascinating aspect of many psychiatric illnesses. Although scientific progress on this complex topic has been challenging, some recent advances focus on dysfunction in neural circuits, specifically in those involving dopaminergic and glutamatergic neurotransmission. Here we review the role of cholinergic neurotransmission in delusions, with a focus on nicotinic receptors, which are known to play a part in some illnesses where these symptoms appear, including delirium, schizophrenia spectrum disorders, bipolar disorder, Parkinson, Huntington, and Alzheimer diseases. Beginning with what we know about the emergence of delusions in these illnesses, we advance a hypothesis of cholinergic disturbance in the dorsal striatum where nicotinic receptors are operative. Striosomes are proposed to play a central role in the formation of delusions. This hypothesis is consistent with our current knowledge about the mechanism of action of cholinergic drugs and with our abstract models of basic cognitive mechanisms at the molecular and circuit levels. We conclude by pointing out the need for further research both at the clinical and translational levels.}, } @article {pmid32530832, year = {2020}, author = {Varan, HD and Kizilarslanoglu, MC and Balci, C and Deniz, O and Coteli, S and Dogrul, RT and Aycicek, GS and Kilic, MK and O'Caoimh, R and Molloy, DW and Svendrovski, A and Halil, M and Cankurtaran, M and Goker, B and Yavuz, BB}, title = {Comparison of the Accuracy of Short Cognitive Screens Among Adults With Cognitive Complaints in Turkey.}, journal = {Alzheimer disease and associated disorders}, volume = {}, number = {}, pages = {}, doi = {10.1097/WAD.0000000000000391}, pmid = {32530832}, issn = {1546-4156}, abstract = {BACKGROUND: Cutoff values of cognitive screen tests vary according to age and educational levels.

OBJECTIVE: The objective of this study was to compare the accuracy and determine cutoffs for 3 short cognitive screening instruments: the Mini-Mental State Examination, Montreal Cognitive Assessment (MoCA), and Quick Mild Cognitive Impairment Screen-Turkish version (Qmci-TR), in older adults with low literacy in Turkey.

METHODS: In all 321 patients, 133 with subjective cognitive complaints (SCC), 88 amnestic-type mild cognitive impairment (aMCI), and 100 with probable Alzheimer disease (AD) with a median of 5 years education were included. Education and age-specific cutoffs were determined.

RESULTS: For the overall population, the Qmci-TR was more accurate than the MoCA in distinguishing between aMCI and AD (area under the curve=0.83 vs. 0.76, P=0.004) and the Qmci-TR and Mini-Mental State Examination were superior to the MoCA in discriminating SCC from aMCI and AD. All instruments had similar accuracy among those with low literacy (primary school and lower educational level or illiterate).

CONCLUSIONS: To distinguish between SCC, aMCI, and AD in a sample of older Turkish adults, the Qmci-TR may be preferable. In very low literacy, the choice of the instrument appears less important.}, } @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 {pmid32528274, year = {2020}, author = {Medina, M and Avila, J}, title = {Editorial: Untangling the Role of Tau in Physiology and Pathology.}, journal = {Frontiers in aging neuroscience}, volume = {12}, number = {}, pages = {146}, doi = {10.3389/fnagi.2020.00146}, pmid = {32528274}, issn = {1663-4365}, } @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 {pmid32525774, year = {2020}, author = {Tang, KS}, title = {Protective Effects of Polydatin Against Dementia-Related Disorders.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/1570159X18666200611144825}, pmid = {32525774}, issn = {1875-6190}, abstract = {Dementia is a collection of symptoms affecting a person's cognition. Dementia is debilitating, and therefore, finding an effective treatment is of the utmost importance. Resveratrol, which exhibits neuroprotective effects, has low bioavailability. However, it's glucoside polydatin is more bioavailable. Here, the evidence that supports the protective role of polydatin against dementia-related diseases such as Alzheimer's disease, vascular dementia, alcohol-related dementia, and Lewy body dementias is presented. The beneficial effects of polydatin from a mechanistic perspective are specifically emphasized in this review. Future directions in this area of research are also discussed.}, } @article {pmid32525547, year = {2020}, author = {Powell, WR and Buckingham, WR and Larson, JL and Vilen, L and Yu, M and Salamat, MS and Bendlin, BB and Rissman, RA and Kind, AJH}, title = {Association of Neighborhood-Level Disadvantage With Alzheimer Disease Neuropathology.}, journal = {JAMA network open}, volume = {3}, number = {6}, pages = {e207559}, pmid = {32525547}, issn = {2574-3805}, abstract = {Importance: Social determinants of health, such as income, education, housing quality, and employment, are associated with disparities in Alzheimer disease and health generally, yet these determinants are rarely incorporated within neuropathology research.

Objective: To establish the feasibility of linking neuropathology data to social determinants of health exposures using neighborhood disadvantage metrics (the validated Area Deprivation Index) and to evaluate the association between neighborhood disadvantage and Alzheimer disease-related neuropathology.

This cross-sectional study consisted of decedents with a known home address who donated their brains to 1 of 2 Alzheimer disease research center brain banks in California and Wisconsin between January 1, 1990, and December 31, 2016. Neither site had preexisting social metrics available for their decedents. Neuropathologic features were obtained from each site for data collected using the standardized Neuropathology Data Set form and from autopsy reports. Data were analyzed from June 7 to October 10, 2019.

Exposures: Geocoded decedent addresses linked to neighborhood disadvantage as measured by the Area Deprivation Index calculated for the year of death.

Main Outcomes and Measures: Presence of Alzheimer disease neuropathology. The association between neighborhood disadvantage and Alzheimer disease neuropathology was evaluated via logistic regression, adjusting for age, sex, and year of death.

Results: The sample consisted of 447 decedents (249 men [56%]; mean [SD] age, 80.3 [9.5] years; median year of death, 2011) spanning 24 years of donation. Fewer decedents (n = 24 [5.4%]) originated from the top 20% most disadvantaged neighborhood contexts. Increasing neighborhood disadvantage was associated with an 8.1% increase in the odds of Alzheimer disease neuropathology for every decile change on the Area Deprivation Index (adjusted odds ratio, 1.08; 95% CI, 1.07-1.09). As such, living in the most disadvantaged neighborhood decile was associated with a 2.18 increased odds of Alzheimer disease neuropathology (adjusted odds ratio, 2.18; 95% CI, 1.99-2.39).

Conclusions and Relevance: The findings of this cross-sectional study suggest that social determinants of health data can be linked to preexisting autopsy samples as a means to study sociobiological mechanisms involved in neuropathology. This novel technique has the potential to be applied to any brain bank within the United States. To our knowledge, this is the first time Alzheimer disease neuropathology has been associated with neighborhood disadvantage.}, } @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 {pmid32522798, year = {2020}, author = {Ebenau, JL and Timmers, T and Wesselman, LMP and Verberk, IMW and Verfaillie, SCJ and Slot, RER and van Harten, AC and Teunissen, CE and Barkhof, F and van den Bosch, KA and van Leeuwenstijn, M and Tomassen, J and Braber, AD and Visser, PJ and Prins, ND and Sikkes, SAM and Scheltens, P and van Berckel, BNM and van der Flier, WM}, title = {ATN classification and clinical progression in subjective cognitive decline: The SCIENCe project.}, journal = {Neurology}, volume = {}, number = {}, pages = {}, doi = {10.1212/WNL.0000000000009724}, pmid = {32522798}, issn = {1526-632X}, abstract = {OBJECTIVE: To investigate the relationship between the ATN classification system (amyloid, tau, neurodegeneration) and risk of dementia and cognitive decline in individuals with subjective cognitive decline (SCD).

METHODS: We classified 693 participants with SCD (60 ± 9 years, 41% women, Mini-Mental State Examination score 28 ± 2) from the Amsterdam Dementia Cohort and Subjective Cognitive Impairment Cohort (SCIENCe) project according to the ATN model, as determined by amyloid PET or CSF β-amyloid (A), CSF p-tau (T), and MRI-based medial temporal lobe atrophy (N). All underwent extensive neuropsychological assessment. For 342 participants, follow-up was available (3 ± 2 years). As a control population, we included 124 participants without SCD.

RESULTS: Fifty-six (n = 385) participants had normal Alzheimer disease (AD) biomarkers (A-T-N-), 27% (n = 186) had non-AD pathologic change (A-T-N+, A-T+N-, A-T+N+), 18% (n = 122) fell within the Alzheimer continuum (A+T-N-, A+T-N+, A+T+N-, A+T+N+). ATN profiles were unevenly distributed, with A-T+N+, A+T-N+, and A+T+N+ containing very few participants. Cox regression showed that compared to A-T-N-, participants in A+ profiles had a higher risk of dementia with a dose-response pattern for number of biomarkers affected. Linear mixed models showed participants in A+ profiles showed a steeper decline on tests addressing memory, attention, language, and executive functions. In the control group, there was no association between ATN and cognition.

CONCLUSIONS: Among individuals presenting with SCD at a memory clinic, those with a biomarker profile A-T+N+, A+T-N-, A+T+N-, and A+T+N+ were at increased risk of dementia, and showed steeper cognitive decline compared to A-T-N- individuals. These results suggest a future where biomarker results could be used for individualized risk profiling in cognitively normal individuals presenting at a memory clinic.}, } @article {pmid32522682, year = {2020}, author = {Bashiri, H and Enayati, M and Bashiri, A and Salari, AA}, title = {Swimming exercise improves cognitive and behavioral disorders in male NMRI mice with sporadic Alzheimer-like disease.}, journal = {Physiology & behavior}, volume = {}, number = {}, pages = {113003}, doi = {10.1016/j.physbeh.2020.113003}, pmid = {32522682}, issn = {1873-507X}, abstract = {Alzheimer's disease (AD) is associated with cognitive deficits and behavioral disorders such as anxiety and depression. Recent clinical and experimental studies have demonstrated that swimming exercise could be a potential therapy for cognitive and behavioral disorders. The prevalence of anxiety and depression is increasing among patients with AD; hence, further studies are needed to develop therapies for these behavioral abnormalities. The purpose of this study was to evaluate the effects of swimming exercise on memory impairment, anxiety, and depression-like behaviors in a mouse model of sporadic Alzheimer-like disease. Eight days after AD induction by streptozotocin (STZ), mice were subjected to the swimming exercise for four weeks. To assess cognitive functions, anxiety- and depression-related behaviors in animals, Y-maze, novel object recognition, open field, zero maze, sucrose preference, and forced swim tests were used. To understand the possible mechanisms, amyloid-β (Aβ)-42, brain-derived neurotrophic factor (BDNF), glutamate, malondialdehyde (MDA), tumor-necrosis-factor (TNF)-α, and interleukin (IL)-6 levels were measured in the hippocampus. The results of this study indicate that STZ administration impaired cognitive functions, increased anxiety- and depression-related behaviors, and elevated Aβ-42, glutamate, MDA, TNF-α, and IL-6 levels in the hippocampus of mice. In contrast, swimming exercise significantly reversed these neurobehavioral disorders, increased BDNF, and decreased both glutamate and TNF-α in the hippocampus of STZ-treated mice. Overall, these findings provide some support for the idea that swimming exercise might be associated with reduced neurobehavioral disorders in patients with Alzheimer's disease. However, further clinical studies on this topic are required to confirm and validate these findings.}, } @article {pmid32521990, year = {2020}, author = {Jeong, HE and Shin, DH and Lee, DC}, title = {Medial Temporal Atrophy Alone is Insufficient to Predict Underlying Alzheimer's Disease Pathology.}, journal = {Korean journal of family medicine}, volume = {}, number = {}, pages = {}, doi = {10.4082/kjfm.18.0144}, pmid = {32521990}, issn = {2005-6443}, abstract = {Background: The medial temporal region is the earliest affected structure in patients with Alzheimer's disease (AD), and its atrophy is known as the hallmark of AD. This study aimed to investigate the value of medial temporal atrophy (MTA) for detecting 18F-florbetaben positron emission tomography (PET)-proven AD pathology.

Methods: We retrospectively enrolled 265 subjects complaining of cognitive decline at a dementia outpatient clinic from March 2015 to December 2017. All subjects underwent brain magnetic resonance imaging, 18F-fluorodeoxyglucose PET, and 18F-florbetaben PET at baseline. We performed multivariable logistic regression analyses on variables including age, sex, years of education, white matter hyperintensities, apolipoprotein E (APOE) genotype, and memory composite scores in various combinations to investigate whether MTA was indicative of underlying AD pathology.

Results: Our sample population of 265 patients comprised 121 with AD-related cognitive impairment, 42 with Lewy bodies-related cognitive impairment, 32 with vascular cognitive impairment, and 70 with other or undetermined pathologies. In the multivariable logistic regression analyses, MTA was not an independent predictor of underlying AD pathology (P>0.200). The predictive power of underlying AD-related cognitive impairment significantly increased when multiple variables including APOE genotype and memory composite scores were considered together (area under the curve >0.750).

Conclusion: Our results suggest that MTA alone may be insufficient to accurately predict the presence of AD pathology. It is necessary to comprehensively consider various other factors such as APOE genotype and a detailed memory function to determine whether the patient is at high risk of AD.}, } @article {pmid32520737, year = {2020}, author = {Moulin Mares, SRA and Groner, JS and de Oliveira, MP and Lírio, LV and Coutinho, PC and Luchi, WM}, title = {Takotsubo Cardiomyopathy in an Alzheimer Disease Patient: The Potential Contribution of Antidepressant Agents.}, journal = {Alzheimer disease and associated disorders}, volume = {}, number = {}, pages = {}, doi = {10.1097/WAD.0000000000000395}, pmid = {32520737}, issn = {1546-4156}, abstract = {Takotsubo cardiomyopathy (TC) is an acute cardiac dysfunction, clinically similar to myocardial ischemia. The physiopathology of the syndrome seems to be related to excessive sympathetic activity that is triggered by physical or emotional stress factors. We report the case of an 83-year-old woman with advanced Alzheimer disease who had recently used nortriptyline and sertraline and was admitted with chest pain. An electrocardiogram showed ST-elevation, and markers of myocardial necrosis were slightly increased. However, coronariography did not demonstrate stenotic lesions. Transthoracic echocardiography and ventriculography identified decreased ventricular function, apical akinesia, and compensatory hyperkinesia of other segments that were compatible with TC. The patient evolved with cardiogenic shock and died. Alzheimer patients may be more susceptible to develop TC, both because of the disease itself and because of the multiple medications they are exposed to that increase catecholamine levels. In this case, antidepressant drugs were considered to be a potential factor that enhanced the susceptibility.}, } @article {pmid32520736, year = {2020}, author = {Stojanovic, M and Jin, Y and Fagan, AM and Benzinger, TL and Hassenstab, J and Cruchaga, C and Morris, JC and Head, D}, title = {Physical Exercise and Longitudinal Trajectories in Alzheimer Disease Biomarkers and Cognitive Functioning.}, journal = {Alzheimer disease and associated disorders}, volume = {}, number = {}, pages = {}, doi = {10.1097/WAD.0000000000000385}, pmid = {32520736}, issn = {1546-4156}, abstract = {INTRODUCTION: Associations of physical exercise with Alzheimer disease (AD) biomarkers and cognitive functioning have been observed cross-sectionally. However, the effects of exercise on longitudinal change in AD biomarkers have not been thoroughly investigated. The current study examined whether individuals with higher baseline exercise exhibited less longitudinal change in AD biomarkers and cognitive functioning, and whether APOE and/or brain-derived neurotrophic factor (BDNF) genotypes moderated the effects of exercise on longitudinal changes.

METHODS: Clinically normal individuals completed a questionnaire on physical exercise over the prior 10-year period at baseline. Ninety-five individuals had serial cerebrospinal fluid samples collected to examine Aβ42, ptau181 and total tau; 181 individuals underwent multiple assessments of amyloid positron emission tomography imaging with Pittsburgh Compound-B; 327 individuals underwent multiple cognitive assessments, including measures of episodic memory, executive functions, verbal fluency, and processing speed.

RESULTS: Greater exercise was associated with less steep decline in processing speed. Baseline exercise did not robustly impact longitudinal change for any other outcomes. Neither APOE nor BDNF genotype robustly moderated the effect of exercise on trajectories of AD biomarkers or cognitive decline.

INTERPRETATION: Results suggest that self-reported physical exercise may be limited as a moderator of changes in AD biomarkers.}, } @article {pmid32520735, year = {2020}, author = {Kim, KH and Seo, JD and Kim, ES and Kim, HS and Jeon, S and Pak, K and Lee, MJ and Lee, JH and Lee, YM and Lee, K and Shin, JH and Ko, JK and Jung, NY and Lee, JM and Yoon, JA and Hwang, C and Ahn, JW and Sung, S and Spina, S and Seeley, WW and Choi, KU and Huh, GY and Kim, EJ}, title = {Comparison of Amyloid in Cerebrospinal Fluid, Brain Imaging, and Autopsy in a Case of Progressive Supranuclear Palsy.}, journal = {Alzheimer disease and associated disorders}, volume = {}, number = {}, pages = {}, doi = {10.1097/WAD.0000000000000396}, pmid = {32520735}, issn = {1546-4156}, abstract = {Cerebrospinal fluid (CSF) amyloid-beta 1-42 (Aβ1-42) and amyloid positron emission tomography (PET) are the 2 main Alzheimer disease amyloid biomarkers that have been validated in neuropathologically confirmed Alzheimer disease cases. Although many studies have shown concordance of amyloid positivity or negativity between CSF Aβ1-42 and amyloid PET, several studies also reported discrepancies between these 2 Aβ biomarkers. We conducted a comparison of CSF Aβ1-42 level, amyloid PET, and autopsy findings in a case with progressive supranuclear palsy in which biomarker acquisition and postmortem pathologic examination were conducted almost at the same time. Our case with antemortem CSF Aβ1-42 (+)/amyloid PET (-) who was pathologically confirmed with Aβ pathology in the cerebral cortex may indicate CSF Aβ1-42 is more sensitive for assessing in vivo Aβ than amyloid PET.}, } @article {pmid32520734, year = {2020}, author = {Wisch, JK and Meeker, KL and Gordon, BA and Flores, S and Dincer, A and Grant, EA and Benzinger, TL and Morris, JC and Ances, BM}, title = {Sex-related Differences in Tau Positron Emission Tomography (PET) and the Effects of Hormone Therapy (HT).}, journal = {Alzheimer disease and associated disorders}, volume = {}, number = {}, pages = {}, doi = {10.1097/WAD.0000000000000393}, pmid = {32520734}, issn = {1546-4156}, support = {R01 AG052550/AG/NIA NIH HHS/United States ; R01 AG057680/AG/NIA NIH HHS/United States ; }, abstract = {IMPORTANCE: Female sex is a major risk factor for late-onset Alzheimer disease (AD), and sex hormones have been implicated as a possible protective factor. Neuroimaging studies that evaluated the effects of sex hormones on brain integrity have primarily emphasized neurodegenerative measures rather than amyloid and tau burden.

OBJECTIVE: We compared cortical amyloid and regional tau positron emission tomography (PET) deposition between cognitively normal males and females. We also compared preclinical AD pathology between females who have and have not used hormone therapy (HT). Finally, we compared the effects of amyloid and tau pathology on cognition, testing for both sex and HT effects.

We analyzed amyloid, tau, and cognition in a cognitively normal cross-sectional cohort of older individuals (n=148) followed at the Knight Alzheimer Disease Research Center. Amyloid and tau PET, medication history, and neuropsychological testing were obtained for each participant.

RESULTS: Within cognitively normal individuals, there was no difference in amyloid burden by sex. Whether or not we controlled for amyloid burden, female participants had significantly higher tau PET levels than males in multiple regions, including the rostral middle frontal and superior and middle temporal regions. HT accounted for a small reduction in tau PET; however, males still had substantially lower tau PET compared with females. Amyloid PET and tau PET burden were negatively associated with cognitive performance, although increasing amyloid PET did not have a deleterious effect on cognitive performance for women with a history of HT.

CONCLUSIONS AND RELEVANCE: Regional sex-related differences in tau PET burden may contribute to the disparities in AD prevalence between males and females. The observed decreases tau PET burden in HT users has important implications for clinical practice and trials and deserves future consideration in longitudinal studies.}, } @article {pmid32520690, year = {2020}, author = {Hadda, TB and Deniz, FSS and Orhan, IE and Zgou, H and Rauf, A and Mabkhot, YN and Bennani, B and Emam, DR and Kheder, NA and Asayari, A and Bin Muhsinah, A and Maalik, A}, title = {Spiro Heterocyclic Compounds as Potential Anti-Alzheimer agents (Part 2): their Metal Chelation Capacity, POM Analyses and DFT Studies.}, journal = {Medicinal chemistry (Shariqah (United Arab Emirates))}, volume = {}, number = {}, pages = {}, doi = {10.2174/1573406416666200610185654}, pmid = {32520690}, issn = {1875-6638}, abstract = {BACKGROUND: One of the best methods to treat Alzheimer disease (AD) is through the effective use of cholinesterase inhibitors as vital drugs due to the identification of acetylcholine deficit in the AD patients.

OBJECTIVE: The present study aims the investigation of spiro heterocyclic compounds as potential AD agents supported by their metal chelation capacity, POM analyses and DFT studies respectively.

METHOD: The cholinesterase inhibition and metal chelation ability was performed on ELISA microtiter assay. Whereas B3LYP method with 6-31+G(d,p) basis set was implemented to study HOMO-LUMO energy calculations. The pharmacokinetic properties of the synthesized molecules were studied through Petra, Osiris and Molinspiration (POM).

RESULTS: The six spiro (1-6) skeletons were tested for their inhibitory potential and metal-chelation capacity. Our findings revealed that the tested spiro skeletons exerted none or lower than 50% inhibition against both cholinesterases, while compound 4 proved to be the most active molecule with 57.21±0.89% of inhibition toward BChE. The spiro molecule 3 exhibited the highest metal-chelation capacity (9.12±5.26%). Molecular docking model for the most active molecule exhibited promising bindings with AChE and BChE's active site pertained to hydrophobic hydrogen bonds and positive ionizable interactions. The POM analyses gave the information about the flexibility at the site of coordination of spiro compounds (1-6).

CONCLUSION: The screening of spirocompounds (1-6) against cholinesterases revealed that some of them show considerable potential to inhibit AChE and BChE. Herein we propose that the spiro molecules after further derivatization could serve interesting AD inhibitor drugs.}, } @article {pmid32518892, year = {2020}, author = {Teahan, Á and Fitzgerald, C and O'Shea, E}, title = {Family carers' perspectives of the Alzheimer Café in Ireland.}, journal = {HRB open research}, volume = {3}, number = {}, pages = {18}, pmid = {32518892}, issn = {2515-4826}, abstract = {Background: The Alzheimer Café is a psychosocial intervention shown to have benefits for family carers of people with dementia. Family carers of people with dementia experience a period of change across all aspects of their lives following a diagnosis of dementia, requiring the development of new skills and tools to navigate these new landscapes. The objective of this research is to investigate family carers' perspectives of the Alzheimer Café in Ireland, and to explore how attendance may translate into broader benefits in their lives. This paper will also provide an overview of Alzheimer Café models, which exist internationally. Methods: This is a qualitative study using semi-structured interviews with nine family carers of people with dementia who were currently attending or have previously attended an Alzheimer Café in the preceding six months. The research was conducted in three Alzheimer Café sites in Ireland. Data analysis was conducted using Braun and Clarke's six step framework for thematic analysis. Results: Community, atmosphere, activity and information were described as core features of the Alzheimer Café in Ireland for family carers. The Alzheimer Café was shown to provide a social outlet which facilitated relationship building within care dyads as well as with other attendees. Several information avenues were identified including broad overviews from guest speakers, attendees' shared experiences, and specific advice from healthcare professionals. Conclusion: The Alzheimer Café offers strong personal support to family carers of people with dementia. It can also help to build family carers' capacity to manage new social, environmental and cultural challenges associated with dementia. While it is important the Alzheimer Café is enjoyable, has useful information and is supportive, it is equally important that these features generate sustained improvements for family carers external to the Alzheimer Café.}, } @article {pmid32518535, year = {2020}, author = {Pedrero-Prieto, CM and García-Carpintero, S and Frontiñán-Rubio, J and Llanos-González, E and Aguilera García, C and Alcaín, FJ and Lindberg, I and Durán-Prado, M and Peinado, JR and Rabanal-Ruiz, Y}, title = {A comprehensive systematic review of CSF proteins and peptides that define Alzheimer's disease.}, journal = {Clinical proteomics}, volume = {17}, number = {}, pages = {21}, pmid = {32518535}, issn = {1542-6416}, abstract = {Background: During the last two decades, over 100 proteomics studies have identified a variety of potential biomarkers in CSF of Alzheimer's (AD) patients. Although several reviews have proposed specific biomarkers, to date, the statistical relevance of these proteins has not been investigated and no peptidomic analyses have been generated on the basis of specific up- or down- regulation. Herein, we perform an analysis of all unbiased explorative proteomics studies of CSF biomarkers in AD to critically evaluate whether proteins and peptides identified in each study are consistent in distribution; direction change; and significance, which would strengthen their potential use in studies of AD pathology and progression.

Methods: We generated a database containing all CSF proteins whose levels are known to be significantly altered in human AD from 47 independent, validated, proteomics studies. Using this database, which contains 2022 AD and 2562 control human samples, we examined whether each protein is consistently present on the basis of reliable statistical studies; and if so, whether it is over- or under-represented in AD. Additionally, we performed a direct analysis of available mass spectrometric data of these proteins to generate an AD CSF peptide database with 3221 peptides for further analysis.

Results: Of the 162 proteins that were identified in 2 or more studies, we investigated their enrichment or depletion in AD CSF. This allowed us to identify 23 proteins which were increased and 50 proteins which were decreased in AD, some of which have never been revealed as consistent AD biomarkers (i.e. SPRC or MUC18). Regarding the analysis of the tryptic peptide database, we identified 87 peptides corresponding to 13 proteins as the most highly consistently altered peptides in AD. Analysis of tryptic peptide fingerprinting revealed specific peptides encoded by CH3L1, VGF, SCG2, PCSK1N, FBLN3 and APOC2 with the highest probability of detection in AD.

Conclusions: Our study reveals a panel of 27 proteins and 21 peptides highly altered in AD with consistent statistical significance; this panel constitutes a potent tool for the classification and diagnosis of AD.}, } @article {pmid32518388, year = {2020}, author = {Datki, Z and Galik-Olah, Z and Janosi-Mozes, E and Szegedi, V and Kalman, J and Hunya, ÁG and Fulop, L and Tamano, H and Takeda, A and Adlard, PA and Bush, AI}, title = {Alzheimer risk factors age and female sex induce cortical Aβ aggregation by raising extracellular zinc.}, journal = {Molecular psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41380-020-0800-y}, pmid = {32518388}, issn = {1476-5578}, abstract = {Aging and female sex are the major risk factors for Alzheimer's disease and its associated brain amyloid-β (Aβ) neuropathology, but the mechanisms mediating these risk factors remain uncertain. Evidence indicates that Aβ aggregation by Zn2+ released from glutamatergic neurons contributes to amyloid neuropathology, so we tested whether aging and sex adversely influences this neurophysiology. Using acute hippocampal slices, we found that extracellular Zn2+-elevation induced by high K+ stimulation was significantly greater with older (65 weeks vs 10 weeks old) rats, and was exaggerated in females. This was driven by slower reuptake of extracellular Zn2+, which could be recapitulated by mitochondrial intoxication. Zn2+:Aβ aggregates were toxic to the slices, but Aβ alone was not. Accordingly, high K+ caused synthetic human Aβ added to the slices to form soluble oligomers as detected by bis-ANS, attaching to neurons and inducing toxicity, with older slices being more vulnerable. Age-dependent energy failure impairing Zn2+ reuptake, and a higher maximal capacity for Zn2+ release by females, could contribute to age and sex being major risk factors for Alzheimer's disease.}, } @article {pmid32518146, year = {2020}, author = {Sakae, N and Santos, OA and Pedraza, O and Litvan, I and Murray, ME and Duara, R and Uitti, RJ and Wszolek, ZK and Graff-Radford, NR and Josephs, KA and Dickson, DW}, title = {Clinical and pathologic features of cognitive-predominant corticobasal degeneration.}, journal = {Neurology}, volume = {}, number = {}, pages = {}, doi = {10.1212/WNL.0000000000009734}, pmid = {32518146}, issn = {1526-632X}, abstract = {OBJECTIVE: To describe clinical and pathologic characteristics of corticobasal degeneration (CBD) with cognitive predominant problems during the disease course.

METHODS: In a series of autopsy-confirmed cases of CBD, we identified patients with cognitive rather than motor predominant features (CBD-Cog), including 5 patients thought to have Alzheimer disease (AD) and 10 patients thought to have behavioral variant frontotemporal dementia (FTD). We compared clinical and pathologic features of CBD-Cog with those from a series of 31 patients with corticobasal syndrome (CBD-CBS). For pathologic comparisons between CBD-Cog and CBD-CBS, we used semiquantitative scoring of neuronal and glial lesion types in multiple brain regions and quantitative assessments of tau burden from image analysis.

RESULTS: Five of 15 patients with CBD-Cog never had significant motor problems during their disease course. The most common cognitive abnormalities in CBD-Cog were executive and visuospatial dysfunction. The frequency of language problems did not differ between CBD-Cog and CBD-CBS. Argyrophilic grain disease, which is a medial temporal tauopathy associated with mild cognitive impairment, was more frequent in CBD-Cog. Apathy was also more frequent in CBD-Cog. Tau pathology in CBD-Cog was greater in the temporal and less in perirolandic cortices than in CBD-CBS.

CONCLUSION: A subset of patients with CBD has a cognitive predominant syndrome than can be mistaken for AD or FTD. Our findings suggest that distribution of tau cortical pathology (greater in temporal and less in perirolandic cortices) may be the basis of this uncommon clinical variant of CBD.}, } @article {pmid32518145, year = {2020}, author = {Buciuc, M and Botha, H and Murray, ME and Schwarz, CG and Senjem, ML and Jones, DT and Knopman, DS and Boeve, BF and Petersen, RC and Jack, CR and Petrucelli, L and Parisi, JE and Dickson, DW and Lowe, V and Whitwell, JL and Josephs, KA}, title = {Utility of FDG-PET in diagnosis of Alzheimer-related TDP-43 proteinopathy.}, journal = {Neurology}, volume = {}, number = {}, pages = {}, doi = {10.1212/WNL.0000000000009722}, pmid = {32518145}, issn = {1526-632X}, abstract = {OBJECTIVE: To evaluate FDG-PET as an antemortem diagnostic tool for Alzheimer-related TAR DNA-binding protein of 43 kDa (TDP-43) proteinopathy.

METHODS: We conducted a cross-sectional neuroimaging-histologic analysis of patients with antemortem FDG-PET and postmortem brain tissue from the Mayo Clinic Alzheimer's Disease Research Center and Study of Aging with Alzheimer spectrum pathology. TDP-43-positive status was assigned when TDP-43-immunoreactive inclusions were identified in the amygdala. Statistical parametric mapping (SPM) analyses compared TDP-43-positive (TDP-43[+]) with TDP-43-negative cases (TDP-43[-]), correcting for field strength, sex, Braak neurofibrillary tangle, and neuritic plaque stages. Cross-validated logistic regression analyses were used to determine whether regional FDG-PET values predict TDP-43 status. We also assessed the ratio of inferior temporal to medial temporal (IMT) metabolism as this was proposed as a biomarker of hippocampal sclerosis.

RESULTS: Of 73 cases, 27 (37%) were TDP-43(+), of which 6 (8%) had hippocampal sclerosis. SPM analysis showed TDP-43(+) cases having greater hypometabolism of medial temporal, frontal superior medial, and frontal supraorbital (FSO) regions (punc < 0.001). Logistic regression analysis showed only FSO and IMT to be associated with TDP-43(+) status, identifying up to 81% of TDP-43(+) cases (p < 0.001). An IMT/FSO ratio was superior to the IMT in discriminating TDP-43(+) cases: 78% vs 48%, respectively.

CONCLUSIONS: Alzheimer-related TDP-43 proteinopathy is associated with hypometabolism in the medial temporal and frontal regions. Combining FDG-PET measures from these regions may be useful for antemortem prediction of Alzheimer-related TDP-43 proteinopathy.

CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that hypometabolism in the medial temporal and frontal regions on FDG-PET is associated with Alzheimer-related TDP-43 proteinopathy.}, } @article {pmid32515311, year = {2020}, author = {Kleandrova, VV and Speck-Planche, A}, title = {PTML Modeling for Alzheimer's Disease: Design and Prediction of Virtual Multi-Target Inhibitors of GSK3B, HDAC1, and HDAC6.}, journal = {Current topics in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/1568026620666200607190951}, pmid = {32515311}, issn = {1873-4294}, abstract = {BACKGROUND: Alzheimer's disease is characterized by a progressive pattern of cognitive and functional impairment, which ultimately leads to death. Computational approaches have played an important role in the context of drug discovery for anti-Alzheimer therapies. However, most of the computational models reported to date have been focused on only one protein associated with Alzheimer, while relying on small datasets of structurally related molecules.

OBJECTIVE: We introduce the first model combining perturbation theory and machine learning based on artificial neural networks (PTML-ANN) for simultaneous prediction and design of inhibitors of three Alzheimer's disease-related proteins, namely glycogen synthase kinase 3 beta (GSK3B), histone deacetylase 1 (HDAC1), and histone deacetylase 6 (HDAC6).

METHOD: The PTML-ANN model was obtained from a dataset retrieved from ChEMBL, and it relied on a classification approach to predict chemicals as active inactive.

RESULTS: The PTML-ANN model displayed sensitivity and specificity higher than 85% in both training and test sets. The physicochemical and structural interpretation of the molecular descriptors in the model permitted the direct extraction of fragments suggested to favorably contribute to enhancing the multi-target inhibitory activity. Based on this information, we assembled ten molecules from several fragments with positive contributions. Seven of these molecules were predicted as triple target inhibitors while the remaining three were predicted as dual-target inhibitors. The estimated physicochemical properties of the designed molecules complied with Lipinski's rule of five and its variants.

CONCLUSION: This work opens new horizons toward the design of multi-target inhibitors for anti-Alzheimer therapies.}, } @article {pmid32515000, year = {2020}, author = {Karimi, A and Ghadiri Moghaddam, F and Valipour, M}, title = {Insights in the biology of extremely low-frequency magnetic fields exposure on human health.}, journal = {Molecular biology reports}, volume = {}, number = {}, pages = {}, doi = {10.1007/s11033-020-05563-8}, pmid = {32515000}, issn = {1573-4978}, support = {61741//Biotechnology Research Center, Tabriz University of Medical Sciences/ ; }, abstract = {The extremely low-frequency magnetic fields (ELF-EMF) are generated by electrical devices and power systems (1 to 300 Hz). In recent decades, exposure to ELF-EMF has emerged potential concerns on public health. Here, we discuss recent progress in the understanding of ELF-EMF biology with a focus on mechanisms of ELF-EMF-mediated disease and summarize the results of more recent experimental and epidemiological studies of ELF-EMF exposure effects on cancer, neurological, cardiovascular, and reproductive disorders. Current views on genomic instability effects, as well as scientific evidence about ELF-EMF therapy, are put forth. According to our literature review, exposure to ELF-EMF has an adverse biological effect depending on the current intensity, strength of the magnetic field, and duration of exposure. Accumulated epidemiologic evidence indicates a correlation between exposure to ELF-EMF and childhood cancer incidence, Alzheimer's disease (AD), and miscarriage. However, adult cancer does not show augmented risk caused by the ELF-EMF. Also, no consistent evidence exists in cardiovascular disease mortality due to ELF-EMF exposure. There is a lack of comprehensive mechanisms for explaining the biological effect of ELF-EMF. Eventually, more studies are needed to clarify the mechanisms of these magnetic fields.}, } @article {pmid32514052, year = {2020}, author = {Kim, HN and Seo, BR and Kim, H and Koh, JY}, title = {Cilostazol restores autophagy flux in bafilomycin A1-treated, cultured cortical astrocytes through lysosomal reacidification: roles of PKA, zinc and metallothionein 3.}, journal = {Scientific reports}, volume = {10}, number = {1}, pages = {9175}, pmid = {32514052}, issn = {2045-2322}, support = {2016R1E1A1A01941212//National Research Foundation of Korea (NRF)/ ; 2017M3C7A1028949//National Research Foundation of Korea (NRF)/ ; HI14C1913//Korea Health Industry Development Institute (KHIDI)/ ; }, abstract = {Cilostazol, a phosphodiesterase 3 inhibitor, reduces the amyloid-beta (Aβ) burden in mouse models of Alzheimer disease by as yet unidentified mechanisms. In the present study, we examined the possibility that cilostazol ameliorates lysosomal dysfunction. Astrocytes treated with bafilomycin A1 (BafA1) exhibited markedly reduced DND-189 and acridine orange (AO) fluorescence, indicating reduced lysosomal acidity. In both cases, BafA1-induced alkalization was reversed by addition of cilostazol, dibutyryl cAMP or forskolin. All three agents significantly increased free zinc levels in lysosomes, and addition of the zinc chelator TPEN abrogated lysosomal reacidification. These treatments did not raise free zinc levels or reverse BafA1-mediated lysosomal alkalization in metallothionein 3 (Mt3)-null astrocytes, indicating that the increases in zinc in astrocytes were derived mainly from Mt3. Lastly, in FITC-Aβ-treated astrocytes, cilostazol reversed lysosomal alkalization, increased cathepsin D activity, and reduced Aβ accumulation in astrocytes. Cilostazol also reduced mHtt aggregate formation in GFP-mHttQ74-expressing astrocytes. Collectively, our results present the novel finding that cAMP/PKA can overcome the v-ATPase blocking effect of BafA1 in a zinc- and Mt3-dependent manner.}, } @article {pmid32514050, year = {2020}, author = {Delaby, C and Alcolea, D and Carmona-Iragui, M and Illán-Gala, I and Morenas-Rodríguez, E and Barroeta, I and Altuna, M and Estellés, T and Santos-Santos, M and Turon-Sans, J and Muñoz, L and Ribosa-Nogué, R and Sala-Matavera, I and Sánchez-Saudinos, B and Subirana, A and Videla, L and Benejam, B and Sirisi, S and Lehmann, S and Belbin, O and Clarimon, J and Blesa, R and Pagonabarraga, J and Rojas-Garcia, R and Fortea, J and Lleó, A}, title = {Differential levels of Neurofilament Light protein in cerebrospinal fluid in patients with a wide range of neurodegenerative disorders.}, journal = {Scientific reports}, volume = {10}, number = {1}, pages = {9161}, pmid = {32514050}, issn = {2045-2322}, abstract = {Cerebrospinal fluid (CSF) biomarkers are useful in the diagnosis and the prediction of progression of several neurodegenerative diseases. Among them, CSF neurofilament light (NfL) protein has particular interest, as its levels reflect neuroaxonal degeneration, a common feature in various neurodegenerative diseases. In the present study, we analyzed NfL levels in the CSF of 535 participants of the SPIN (Sant Pau Initiative on Neurodegeneration) cohort including cognitively normal participants, patients with Alzheimer disease (AD), Down syndrome (DS), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). We evaluated the differences in CSF NfL accross groups and its association with other CSF biomarkers and with cognitive scales. All neurogenerative diseases showed increased levels of CSF NfL, with the highest levels in patients with ALS, FTD, CBS and PSP. Furthermore, we found an association of CSF NfL levels with cognitive impairment in patients within the AD and FTD spectrum and with AD pathology in DLB and DS patients. These results have implications for the use of NfL as a marker in neurodegenerative diseases.}, } @article {pmid32513474, year = {2020}, author = {Tresker, S}, title = {A typology of clinical conditions.}, journal = {Studies in history and philosophy of biological and biomedical sciences}, volume = {}, number = {}, pages = {101291}, pmid = {32513474}, issn = {1879-2499}, abstract = {In the philosophy of medicine, great attention has been paid to defining disease, yet less attention has been paid to the classification of clinical conditions. These include conditions that look like diseases but are not; conditions that are diseases but that (currently) have no diagnostic criteria; and other types, including those relating to risk for disease. I present a typology of clinical conditions by examining factors important for characterizing clinical conditions. By attending to the types of clinical conditions possible on the basis of these key factors (symptomaticity, dysfunction, and the meeting of diagnostic criteria), I draw attention to how diseases and other clinical conditions as currently classified can be better categorized, highlighting the issues pertaining to certain typology categories. Through detailed analysis of a wide variety of clinical examples, including Alzheimer disease as a test case, I show how nosology, research, and decisions about diagnostic criteria should include normative as well as naturalistically describable factors.}, } @article {pmid32512218, year = {2020}, author = {da Silveira Souza, B and Poloni, KM and Ferrari, RJ}, title = {Detector of 3-D salient points based on the dual-tree complex wavelet transform for the positioning of hippocampi meshes in magnetic resonance images.}, journal = {Journal of neuroscience methods}, volume = {341}, number = {}, pages = {108789}, doi = {10.1016/j.jneumeth.2020.108789}, pmid = {32512218}, issn = {1872-678X}, abstract = {BACKGROUND: Brain Magnetic Resonance (MR) image segmentation methods based on deformable models depend on the initial positioning to maximize the chances of successful segmentation. To minimize this limitation, salient-point based registration is used to perform the initial positioning of brain structure meshes close to their image target representation. The analysis of brain structures (such as the hippocampus) can help in the diagnosis and follow-up of neurodegenerative diseases like Alzheimer's.

METHODS: We present a technique for detection and description of 3-D salient points, which combines filter response maps estimated for different scales and orientations of the dual-tree complex wavelet transform (DT-CWT). We apply our technique to detect salient points in volumetric brain MR images and use the detected points in a positioning methodology. To illustrate the applicability, we applied our method for the positioning of hippocampi meshes in 3-D brain MR images and assessed the results by overlapping the positioned meshes with manual annotations made by medical specialists.

RESULTS: Our method yielded mean values of normalized Dice Similarity Coefficient (nDSC) of 0.74/0.68 and Hausdorff Average Distance (HAD) of 0.73/0.75 for the left and right hippocampus, respectively.

COMPARISON WITH OTHER METHODS: The mean nDSC and HAD results of our detector were significantly better than the ones achieved by an Affine and a Phase Congruency (PC) guided positioning.

CONCLUSIONS: The detection via DT-CWT decomposition is computationally less demanding than the detection via PC and represents a robust alternative for the positioning of mesh models.}, } @article {pmid32511670, year = {2020}, author = {Komaroff, AL}, title = {Can Infections Cause Alzheimer Disease?.}, journal = {JAMA}, volume = {}, number = {}, pages = {}, doi = {10.1001/jama.2020.4085}, pmid = {32511670}, issn = {1538-3598}, } @article {pmid32511043, year = {2020}, author = {Kinfe, TM 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 = {}, number = {}, pages = {}, doi = {10.1080/14737175.2020.1779590}, pmid = {32511043}, issn = {1744-8360}, 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 re-examine the preliminary findings for the treatment of psychiatric disorders.}, } @article {pmid32510331, year = {2020}, author = {Sebastian Monasor, L and Müller, SA and Colombo, AV and Tanrioever, G and König, J and Roth, S and Liesz, A and Berghofer, A and Piechotta, A and Prestel, M and Saito, T and Saido, TC and Herms, J and Willem, M and Haass, C and Lichtenthaler, SF and Tahirovic, S}, title = {Fibrillar Aβ triggers microglial proteome alterations and dysfunction in Alzheimer mouse models.}, journal = {eLife}, volume = {9}, number = {}, pages = {}, pmid = {32510331}, issn = {2050-084X}, support = {18014//Alzheimer Forschung Initiative/International ; EXC 2145 SyNergy ID 390857198//Deutsche Forschungsgemeinschaft/International ; Koselleck Project HA1737/16-1//Deutsche Forschungsgemeinschaft/International ; ERC-StG 802305//H2020 European Research Council/International ; ZT-0027//Helmholtz-Gemeinschaft/International ; JPND PMG-AD//Bundesministerium für Bildung und Forschung/International ; CLINSPECT-M//Bundesministerium für Bildung und Forschung/International ; 01133//NCL Foundation/International ; }, abstract = {Microglial dysfunction is a key pathological feature of Alzheimer's disease (AD), but little is known about proteome-wide changes in microglia during the course of AD and their functional consequences. Here, we performed an in-depth and time-resolved proteomic characterization of microglia in two mouse models of amyloid β (Aβ) pathology, the overexpression APPPS1 and the knock-in APP-NL-G-F (APP-KI) model. We identified a large panel of Microglial Aβ Response Proteins (MARPs) that reflect heterogeneity of microglial alterations during early, middle and advanced stages of Aβ deposition and occur earlier in the APPPS1 mice. Strikingly, the kinetic differences in proteomic profiles correlated with the presence of fibrillar Aβ, rather than dystrophic neurites, suggesting that fibrillar Aβ may trigger the AD-associated microglial phenotype and the observed functional decline. The identified microglial proteomic fingerprints of AD provide a valuable resource for functional studies of novel molecular targets and potential biomarkers for monitoring AD progression or therapeutic efficacy.}, } @article {pmid32510120, year = {2020}, author = {Simões, ALS and Oliva Filho, A and Hebling, E}, title = {Signs for Early Detection of Dysphagia in Older Adults with Severe Alzheimer's Disease.}, journal = {The journal of nutrition, health & aging}, volume = {24}, number = {6}, pages = {659-664}, doi = {10.1007/s12603-020-1382-8}, pmid = {32510120}, issn = {1760-4788}, abstract = {OBJECTIVES: The aim of this study was to detect signs of dysphagia in older adults with and without Alzheimer's disease (AD).

STUDY DESIGN: A cross-sectional study.

SETTING AND PARTICIPANTS: A total of 280 institutionalized older adults (with AD = 145; without AD = 135), aged > 70 years, with oral feeding, both sexes were examined.

MEASUREMENTS: Modified water-swallowing test determined the dysphagia. Independent variables were dependency level (modified Barthel Index), oral health and function status (residual teeth, occlusal contacts, passive lip sealing, tongue function, rinsing and gargling ability), nutritional status (Body Mass Index, Mini Nutritional Assessment), and diet-related assessments (appetite, storing or stuffing food in the mouth). Statistical analysis was carried out by Fisher´s Exact and chi-square tests. The analyzes of associations with the dysphagia outcome were performed by simple and multiple logistic regression models.

RESULTS: Severity of AD was significantly associated with dysphagia. The signs associated with dysphagia were decreased nutritional status, absence of appetite, and storing food in the mouth.

CONCLUSION: These signs can be useful tools for early diagnosis of dysphagia in AD older adults.}, } @article {pmid32508874, year = {2020}, author = {Deng, Y and He, T and Fang, R and Li, S and Cao, H and Cui, Y}, title = {Genome-Wide Gene-Based Multi-Trait Analysis.}, journal = {Frontiers in genetics}, volume = {11}, number = {}, pages = {437}, pmid = {32508874}, issn = {1664-8021}, abstract = {Genome-wide association studies focusing on a single phenotype have been broadly conducted to identify genetic variants associated with a complex disease. The commonly applied single variant analysis is limited by failing to consider the complex interactions between variants, which motivated the development of association analyses focusing on genes or gene sets. Moreover, when multiple correlated phenotypes are available, methods based on a multi-trait analysis can improve the association power. However, most currently available multi-trait analyses are single variant-based analyses; thus have limited power when disease variants function as a group in a gene or a gene set. In this work, we propose a genome-wide gene-based multi-trait analysis method by considering genes as testing units. For a given phenotype, we adopt a rapid and powerful kernel-based testing method which can evaluate the joint effect of multiple variants within a gene. The joint effect, either linear or nonlinear, is captured through kernel functions. Given a series of candidate kernel functions, we propose an omnibus test strategy to integrate the test results based on different candidate kernels. A p-value combination method is then applied to integrate dependent p-values to assess the association between a gene and multiple correlated phenotypes. Simulation studies show a reasonable type I error control and an excellent power of the proposed method compared to its counterparts. We further show the utility of the method by applying it to two data sets: the Human Liver Cohort and the Alzheimer Disease Neuroimaging Initiative data set, and novel genes are identified. Our method has broad applications in other fields in which the interest is to evaluate the joint effect (linear or nonlinear) of a set of variants.}, } @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 = {}, number = {}, pages = {}, pmid = {32507686}, issn = {1545-7214}, 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}, support = {2010071420012//National Natural Science Foundation of Chin/ ; 1000071220002//National Natural Science Foundation of Chin/ ; 2010072120020//National Natural Science Foundation of Chin/ ; 2010072220008//National Natural Science Foundation of Chin/ ; 20180072020005//National Natural Science Foundation of Chin/ ; }, 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 {pmid32504837, year = {2020}, author = {Rueda-Ruzafa, L and Cruz, F and Cardona, D and Hone, AJ and Molina-Torres, G and Sánchez-Labraca, N and Roman, P}, title = {Opioid system influences gut-brain axis: Dysbiosis and related alterations.}, journal = {Pharmacological research}, volume = {159}, number = {}, pages = {104928}, doi = {10.1016/j.phrs.2020.104928}, pmid = {32504837}, issn = {1096-1186}, abstract = {Opioid drugs are widely used to treat chronic pain, but their misuse can lead to tolerance, dependence, and addiction and have created a significant public health problem. In addition, food-derived opioid peptides, known as exorphins, like gluten exorphins have been shown to have harmful effects in certain pathologies like celiac disease, for example. Several studies support the involvement of the opioid system in the development of disorders such as autism spectrum syndrome. Moreover, bidirectional communication between the intestine and brain has been shown to be altered in various neurodegenerative diseases including Alzheimer´s and Parkinson´s. The presence of opioid receptors in both the digestive tract and the central nervous system (CNS) suggests that opioid drugs and exorphins may modulate the gut-brain axis. Morphine, for example, has shown a dysbiotic effect on the bacterial microbiota in addition to inducing an increase in intestinal permeability facilitating bacterial translocation. Furthermore, certain components of bacteria can modify the expression of opioid receptors at the central level increasing sensitivity to pain. Strategies based on use of probiotics have resulted in improvements in symptoms of autism and Parkinson´s disease. In this manuscript, we review the role of the opioid system in disorders and CNS pathologies and the involvement of the gut-brain axis.}, } @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}, 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 {pmid32503894, year = {2020}, author = {Zhang, Y and Fung, ITH and Sankar, P and Chen, X and Robison, LS and Ye, L and D'Souza, SS and Salinero, AE and Kuentzel, ML and Chittur, SV and Zhang, W and Zuloaga, KL and Yang, Q}, title = {Depletion of NK Cells Improves Cognitive Function in the Alzheimer Disease Mouse Model.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {}, number = {}, pages = {}, doi = {10.4049/jimmunol.2000037}, pmid = {32503894}, issn = {1550-6606}, abstract = {Despite mounting evidence suggesting the involvement of the immune system in regulating brain function, the specific role of immune and inflammatory cells in neurodegenerative diseases remain poorly understood. In this study, we report that depletion of NK cells, a type of innate lymphocytes, alleviates neuroinflammation, stimulates neurogenesis, and improves cognitive function in a triple-transgenic Alzheimer disease (AD) mouse model. NK cells in the brains of triple-transgenic AD mouse model (3xTg-AD) mice exhibited an enhanced proinflammatory profile. Depletion of NK cells by anti-NK1.1 Abs drastically improved cognitive function of 3xTg-AD mice. NK cell depletion did not affect amyloid β concentrations but enhanced neurogenesis and reduced neuroinflammation. Notably, in 3xTg-AD mice depleted of NK cells, microglia demonstrated a homeostatic-like morphology, decreased proliferative response and reduced expression of neurodestructive proinflammatory cytokines. Together, our results suggest a proinflammatory role for NK cells in 3xTg-AD mice and indicate that targeting NK cells might unlock novel strategies to combat AD.}, } @article {pmid32503282, year = {2020}, author = {López-Cuenca, I and de Hoz, R and Salobrar-García, E and Elvira-Hurtado, L and Rojas, P and Fernández-Albarral, JA and Barabash, A and Salazar, JJ and Ramírez, AI and Ramírez, JM}, title = {Macular Thickness Decrease in Asymptomatic Subjects at High Genetic Risk of Developing Alzheimer's Disease: An OCT Study.}, journal = {Journal of clinical medicine}, volume = {9}, number = {6}, pages = {}, doi = {10.3390/jcm9061728}, pmid = {32503282}, issn = {2077-0383}, support = {OFTARED (RD16/0008/0005)//Instituto de Salud Carlos III/ ; RETIBRAIN (RED2018-102499-T)//Ministerio de Ciencia e Innovación/ ; CT42/18-CT43/18//Universidad Complutense de Madrid/ ; FPU17/01023//Ministerio de Ciencia, Innovación y Universidades/ ; }, abstract = {In this case control study, we examined the retinal thickness of the different layers in the macular region and peripapillary retinal nerve fiber layer (RNFL) with optical coherence tomography (OCT) in healthy cognitive subjects (from 51 to 74 years old) at high genetic risk for developing Alzheimer's disease (AD). Thirty-five subjects with a family history of Alzheimer disease (AD) (FH+) and ApoE ɛ4 carriers and 29 age-matched control subjects without a family history of AD (FH-) and ApoE ɛ4 non-carriers were included. Compared to FH- ApoE ɛ4 non-carriers, in FH+ ApoE ɛ4 carriers, there were statistically significant decreases (p < 0.05) in (i) the foveal area of mRNFL; (ii) the inferior and nasal sectors in the outer and inner macular ring in the inner plexiform layer (IPL); (iii) the foveal area and the inferior sector in the outer macular ring in the inner nuclear layer (INL); and (iv) the inferior sector of the outer macular ring in the outer plexiform layer (OPL). However, no statistically significant differences were found in the peripapillary thickness of RNFL between both study groups. In subjects with cognitive health and high genetic risk for the development of AD, initial changes appeared in the macular area. OCT could be a promising, cost-effective and non-invasive test useful in early AD, before the onset of clinical symptoms.}, } @article {pmid32503261, year = {2020}, author = {Temviriyanukul, P and Sritalahareuthai, V and Jom, KN and Jongruaysup, B and Tabtimsri, S and Pruesapan, K and Thangsiri, S and Inthachat, W and Siriwan, D and Charoenkiatkul, S and Suttisansanee, U}, title = {Comparison of Phytochemicals, Antioxidant, and In Vitro Anti-Alzheimer Properties of Twenty-Seven Morus spp. Cultivated in Thailand.}, journal = {Molecules (Basel, Switzerland)}, volume = {25}, number = {11}, pages = {}, doi = {10.3390/molecules25112600}, pmid = {32503261}, issn = {1420-3049}, support = {22/2561//Biodiversity-Based Economy Development Office (BEDO)/ ; -//Grants-in-Aid from JSPS Core to-Core Program B. Asia-Africa Science Platforms/ ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder. To fight the disease, natural products, including mulberry, with antioxidant activities and inhibitory activities against key enzymes (acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and beta-secretase 1 (BACE-1)) are of interest. However, even in the same cultivars, mulberry trees grown in different populated locations might possess disparate amounts of phytochemical profiles, leading to dissimilar health properties, which cause problems when comparing different cultivars of mulberry. Therefore, this study aimed to comparatively investigate the phytochemicals, antioxidant activities, and inhibitory activities against AChE, BChE, and BACE-1, of twenty-seven Morus spp. cultivated in the same planting area in Thailand. The results suggested that Morus fruit samples were rich in phenolics, especially cyanidin, kuromanin, and keracyanin. Besides, the aqueous Morus fruit extracts exhibited antioxidant activities, both in single electron transfer (SET) and hydrogen atom transfer (HAT) mechanisms, while strong inhibitory activities against AD key enzymes were observed. Interestingly, among the twenty-seven Morus spp., Morus sp. code SKSM 810191 with high phytochemicals, antioxidant activities and in vitro anti-AD properties is a promising cultivar for further developed as a potential mulberry resource with health benefits against AD.}, } @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}, 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 {pmid32501203, year = {2019}, author = {Heron, M}, title = {Deaths: Leading Causes for 2017.}, journal = {National vital statistics reports : from the Centers for Disease Control and Prevention, National Center for Health Statistics, National Vital Statistics System}, volume = {68}, number = {6}, pages = {1-77}, pmid = {32501203}, issn = {1551-8930}, abstract = {Objectives-This report presents final 2017 data on the 10 leading causes of death in the United States by age, sex, race, and Hispanic origin. Leading causes of infant, neonatal, and postneonatal death are also presented. This report supplements "Deaths: Final Data for 2017," the National Center for Health Statistics' annual report of final mortality statistics. Methods-Data in this report are based on information from all death certificates filed in the 50 states and the District of Columbia in 2017. Causes of death classified by the International Classification of Diseases, 10th Revision (ICD-10) are ranked according to the number of deaths assigned to rankable causes. Cause-of-death statistics are based on the underlying cause of death. Results-In 2017, the 10 leading causes of death were, in rank order: Diseases of heart; Malignant neoplasms; Accidents (unintentional injuries); Chronic lower respiratory diseases; Cerebrovascular diseases; Alzheimer disease; Diabetes mellitus; Influenza and pneumonia; Nephritis, nephrotic syndrome and nephrosis; and Intentional self-harm (suicide). They accounted for 74% of all deaths occurring in the United States. Differences in the rankings are evident by age, sex, race, and Hispanic origin. Leading causes of infant death for 2017 were, in rank order: Congenital malformations, deformations and chromosomal abnormalities; Disorders related to short gestation and low birth weight, not elsewhere classified; Newborn affected by maternal complications of pregnancy; Sudden infant death syndrome; Accidents (unintentional injuries); Newborn affected by complications of placenta, cord and membranes; Bacterial sepsis of newborn; Diseases of the circulatory system; Respiratory distress of newborn; and Neonatal hemorrhage. Important variations in the leading causes of infant death are noted for the neonatal and postneonatal periods.}, } @article {pmid32499247, year = {2020}, author = {Reith, F and Koran, ME and Davidzon, G and Zaharchuk, G and , }, title = {Application of Deep Learning to Predict Standardized Uptake Value Ratio and Amyloid Status on 18F-Florbetapir PET Using ADNI Data.}, journal = {AJNR. American journal of neuroradiology}, volume = {41}, number = {6}, pages = {980-986}, doi = {10.3174/ajnr.A6573}, pmid = {32499247}, issn = {1936-959X}, abstract = {BACKGROUND AND PURPOSE: Cortical amyloid quantification on PET by using the standardized uptake value ratio is valuable for research studies and clinical trials in Alzheimer disease. However, it is resource intensive, requiring co-registered MR imaging data and specialized segmentation software. We investigated the use of deep learning to automatically quantify standardized uptake value ratio and used this for classification.

MATERIALS AND METHODS: Using the Alzheimer's Disease Neuroimaging Initiative dataset, we identified 2582 18F-florbetapir PET scans, which were separated into positive and negative cases by using a standardized uptake value ratio threshold of 1.1. We trained convolutional neural networks (ResNet-50 and ResNet-152) to predict standardized uptake value ratio and classify amyloid status. We assessed performance based on network depth, number of PET input slices, and use of ImageNet pretraining. We also assessed human performance with 3 readers in a subset of 100 randomly selected cases.

RESULTS: We have found that 48% of cases were amyloid positive. The best performance was seen for ResNet-50 by using regression before classification, 3 input PET slices, and pretraining, with a standardized uptake value ratio root-mean-square error of 0.054, corresponding to 95.1% correct amyloid status prediction. Using more than 3 slices did not improve performance, but ImageNet initialization did. The best trained network was more accurate than humans (96% versus a mean of 88%, respectively).

CONCLUSIONS: Deep learning algorithms can estimate standardized uptake value ratio and use this to classify 18F-florbetapir PET scans. Such methods have promise to automate this laborious calculation, enabling quantitative measurements rapidly and in settings without extensive image processing manpower and expertise.}, } @article {pmid32498299, year = {2020}, author = {Yang, PS and Sung, JH and Jang, E and Yu, HT and Kim, TH and Uhm, JS and Kim, JY and Pak, HN and Lee, MH and Lip, GYH and Joung, B}, title = {The Effect of Integrated Care Management on Dementia in Atrial Fibrillation.}, journal = {Journal of clinical medicine}, volume = {9}, number = {6}, pages = {}, doi = {10.3390/jcm9061696}, pmid = {32498299}, issn = {2077-0383}, abstract = {Clinical outcomes of patients with atrial fibrillation (AF) can be improved by an integrated care approach. We analyzed whether adherence with the AF Better Care (ABC) pathway for integrated care management would reduce the risk of dementia in a nationwide AF cohort. Using the National Health Insurance Service database of Korea, 228,026 non-valvular AF patients were retrospectively evaluated between 2005 and 2015. Patients meeting all criteria of the ABC pathway were classified as the "ABC" group and those not classified as the "non-ABC" group. During a median (25th, 75th percentiles) follow-up of 6.0 (3.3, 9.5) years, the ABC group had lower rates and risk of overall dementia (0.17 vs. 1.11 per 100 person-years, p < 0.001; hazard ratio (HR) 0.80; 95% CI 0.73-0.87) and both Alzheimer's (HR 0.79, 95% CI 0.71-0.88) and vascular dementia (HR 0.76, 95% CI 0.59-0.98) than the non-ABC group. The stratified analysis showed that the ABC pathway reduced the risk of dementia regardless of sex, comorbidities, and in patients with high stroke risk. Adherence with the ABC pathway is associated with a reduced risk of dementia in AF patients. Due to the high medical burden of AF, it is necessary to implement integrated AF management to reduce the risk of dementia.}, } @article {pmid32497293, year = {2020}, author = {Zampar, S and Klafki, HW and Sritharen, K and Bayer, TA and Wiltfang, J and Rostagno, A and Ghiso, J and A Miles, L and Wirths, O}, title = {N-terminal heterogeneity of parenchymal and vascular amyloid-β deposits in Alzheimer's disease.}, journal = {Neuropathology and applied neurobiology}, volume = {}, number = {}, pages = {}, doi = {10.1111/nan.12637}, pmid = {32497293}, issn = {1365-2990}, abstract = {AIMS: The deposition of amyloid-β (Aβ) peptides in the form of extracellular plaques in the brain represents one of the classical hallmarks of Alzheimer's disease (AD). In addition to "full length" Aβ starting with aspartic acid (Asp-1), considerable amounts of various shorter, N-terminally truncated Aβ peptides have been identified by mass spectrometry in autopsy samples from individuals with AD.

METHODS: Selectivity of several antibodies detecting full-length, total or N-terminally truncated Aβ species has been characterized with capillary isoelectric focusing assays using a set of synthetic Aβ peptides comprising different N-termini. We further assessed the N-terminal heterogeneity of extracellular and vascular Aβ peptide deposits in the human brain by performing immunohistochemical analyses using sporadic AD cases with antibodies targeting different N-terminal residues, including the biosimilar antibodies Bapineuzumab and Crenezumab.

RESULTS: While antibodies selectively recognizing Aβ1-x showed a much weaker staining of extracellular plaques and tended to accentuate cerebrovascular amyloid deposits, antibodies detecting Aβ starting with phenylalanine at position 4 of the Aβ sequence showed abundant amyloid plaque immunoreactivity in the brain parenchyma. The biosimilar antibody Bapineuzumab recognized Aβ starting at Asp-1 and demonstrated abundant immunoreactivity in AD brains.

DISCUSSION: In contrast to other studied Aβ1-x specific antibodies, Bapineuzumab displayed stronger immunoreactivity on fixed tissue samples than with SDS-denatured samples on Western blots. This suggests conformational preferences of this antibody. The diverse composition of plaques and vascular deposits stresses the importance of understanding the roles of various Aβ variants during disease development and progression in order to generate appropriate target-developed therapies.}, } @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 = {}, number = {}, pages = {}, doi = {10.1002/ptr.6720}, pmid = {32496629}, issn = {1099-1573}, 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 {pmid32496297, year = {2020}, author = {Mendez, MF and Chavez, D and Desarzant, RE and Yerstein, O}, title = {Clinical Features of Late-onset Semantic Dementia.}, journal = {Cognitive and behavioral neurology : official journal of the Society for Behavioral and Cognitive Neurology}, volume = {33}, number = {2}, pages = {122-128}, pmid = {32496297}, issn = {1543-3641}, support = {R01 AG034499/AG/NIA NIH HHS/United States ; RF1 AG050967/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: Semantic dementia (SD) is characterized by progressive semantic anomia extending to a multimodal loss of semantic knowledge. Although often considered an early-onset dementia, SD also occurs in later life, when it may be misdiagnosed as Alzheimer disease (AD).

OBJECTIVE: To evaluate late-onset SD in comparison to early-onset SD and to AD.

METHODS: We identified 74 individuals with SD and then compared those with late-onset SD (≥65 years of age) to those with early-onset SD (<65) on demographic and clinical features. We also compared a subgroup of 23 of the late-onset SD individuals with an equal number of individuals with clinically probable AD.

RESULTS: Twenty-six (35.1%) of the SD individuals were late onset, and 48 (64.9%) were early onset. There were no differences between the two groups on clinical measures, although greater asymmetry of temporal involvement trended to significance in the late-onset SD group. Compared to the 23 AD individuals, the subgroup of 23 late-onset SD individuals had worse performance on confrontational naming, irregular word reading, and face recognition; however, this subgroup displayed better verbal delayed recall and constructions. The late-onset SD individuals also experienced early personality changes at a time when most individuals with AD had not yet developed behavioral changes.

CONCLUSIONS: Approximately one-third of SD individuals may be late onset, and the differentiation of late-onset SD from AD can lead to better disease management, education, and prognosis. SD may be distinguished by screening for disproportionate changes in reading, face recognition, and personality.}, } @article {pmid32493775, year = {2020}, author = {Abskharon, R and Seidler, PM and Sawaya, MR and Cascio, D and Yang, TP and Philipp, S and Williams, CK and Newell, KL and Ghetti, B and DeTure, MA and Dickson, DW and Vinters, HV and Felgner, PL and Nakajima, R and Glabe, CG and Eisenberg, DS}, title = {Crystal structure of a conformational antibody that binds tau oligomers and inhibits pathological seeding by extracts from donors with Alzheimer's disease.}, journal = {The Journal of biological chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1074/jbc.RA120.013638}, pmid = {32493775}, issn = {1083-351X}, abstract = {Soluble oligomers of aggregated tau accompany the accumulation of insoluble amyloid fibrils, a histological hallmark of Alzheimer disease (AD) and two dozen related neurodegenerative diseases. Both oligomers and fibrils seed the spread of tau pathology, and by virtue of their low molecular weight and relative solubility, oligomers may be particularly pernicious seeds. Here, we report the formation of in vitro tau oligomers formed by an ionic liquid (IL15). Using IL15-induced recombinant tau oligomers and a dot blot assay, we discovered a monoclonal antibody (M204) that binds oligomeric tau, but not tau monomers or fibrils. M204 and an engineered single-chain variable-fragment (scFv) inhibited seeding by IL15-induced tau oligomers and pathological extracts from donors with AD and chronic traumatic encephalopathy (CTE). This finding suggests that M204-scFv targets pathological structures that are formed by tau in neurodegenerative diseases. We found that M204-scFv itself partitions into oligomeric forms that inhibit seeding differently, and crystal structures of the M204-scFv monomer, dimer, and trimer revealed conformational differences that explain differences among these forms in binding and inhibition. The efficiency of M204-scFv antibodies to inhibit the seeding by brain tissue extracts from different donors with tauopathies varied among individuals, indicating the possible existence of distinct amyloid polymorphs. We propose that by binding to oligomers, which are hypothesized to be the earliest seeding-competent species, M204-scFv may have potential as an early-stage diagnostic for AD and tauopathies, and also could guide the development of promising therapeutic antibodies.}, } @article {pmid32490841, year = {2020}, author = {Hane, CA and Nori, VS and Crown, WH and Sanghavi, DM and Bleicher, P}, title = {Predicting Onset of Dementia Using Clinical Notes and Machine Learning: Case-Control Study.}, journal = {JMIR medical informatics}, volume = {8}, number = {6}, pages = {e17819}, doi = {10.2196/17819}, pmid = {32490841}, issn = {2291-9694}, abstract = {BACKGROUND: Clinical trials need efficient tools to assist in recruiting patients at risk of Alzheimer disease and related dementias (ADRD). Early detection can also assist patients with financial planning for long-term care. Clinical notes are an important, underutilized source of information in machine learning models because of the cost of collection and complexity of analysis.

OBJECTIVE: This study aimed to investigate the use of deidentified clinical notes from multiple hospital systems collected over 10 years to augment retrospective machine learning models of the risk of developing ADRD.

METHODS: We used 2 years of data to predict the future outcome of ADRD onset. Clinical notes are provided in a deidentified format with specific terms and sentiments. Terms in clinical notes are embedded into a 100-dimensional vector space to identify clusters of related terms and abbreviations that differ across hospital systems and individual clinicians.

RESULTS: When using clinical notes, the area under the curve (AUC) improved from 0.85 to 0.94, and positive predictive value (PPV) increased from 45.07% (25,245/56,018) to 68.32% (14,153/20,717) in the model at disease onset. Models with clinical notes improved in both AUC and PPV in years 3-6 when notes' volume was largest; results are mixed in years 7 and 8 with the smallest cohorts.

CONCLUSIONS: Although clinical notes helped in the short term, the presence of ADRD symptomatic terms years earlier than onset adds evidence to other studies that clinicians undercode diagnoses of ADRD. De-identified clinical notes increase the accuracy of risk models. Clinical notes collected across multiple hospital systems via natural language processing can be merged using postprocessing techniques to aid model accuracy.}, } @article {pmid32490138, year = {2020}, author = {Allegri, RF and Chrem Méndez, P and Calandri, I and Cohen, G and Martín, ME and Russo, MJ and Crivelli, L and Pertierra, L and Tapajóz, F and Clarens, MF and Campos, J and Nahas, FE and Vázquez, S and Surace, E and Sevlever, G}, title = {Prognostic value of ATN Alzheimer biomarkers: 60-month follow-up results from the Argentine Alzheimer's Disease Neuroimaging Initiative.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {12}, number = {1}, pages = {e12026}, pmid = {32490138}, issn = {2352-8729}, abstract = {Purpose: To describe results of the Amyloid, Tau, Neurodegeneration (ATN) research framework classification in the Argentine-Alzheimer's Disease Neuroimaging Initiative (arg-ADNI) cohort.

Methods: Twenty-three patients with mild cognitive impairment (MCI), 12 dementia of Alzheimer's type (DAT), and 14 normal controls were studied following the ADNI2 protocol. Patients were categorized according to presence or absence of the biomarkers for amyloid beta (Aβ; A: amyloid positron emission tomography [PET] scan or cerebrospinal fluid [CSF] Aβ42), tau (T: CSF phosphorylated-tau), and neurodegeneration (N: CSF total-tau, fluorodeoxyglucose [FDG]-PET scan, or structural magnetic resonance imaging [MRI] scan).

Results: A+T+N+ biomarker profile was identified at baseline in 91% of mild dementia patients, 20% of early MCI patients, 46% of late MCI patients, and 14% of control subjects. Suspected non-AD pathophysiology (SNAP, A-T-N+) was found in 8% of mild dementia, 20% of early MCI, 15% of late MCI, and 7% of control subjects. Conversion rates to dementia after 5-year follow-up were 85% in A+T+N+ MCI patients and 50% in A-T-N+ patients.

Conclusions: We present initial 5-year follow-up results of a regional ADNI based on AD biomarkers and the ATN classification.}, } @article {pmid32489952, year = {2019}, author = {Bewicz-Binkowska, D and Zgorzynska, E and Dziedzic, B and Walczewska, A}, title = {Docosahexaenoic Acid (DHA) Inhibits FADS2 Expression in Astrocytes but Increases Survival of Neurons Co-cultured with DHA-enriched Astrocytes.}, journal = {International journal of molecular and cellular medicine}, volume = {8}, number = {3}, pages = {232-240}, pmid = {32489952}, issn = {2251-9637}, abstract = {Docosahexaenoic acid (DHA), the most abundant n-3 polyunsaturated fatty acid (n-3PUFA) in the brain, has attracted great importance for a variety of neuronal functions such as signal transduction through plasma membranes, neuronal plasticity, and neuroprotection. Astrocytes that provide structural, functional, and metabolic support for neurons, express ∆6- desaturase encoded by FADS2 gene that can be, next to the plasma DHA pool, additional source of DHA in the brain. Furthermore, the genetic variations of FADS gene cluster has been found in children with developmental disorders, and are associated with cognitive functions. Since, the regulation of DHA biosynthesis in astrocytes remains poorly studied the aim of this study was to determine the effect of palmitic acid (PA), α-linolenic acid (ALA) or docosahexaenoic acid (DHA), on the transcription of FADS2 gene in astrocytes and survival of neurons challenged with oxidative compounds after co-culture with astrocytes exposed to DHA. The lipid profile in cell membranes after incubation with fatty acids was determined by gas chromatography, and FADS2 expression was analyzed using real-time PCR. The viability of neurons cocultured with PUFA-enriched astrocytes was investigated by flow cytometry after staining cells with annexin V-FITC and PI. The results showed that DHA suppressed (P <0.01), PA stimulated (P <0.01), while ALA did not change the FADS2 gene expression after 24 h incubation of astrocytes with fatty acids. Although FADS2 mRNA was down-regulated by DHA, its level in astrocytic membranes significantly increased (P <0.01). Astrocytes with DHA-enriched membrane phospholipids markedly enhanced neuronal resistance to cytotoxic compounds and neuronal survival. These results suggest that beneficial effects of supplementation with n-3 PUFA in Alzheimer disease and in psychiatric disorders is caused, in part, by increased efficacy of DHA-enriched astrocytes to protect neurons under adverse conditions in the brain.}, } @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 = {}, number = {}, pages = {}, 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/ ; }, 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 {pmid32487053, year = {2020}, author = {Jung, M and Ko, W and Muhwava, W and Choi, Y and Kim, H and Park, YS and Jambere, GB and Cho, Y}, title = {Mind the gaps: age and cause specific mortality and life expectancy in the older population of South Korea and Japan.}, journal = {BMC public health}, volume = {20}, number = {1}, pages = {819}, pmid = {32487053}, issn = {1471-2458}, support = {No.21B20151213037, 2017R1C1B1004892//National Research Foundation of Korea/ ; }, abstract = {BACKGROUND: Recent life expectancy gains in high-income Asia-pacific countries have been largely the result of postponement of death from non-communicable diseases in old age, causing rapid demographic ageing. This study compared and quantified age- and cause-specific contributions to changes in old-age life expectancy in two high-income Asia-pacific countries with ageing populations, South Korea and Japan.

METHODS: This study used Pollard's actuarial method of decomposing life expectancy to compare age- and cause-specific contributions to changes in old-age life expectancy between South Korea and Japan during 1997 and 2017.

RESULTS: South Korea experienced rapid population ageing, and the gaps in life expectancy at 60 years old between South Korea and Japan were reduced by 2.47 years during 1997 and 2017. Decomposition analysis showed that mortality reductions from non-communicable diseases in South Korea were the leading causes of death contributing to the decreased gaps in old-age life expectancy between the two countries. More specifically, mortality reductions from cardiovascular diseases (stroke, ischaemic and hypertensive heart disease) and cancers (stomach, liver, lung, pancreatic cancers) in South Korea contributed to the decreased gap by 1.34 and 0.41 years, respectively. However, increased mortality from Alzheimer and dementia, lower respiratory tract disease, self-harm and falls in South Korea widened the gaps by 0.41 years.

CONCLUSIONS: Age- and cause- specific contributions to changes in old-age life expectancy can differ between high-income Asia-pacific countries. Although the gaps in old-age life expectancy between high-income Asia-pacific countries are primarily attributed to mortality changes in non-communicable diseases, these countries should also identify potential emerging threats of communicable diseases and injuries along with demographic ageing in pursuit of healthy life years in old age.}, } @article {pmid32486466, year = {2020}, author = {Park, D and Choi, EK and Cho, TH and Joo, SS and Kim, YB}, title = {Human Neural Stem Cells Encoding ChAT Gene Restore Cognitive Function via Acetylcholine Synthesis, Aβ Elimination, and Neuroregeneration in APPswe/PS1dE9 Mice.}, journal = {International journal of molecular sciences}, volume = {21}, number = {11}, pages = {}, doi = {10.3390/ijms21113958}, pmid = {32486466}, issn = {1422-0067}, support = {2017R1A2A2A05069417//National Research Foundation of Korea/ ; }, abstract = {In Alzheimer disease (AD) patients, degeneration of the cholinergic system utilizing acetylcholine for memory acquisition is observed. Since AD therapy using acetylcholinesterase (AChE) inhibitors are only palliative for memory deficits without slowing or reversing disease progress, there is a need for effective therapies, and stem cell-based therapeutic approaches targeting AD should fulfill this requirement. We established a human neural stem cell (NSC) line encoding choline acetyltransferase (ChAT) gene, an acetylcholine-synthesizing enzyme. APPswe/PS1dE9 AD model mice transplanted with the F3.ChAT NSCs exhibited improved cognitive function and physical activity. Transplanted F3.ChAT NSCs in the AD mice differentiated into neurons and astrocytes, produced ChAT protein, increased the ACh level, and improved the learning and memory function. F3.ChAT cell transplantation reduced Aβ deposits by recovering microglial function; i.e., the down-regulation of β-secretase and inflammatory cytokines and up-regulation of Aβ-degrading enzyme neprilysin. F3.ChAT cells restored growth factors (GFs) and neurotrophic factors (NFs), and they induced the proliferation of NSCs in the host brain. These findings indicate that NSCs overexpressing ChAT can ameliorate complex cognitive and physical deficits of AD animals by releasing ACh, reducing Aβ deposit, and promoting neuroregeneration by the production of GFs/NFs. It is suggested that NSCs overexpressing ChAT could be a candidate for cell therapy in advanced AD therapy.}, } @article {pmid32485711, year = {2020}, author = {Korhonen, T and Katisko, K and Cajanus, A and Hartikainen, P and Koivisto, AM and Haapasalo, A and Remes, AM and Solje, E}, title = {Comparison of Prodromal Symptoms of Patients with Behavioral Variant Frontotemporal Dementia and Alzheimer Disease.}, journal = {Dementia and geriatric cognitive disorders}, volume = {}, number = {}, pages = {1-9}, doi = {10.1159/000507544}, pmid = {32485711}, issn = {1421-9824}, abstract = {INTRODUCTION: Behavioral variant frontotemporal dementia (bvFTD) is the most common clinical subtype of frontotemporal lobar degeneration. bvFTD is often characterized by changes in behavior and personality, frequently leading to psychiatric misdiagnoses. On the other hand, substantial clinical overlap with other neurodegenerative diseases, such as Alzheimer disease (AD), further complicates the diagnostics.

OBJECTIVE: Our aim was to identify the main differences in early symptoms of bvFTD and AD in the prodromal stages of the diseases. In addition, patients with bvFTD were analyzed separately according to whether they carry the C9orf72repeat expansion or not.

METHODS: Patient records of bvFTD (n = 75) and AD (n = 83) patients were analyzed retrospectively for memory and neuropsychiatric symptoms, sleeping disorders, and somatic complaints before the setting of the accurate diagnosis.

RESULTS: A total of 84% of bvFTD patients (n = 63) and 98.8% of AD patients (n = 82) reported subjective memory disturbances in the prodromal phases of the disease. bvFTD patients presented significantly more often with sleeping disorders, headache, inexplicable collapses, transient loss of consciousness, somatization, delusions, and hallucinations, suicidality, changes in oral behaviors, and urinary problems. In addition, poor financial judgement was frequently detected in patients with prodromal bvFTD. Aberrant sensations in the nose and throat without any physical explanation, regarded as somatizations, emerged only in bvFTD patients with the C9orf72 repeat expansion.

CONCLUSIONS: Subjective reporting of impaired episodic memory is a poor indicator in differentiating bvFTD from AD. Sleeping disturbances, delusions, hallucinations, and unexplained somatic complaints in a patient with cognitive disturbances should prompt the clinicians to consider bvFTD as a possible diagnostic option behind these symptoms. The spectrum of symptoms in the prodromal stages of bvFTD may be more diverse than the latest criteria suggest.}, } @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}, 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}, 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 = {}, number = {}, pages = {1060028020930189}, doi = {10.1177/1060028020930189}, pmid = {32483988}, issn = {1542-6270}, 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. Study Selection and Data Extraction: 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. Relevance to Patient Care and Clinical Practice: 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 {pmid32483828, year = {2020}, author = {Gelpi, E and Rahimi, J and Klotz, S and Schmid, S and Ricken, G and Forcen-Vega, S and Budka, H and Kovacs, GG}, title = {The autophagic marker p62 highlights Alzheimer type II astrocytes in metabolic/hepatic encephalopathy.}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {}, number = {}, pages = {}, doi = {10.1111/neup.12660}, pmid = {32483828}, issn = {1440-1789}, abstract = {Metabolic/hepatic encephalopathy is neuropathologically characterized by the presence of Alzheimer type II astrocytes (AA II) with large and clear nuclear morphology. To date, there is no good immunohistochemical marker to better identify these cells. Here, we assessed cases of hepatic encephalopathy of different etiologies by immunohistochemistry using an anti-p62 antibody. We observed peripheral or diffuse nuclear staining of variable intensity in AA II in all cases but not in normal controls or reactive astrocytes. We conclude that p62 is a useful immunohistochemical marker for the identification of AA II and may be helpful for the neuropathological diagnosis of metabolic/hepatic encephalopathy in difficult or equivocal cases.}, } @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 {pmid32483017, year = {2020}, author = {Sachs, BC and Steenland, K and Zhao, L and Hughes, TM and Weintraub, S and Dodge, HH and Barnes, LL and Craft, S and Parker, ML and Goldstein, FC}, title = {Expanded Demographic Norms for Version 3 of the Alzheimer Disease Centers' Neuropsychological Test Battery in the Uniform Data Set.}, journal = {Alzheimer disease and associated disorders}, volume = {}, number = {}, pages = {}, doi = {10.1097/WAD.0000000000000388}, pmid = {32483017}, issn = {1546-4156}, abstract = {BACKGROUND: Norms for the Uniform Data Set Version 3 Neuropsychological Battery are available for cognitively normal individuals based on age, education, and sex; however, these norms do not include race. We provide expanded norms for African Americans and whites.

METHODS: Data from 32 Alzheimer's Disease Centers (ADCs) and ADC affiliated cohorts with global Clinical Dementia Rating Scale (CDR) Dementia Staging Instrument scores of 0 were included. Descriptive statistics for each test were calculated by age, sex, race, and education. Multiple linear regressions were conducted to estimate the effect of each demographic variable; squared semipartial correlation coefficients measured the relative importance of variables.

RESULTS: There were 8313 participants (16% African American) with complete demographic information, ranging from 6600 to 7885 depending on the test. Lower scores were found for older and less educated groups, and African Americans versus whites. Education was the strongest predictor for most tests, followed in order by age, race, and sex. Quadratic terms were significant for age and education, indicating some nonlinearity, but did not substantially increase R.

CONCLUSIONS: Although race-based norms represent incomplete proxies for other sociocultural variables, the appropriate application of these norms is important given the potential to improve diagnostic accuracy and to reduce misclassification bias in cognitive disorders of aging such as Alzheimer disease.}, } @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 {pmid32481389, year = {2020}, author = {Sohn, JH and Lee, SH and Kwon, YS and Kim, JH and Kim, Y and Lee, JJ}, title = {The impact of tamsulosin on cognition in Alzheimer disease with benign prostate hyperplasia: A study using the Hallym Smart Clinical Data Warehouse.}, journal = {Medicine}, volume = {99}, number = {22}, pages = {e20240}, doi = {10.1097/MD.0000000000020240}, pmid = {32481389}, issn = {1536-5964}, mesh = {Adrenergic alpha-1 Receptor Antagonists/*adverse effects/therapeutic use ; Aged ; Alzheimer Disease/complications/*psychology ; Cognition/*drug effects ; Data Warehousing ; Humans ; Male ; Propensity Score ; Prostatic Hyperplasia/complications/*drug therapy ; Regression Analysis ; Retrospective Studies ; Tamsulosin/*adverse effects/therapeutic use ; Urological Agents/*adverse effects/therapeutic use ; }, abstract = {Studies suggest that the use of alpha-blockers increases the risk of dementia in patients with benign prostate hyperplasia (BPH). Due to study limitations, the relationship between the use of alpha-blockers, such as tamsulosin, and the risk of dementia is still unclear. However, alpha1-adrenoreceptors are also present in the brain, so there is potential for adverse effects on cognitive function. Therefore, we investigated possible associations between the use of alpha-blockers and aggravation of cognitive decline in dementia patients using a clinical data analytic solution called the Smart Clinical Data Warehouse (CDW).We retrospectively investigated clinical data using the Smart CDW of Hallym University Medical Center from 2009 to 2019. We enrolled patients with probable Alzheimer disease (AD) who had completed the Mini-Mental State Examination (MMSE) at least twice during follow-up, and who had BPH. We compared the difference in MMSE scores between patients who took tamsulosin for >1000 days and those who did not take any alpha-blocker. We tested the effect of tamsulosin on cognitive decline in patients with AD, using propensity score-matched logistic regression analysis.Eligible cases were included in the tamsulosin (n = 68) or no-medication (n = 153) groups. After propensity score matching, clinical characteristics such as educational attainment and vascular risk factors were similar in the tamsulosin and no-medication groups. The MMSE scores did not differ significantly between the tamsulosin and no-medication groups (P = .470).The results suggest that tamsulosin for BPH is not associated with worsening of the cognitive decline in patients with AD.}, } @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}, 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 {pmid32480019, year = {2020}, author = {Saranya, V and Mary, PV and Vijayakumar, S and Shankar, R}, title = {The hazardous effects of the environmental toxic gases on amyloid beta-peptide aggregation: A theoretical perspective.}, journal = {Biophysical chemistry}, volume = {263}, number = {}, pages = {106394}, doi = {10.1016/j.bpc.2020.106394}, pmid = {32480019}, issn = {1873-4200}, abstract = {Alzheimer's disease (AD) is one of the leading causes of dementia in elderly people. It has been well documented that the exposure to environmental toxins such as CO, CO2, SO2 and NO2 that are present in the air is considered as a hallmark for the progression of Alzheimer's disease. However, their actual mechanism by which environmental toxin triggers the aggregation of Aβ42 peptide at the molecular and atomic levels remain unknown. In this study, molecular dynamics simulation was carried out to study the aggregation mechanism of the Aβ42 peptide due to its interaction of toxic gas (CO, CO2, SO2 and NO2). During the 400 ns simulation, all the Aβ42 interacted toxic gas (CO, CO2, SO2, and NO2) complexes have smaller Root Mean Square Deviation values when compared to the Aβ42 peptide, which shows that the interaction of toxic gases (CO, CO2, SO2, and NO2) would increase the Aβ42 peptide structural stability. The radius of gyration analysis also supports that Aβ42 interacted CO2 and SO2 complexes have the minimum value in the range of 0.95 nm and 1.5 nm. It is accounted that the Aβ42 interacted CO2 and SO2 complexes have a greater compact structure in comparison to Aβ42 interacted CO and NO2 complexes. Furthermore, all the Aβ42 interacted toxic gas (CO, CO2, SO2, and NO2) complexes exhibited an enhanced secondary structural probability for coil and turn regions with a reduced α-helix probability, which indicates that the interaction of toxic gases may enhance the toxicity and aggregation of Aβ42.}, } @article {pmid32479974, year = {2020}, author = {Kartalou, GI and Endres, T and Lessmann, V and Gottmann, K}, title = {Golgi-Cox impregnation combined with fluorescence staining of amyloid plaques reveals local spine loss in an Alzheimer mouse model.}, journal = {Journal of neuroscience methods}, volume = {341}, number = {}, pages = {108797}, doi = {10.1016/j.jneumeth.2020.108797}, pmid = {32479974}, issn = {1872-678X}, abstract = {BACKGROUND: Spine loss is a hallmark of Alzheimer´s and other neurodegenerative diseases, and testing candidate therapeutic drugs needs quantitative analysis of dendritic spine densities. Golgi-Cox impregnation of neurons is a classical method to visualize dendritic spines in diseased brains. Importantly, at early disease stages spine loss occurs locally in the vicinity of amyloid plaques, and concomitant fluorescence labeling of amyloid plaques is required to detect local spine damage.

NEW METHOD: Because Golgi-Cox impregnation is done on unsectioned brains, whereas fluorescence staining is performed on sectioned material, the combination is technically challenging. We have now developed a novel combination of Golgi-Cox impregnation with methoxy-X04 fluorescence labeling of plaques that is performed on unsectioned brains.

RESULTS: We used this new combination method to quantify dendritic spine densities in mouse hippocampal CA1 pyramidal neurons. Comparison of neurons from wildtype and APP/PS1 mice revealed local spine loss in the vicinity of amyloid plaques in both male and female APP/PS1 mice.

Golgi-Cox impregnation of neurons combined with methoxy-X04 staining of amyloid plaques is a highly reliable, easy-to-use method for permanent visualization of spines as compared to the technically more sophisticated and less stable fluorescence imaging of spines.

CONCLUSION: Our novel combination method will be highly useful for testing potential therapeutic drugs in Alzheimer mouse models.}, } @article {pmid32479315, year = {2020}, author = {Hu, M and Shu, X and Wu, X and Chen, F and Hu, H and Zhang, J and Yan, P and Feng, H}, title = {Neuropsychiatric symptoms as prognostic makers for the elderly with mild cognitive impairment: a meta-analysis.}, journal = {Journal of affective disorders}, volume = {271}, number = {}, pages = {185-192}, doi = {10.1016/j.jad.2020.03.061}, pmid = {32479315}, issn = {1573-2517}, abstract = {BACKGROUND: Although several neuropsychiatric symptoms (NPSs) have been demonstrated to have value in the prediction of the progression of mild cognitive impairment (MCI) to dementia, these symptoms are less studied for the prediction of the transition from normal cognition (NC) to MCI.

METHODS: Prospective cohort studies were included if they reported on at least one NPS at baseline and had MCI as the outcome.

RESULTS: We obtained 13 cohort studies with a total population of 33,066. Depression was the most common neuropsychiatric symptom and could significantly predict transition to MCI (RR = 1.49, 95% CI: 1.13-1.86). However, depression was more capable of predicting amnestic MCI (RR=1.43, 95% CI: 1.04-1.83) than non-aMCI (RR= 0.96, 95% CI 95% CI: 0.60-1.33). Subgroup analysis suggested that the association between depression and MCI changed with depression severity, depression criteria, apolipoprotein-E-adjusted status, age, the percentage of females, and follow-up times, but some data were too sparse for a reliable estimate. Regarding other NPSs, there were insufficient data to assess their effect on the development of MCI. However, apathy, anxiety, sleep disturbances, irritability, and agitation might be risk factors for the prediction of NC-MCI transition with strong predictive value.

CONCLUSIONS: Depression was associated with an approximately 1.5-fold sincreased risk of the progression to MCI in the population with normal cognition. Other NPSs with underlying predictive value deserve more attention.}, } @article {pmid32479194, year = {2020}, author = {Larsson, SC and Gill, D and Mason, AM and Jiang, T and Bäck, M and Butterworth, AS and Burgess, S}, title = {Lipoprotein(a) in Alzheimer, Atherosclerotic, Cerebrovascular, Thrombotic, and Valvular Disease: Mendelian Randomization Investigation.}, journal = {Circulation}, volume = {141}, number = {22}, pages = {1826-1828}, doi = {10.1161/CIRCULATIONAHA.120.045826}, pmid = {32479194}, issn = {1524-4539}, } @article {pmid32478662, year = {2020}, author = {Dermody, G and Whitehead, L and Wilson, G and Glass, C}, title = {The Role of Virtual Reality in Improving Health Outcomes for Community-Dwelling Older Adults: Systematic Review.}, journal = {Journal of medical Internet research}, volume = {22}, number = {6}, pages = {e17331}, doi = {10.2196/17331}, pmid = {32478662}, issn = {1438-8871}, abstract = {BACKGROUND: Virtual reality (VR) delivered through immersive headsets creates an opportunity to deliver interventions to improve physical, mental, and psychosocial health outcomes. VR app studies with older adults have primarily focused on rehabilitation and physical function including gait, balance, fall prevention, pain management, and cognition. Several systematic reviews have previously been conducted, but much of the extant literature is focused on rehabilitation or other institutional settings, and little is known about the effectiveness of VR apps using immersive headsets to target health outcomes among community-dwelling older adults.

OBJECTIVE: The objective of this review was to evaluate the effectiveness of VR apps delivered using commercially available immersive headsets to improve physical, mental, or psychosocial health outcomes in community-dwelling older adults.

METHODS: Peer-reviewed publications that included community-dwelling older adults aged ≥60 years residing in residential aged care settings and nursing homes were included. This systematic review was conducted in accordance with the Joanna Briggs Institute (JBI) methodology for systematic reviews of effectiveness evidence. The title of this review was registered with JBI, and the systematic review protocol was registered with the International Prospective Register of Systematic Reviews.

RESULTS: In total, 7 studies that specifically included community-dwelling older adults were included in this review. VR apps using a head-mounted display led to improvements in a number of health outcomes, including pain management, posture, cognitive functioning specifically related to Alzheimer disease, and a decreased risk of falls. A total of 6 studies reported a statistically significant difference post VR intervention, and 1 study reported an improvement in cognitive function to reduce navigational errors. Only one study reported on the usability and acceptability of the interventions delivered through VR. While one study used a distraction mechanism for pain management, none of the studies used gaming technology to promote enjoyment.

CONCLUSIONS: Interventions to improve health outcomes through VR have demonstrated potential; however, the ability to synthesize findings by primary outcome for the older adult population is not possible. A number of factors, especially related to frailty, usability, and acceptability, also need to be explored before more substantial recommendations on the effectiveness of VR interventions for older adults can be made.

TRIAL REGISTRATION: PROSPERO CRD42019143504; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=143504.}, } @article {pmid32478154, year = {2020}, author = {Macron, C and Lavigne, R and Núñez Galindo, A and Affolter, M and Pineau, C and Dayon, L}, title = {Exploration of human cerebrospinal fluid: A large proteome dataset revealed by trapped ion mobility time-of-flight mass spectrometry.}, journal = {Data in brief}, volume = {31}, number = {}, pages = {105704}, pmid = {32478154}, issn = {2352-3409}, abstract = {Cerebrospinal fluid (CSF) is a biofluid in direct contact with the brain and as such constitutes a sample of choice in neurological disorder research, including neurodegenerative diseases such as Alzheimer or Parkinson. Human CSF has still been less studied using proteomic technologies compared to other biological fluids such as blood plasma or serum. In this work, a pool of "normal" human CSF samples was analysed using a shotgun proteomic workflow that combined removal of highly abundant proteins by immunoaffinity depletion and isoelectric focussing fractionation of tryptic peptides to alleviate the complexity of the biofluid. The resulting 24 fractions were analysed using liquid chromatography coupled to a high-resolution and high-accuracy timsTOF Pro mass spectrometer. This state-of-the-art mass spectrometry-based proteomic workflow allowed the identification of 3'174 proteins in CSF. The dataset reported herein completes the pool of the most comprehensive human CSF proteomes obtained so far. An overview of the identified proteins is provided based on gene ontology annotation. Mass and tandem mass spectra are made available as a possible starting point for further studies exploring the human CSF proteome.}, } @article {pmid32477473, year = {2019}, author = {Nikbakht, F and Khadem, Y and Haghani, S and Hoseininia, H and Moein Sadat, A and Heshemi, P and Jamali, N}, title = {Protective Role of Apigenin Against Aβ 25-35 Toxicity Via Inhibition of Mitochondrial Cytochrome c Release.}, journal = {Basic and clinical neuroscience}, volume = {10}, number = {6}, pages = {557-566}, pmid = {32477473}, issn = {2008-126X}, abstract = {Introduction: Cognitive dysfunction is the most common problem of patients with Alzheimer Disease (AD). The pathological mechanism of cognitive impairment in AD may contribute to neuronal loss, synaptic dysfunction, and alteration in neurotransmitters receptors. Mitochondrial synapses dysfunction due to the accumulation of Amyloid Beta (Aβ) is one of the earliest pathological features of AD. The flavone apigenin has been reported to play some protective roles in AD through the anti-oxidative and anti-inflammatory properties. This study aimed at investigating the effects of apigenin on spatial working memory and neural protection by restoring mitochondrial dysfunction and inhibition of caspase 9.

Methods: Intracerebroventricular (ICV) microinjection of Aβ 25-35 was used for AD modeling. Working memory was assessed 21 days later using the Y maze test. Neuronal loss was detected in the hilar area of the hippocampus using Nissl and Fluoro-jade B staining, whereas immunohistochemistry was used to illustrate cytochrome c positive cells and caspase 9.

Results: The results revealed that apigenin significantly ameliorated spatial working memory. It also significantly reduced the number of degenerative neurons in the hilus area. Apigenin almost completely blocked the release of cytochrome c and caspase 9 in hilus.

Conclusion: Apigenin may improve the spatial working memory deficits and neuronal degeneration through the amelioration of the mitochondrial dysfunction.}, } @article {pmid32477472, year = {2019}, author = {Amiri, S and Azadmanesh, K and Dehghan Shasaltaneh, M and Khoshkholgh-Sima, B and Naghdi, N}, title = {Protein Kinase Cɛ in the Platelet and Hippocampal Tissue as a Diagnostic Biological Marker in Alzheimer Disease.}, journal = {Basic and clinical neuroscience}, volume = {10}, number = {6}, pages = {545-556}, pmid = {32477472}, issn = {2008-126X}, abstract = {Introduction: Alzheimer Disease (AD) is a neurodegenerative disorder characterized by the progressive loss of memory and other cognitive functions. Protein Kinase Cɛ (PKCɛ) is an isoform that most effectively suppresses Amyloid Beta (Aβ) production and synaptic loss.

Methods: In this study, spatial learning and memory for treated rats were evaluated by the Morris water maze test. The activity (total PKC), mRNA expression, and protein level of PKCɛ in the platelet and hippocampal tissue were evaluated using immunosorbent assay, real-time qPCR, and western blotting analysis, respectively.

Results: The traveled distance was significantly prolonged, and escape latency significantly increased in Aβ-treated groups. PKC activity assay showed that there was a remarkable difference between the Aβ-treated and sham-operated groups on days 10 and 30 in the hippocampus and also day 30 in platelet after the injection of Aβ. A significant effect in PKC activity was observed between days 0 and 10, days 0 and 30, as well as days 5 and 30. Aβ significantly downregulated the PKCɛ mRNA expression in the hippocampus of rats on day 30; however, no significant difference was observed in platelet. Western blot analysis demonstrated that Aβ significantly reduced PKCɛ protein expression in the hippocampus of treated groups on day 30.

Conclusion: The expression level of PKCɛ was downregulated following the injection of Aβ in the hippocampus, but no significant difference was observed between the AD and sham groups in platelet that may be due to the low concentration of PKCɛ or duration of Aβ exposure in the rat brain.}, } @article {pmid32476318, year = {2020}, author = {Williams, A and Gow, A and Kilpatrick, S and Tivers, M and Lipscomb, V and Smith, K and Day, MO and Jeffery, N and Mellanby, RJ}, title = {Astrocyte lesions in cerebral cortex and cerebellum of dogs with congenital ortosystemic shunting.}, journal = {Journal of veterinary science}, volume = {21}, number = {3}, pages = {e44}, pmid = {32476318}, issn = {1976-555X}, abstract = {BACKGROUND: Congenital portosystemic shunt (cPSS) is one of the most common congenital disorders diagnosed in dogs. Hepatic encephalopathy (HE) is a frequent complication in dogs with a cPSS and is a major cause of morbidity and mortality. Despite HE been a major cause of morbidity in dogs with a cPSS, little is known about the cellular changes that occur in the central nervous system of dogs with a cPSS.

OBJECTIVES: The objective of this study was to characterise the histological changes in the cerebral cortex and cerebellum of dogs with cPSS with particular emphasis on astrocyte morphology.

METHODS: Eight dogs with a confirmed cPSS were included in the study.

RESULTS: Six dogs had substantial numbers of Alzheimer type II astrocytes and all cases had increased immunoreactivity for glial fibrillary acidic protein in the cerebral cortex, even if there were minimal other morphological changes.

CONCLUSIONS: This study demonstrates that dogs with a cPSS have marked cellular changes in the cerebral cortex and cerebellum. The cellular changes that occur in the cerebral cortex and cerebellum of dogs with spontaneously arising HE are similar to changes which occur in humans with HE, further validating dogs with a cPSS as a good model for human HE.}, } @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 = {}, number = {}, pages = {}, 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/ ; }, 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 {pmid32473247, year = {2020}, author = {Saffari, PM and Alijanpour, S and Takzaree, N and Sahebgharani, M and Etemad-Moghadam, S and Noorbakhsh, F and Partoazar, A}, title = {Metformin loaded phosphatidylserine nanoliposomes improve memory deficit and reduce neuroinflammation in streptozotocin-induced Alzheimer's disease model.}, journal = {Life sciences}, volume = {255}, number = {}, pages = {117861}, doi = {10.1016/j.lfs.2020.117861}, pmid = {32473247}, issn = {1879-0631}, abstract = {Alzheimer's disease (AD) is closely associated with neuroinflammation development in the brain. Co-delivery of metformin (MET) with phosphatidylserine liposomes neuroprotectant may be beneficial in ameliorating AD-related symptoms like memory impairment and inflammation. Therefore, we aimed to prepare metformin containing phosphatidylserine nanoliposomes formulation (MET-PSL) and to evaluate its effect on rats subjected to AD. Alzheimer's disease model was induced by bilateral intracerebroventricular injection of streptozotocin (3 mg/kg) into rat brains using the stereotactic technique. MET-PSL, MET, and PSL alone were administered intraperitoneally to AD-induced animals and factors including learning and memory storage in addition to cytokine and tissue inflammatory changes were evaluated after a 22-day experiment period. The learning and memory parameters significantly (P < 0.05) improved in AD-rats treated with MET-PSL. Moreover, MET-PSL administration significantly (P < 0.05) decreased cytokine levels of IL1-β, TNF-α, and TGF-β in hippocampal tissues of rats with AD. Histological results indicated a considerable reduction in inflammatory and necrotic neural cells along with significantly (P < 0.05) increased neurogenesis in MET-PSL treated rats. Furthermore, our results showed that MET-PSL formulation could potentially act better than the free form of MET and PSL alone in the recovery process of rats with AD. In general, our data suggest that combination therapy of metformin loaded phosphatidylserine liposomes may enhance the therapeutic performance in AD patients of a clinical study.}, } @article {pmid32472747, year = {2020}, author = {Soyal, SM and Kwik, M and Kalev, O and Lenz, S and Zara, G and Strasser, P and Patsch, W and Weis, S}, title = {A TOMM40/APOE allele encoding APOE-E3 predicts high likelihood of late-onset Alzheimer's disease in autopsy cases.}, journal = {Molecular genetics & genomic medicine}, volume = {}, number = {}, pages = {e1317}, doi = {10.1002/mgg3.1317}, pmid = {32472747}, issn = {2324-9269}, support = {//Austrian Science Fund/ ; //Kurt und Senta Herrmann Stiftung/ ; //Paracelsus Medical University Salzburg/ ; }, abstract = {BACKGROUND: The APOE-ε4 allele is an established risk factor for Alzheimer's disease (AD). TOMM40 located adjacent to APOE has also been implicated in AD but reports of TOMM40 associations with AD that are independent of APOE-ε4 are at variance.

METHODS: We investigated associations of AD with haplotypes defined by three TOMM40 and two APOE single nucleotide polymorphisms in 73 and 71 autopsy cases with intermediate and high likelihood of AD (defined by BRAAK stages
RESULTS: We observed eight haplotypes with a frequency >0.02. The two haplotypes encoding APOE-E4 showed strong associations with AD that did not differ between intermediate and high likelihood AD. In contrast, a TOMM40 haplotype encoding APOE-E3 was identified as risk haplotype of high- (p = .0186), but not intermediate likelihood AD (p = .7530). Furthermore, the variant allele of rs2075650 located in intron 2 of TOMM40, increased the risk of high-, but not intermediate likelihood AD on the APOE-ε3/ε3 background (p = .0230).

CONCLUSION: The striking association of TOMM40 only with high likelihood AD may explain some contrasting results for TOMM40 in clinical studies and may reflect an association with more advanced disease and/or suggest a role of TOMM40 in the pathogenesis of neurofibrillary tangles.}, } @article {pmid32470423, year = {2020}, author = {Quiroz, YT and Zetterberg, H and Reiman, EM and Chen, Y and Su, Y and Fox-Fuller, JT and Garcia, G and Villegas, A and Sepulveda-Falla, D and Villada, M and Arboleda-Velasquez, JF and Guzmán-Vélez, E and Vila-Castelar, C and Gordon, BA and Schultz, SA and Protas, HD and Ghisays, V and Giraldo, M and Tirado, V and Baena, A and Munoz, C and Rios-Romenets, S and Tariot, PN and Blennow, K and Lopera, F}, title = {Plasma neurofilament light chain in the presenilin 1 E280A autosomal dominant Alzheimer's disease kindred: a cross-sectional and longitudinal cohort study.}, journal = {The Lancet. Neurology}, volume = {19}, number = {6}, pages = {513-521}, doi = {10.1016/S1474-4422(20)30137-X}, pmid = {32470423}, issn = {1474-4465}, abstract = {BACKGROUND: Neurofilament light chain (NfL) is a promising biomarker of active axonal injury and neuronal degeneration. We aimed to characterise cross-sectional and longitudinal plasma NfL measurements and determine the age at which NfL concentrations begin to differentiate between carriers of the presenilin 1 (PSEN1) E280A (Glu280Ala) mutation and age-matched non-carriers from the Colombian autosomal dominant Alzheimer's disease kindred.

METHODS: In this cross-sectional and longitudinal cohort study, members of the familial Alzheimer's disease Colombian kindred aged 8-75 years with no other neurological or health conditions were recruited from the Alzheimer's Prevention Initiative Registry at the University of Antioquia (Medellín, Colombia) between Aug 1, 1995, and Dec 15, 2018. We used a single molecule array immunoassay and log-transformed data to examine the relationship between plasma NfL concentrations and age, and establish the earliest age at which NfL concentrations begin to diverge between mutation carriers and non-carriers.

FINDINGS: We enrolled a cohort of 1070 PSEN1 E280A mutation carriers and 1074 non-carriers with baseline assessments; of these participants, longitudinal measures (with a mean follow-up of 6 years) were available for 242 mutation carriers and 262 non-carriers. Plasma NfL measurements increased with age in both groups (p<0·0001), and began to differentiate carriers from non-carriers when aged 22 years (22 years before the estimated median age at mild cognitive impairment onset of 44 years), although the ability of plasma NfL to discriminate between carriers and non-carriers only reached high sensitivity close to the age of clinical onset.

INTERPRETATION: Our findings further support the promise of plasma NfL as a biomarker of active neurodegeneration in the detection and tracking of Alzheimer's disease and the evaluation of disease-modifying therapies.

FUNDING: National Institute on Aging, National Institute of Neurological Disorders and Stroke, Banner Alzheimer's Foundation, COLCIENCIAS, the Torsten Söderberg Foundation, the Swedish Research Council, the Swedish Alzheimer Foundation, the Swedish Brain Foundation, and the Swedish state under the ALF-agreement.}, } @article {pmid32469701, year = {2020}, author = {Akbarialiabad, H and Dahroud, MD and Khazaei, MM and Razmeh, S and Zarshenas, MM}, title = {Green Tea, A medicinal food with promising neurological benefits.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/1570159X18666200529152625}, pmid = {32469701}, issn = {1875-6190}, abstract = {Neurological disorders and their sequelae, as of the widespread and critical humans complications, affect the body's nervous systems, organ functions, and behaviors. According to WHO, neurological disorders are currently predicted to affect more than one billion people globally. It is well-established that complementary medicine is one of the high accepted interventions that could have been considered for the management of neurological ailments. The current review aimed to compile a frame from all the crucial data reporting the investigation on the conspicuous intervention of green tea (made of Camellia sinensis) and related lead compounds (especially l-theanine, epigallocatechin-3-gallate, epicatechin-3-gallate, epicatechin, and epigallocatechin) for their neurological activities, mechanisms of action, and clinical properties. According to the documents, green tea exhibits antidepressant, anti-neurodegenerative (e.g., anti-Parkinson and anti-Alzheimer), as well as neuroprotective effects. Chief among them, for offering novel work, it is worth focusing on several related assessments with great attention to more extensive standardized clinical trials, and subsequently more in-depth pharmacokinetic studies to safely introduce this beneficial medicinal food as a neuro-effective agent.}, } @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}, doi = {10.1007/978-3-030-32633-3_15}, pmid = {32468465}, issn = {0065-2598}, 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 {pmid32468311, year = {2020}, author = {Xristina, F and Demeter, K and John, G and Maria, C}, title = {The Role of the Family in the Care of Alzheimer Patients.}, journal = {Advances in experimental medicine and biology}, volume = {1196}, number = {}, pages = {103-107}, doi = {10.1007/978-3-030-32637-1_10}, pmid = {32468311}, issn = {0065-2598}, abstract = {According to the World Health Organisation (WHO 2002), people's life expectancy worldwide is continuously growing, and on the one hand, that is one of the greatest triumphs of humanity to date. But at the same time, it is also one of the most important challenges as the aging of the population raises economic and social requirements in all countries.}, } @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 = {}, doi = {10.1038/s41380-020-0776-7}, pmid = {32467645}, issn = {1476-5578}, support = {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 {pmid32467426, year = {2020}, author = {Gourley, D and Pasha, EP and Kaur, SS and Haley, AP and Tanaka, H}, title = {Association of Dementia and Vascular Risk Scores With Cortical Thickness and Cognition in Low-risk Middle-aged Adults.}, journal = {Alzheimer disease and associated disorders}, volume = {}, number = {}, pages = {}, doi = {10.1097/WAD.0000000000000392}, pmid = {32467426}, issn = {1546-4156}, abstract = {BACKGROUND: Increased risk for the future development of Alzheimer disease begins as early as midlife. Algorithm-based scores, such as the Cardiovascular Risk Factors, Aging and Incidence of Dementia (CAIDE) dementia risk score, and the Framingham general cardiovascular disease (CVD) risk score, have been used to determine future risk for the development of cognitive decline and dementia. We evaluated the association between neuroimaging and cognitive measures with the 2 risk scores in middle-aged, cognitively intact adults (49±6 y).

METHODS: In a cohort of 132 participants collected in 2014, magnetic resonance imaging was used to determine measures of cortical thickness in a priori regions of interest and a neuropsychological battery to assess memory and executive function.

RESULTS: The CAIDE dementia risk score was significantly and inversely associated with the cortical thickness of the parahippocampal (r=-0.266; P=0.002) and superior frontal gyrus (r=-0.261; P=0.002) despite a considerable percentage of individuals (99.3%) at low risk for CVD. There was a significant negative association between CAIDE and memory (r=-0.251; P=0.003). Framingham general CVD score was not associated with brain structure or cognitive function.

CONCLUSIONS: These results indicate that the CAIDE dementia risk score is associated with cortical thickness and cognitive function at midlife in a low-risk population. These data provide insight into subclinical structural and functional changes occurring during midlife associated with future risk for the development of dementia.}, } @article {pmid32467425, year = {2020}, author = {Gandhi, P and Klatt, BN and Agrawal, Y}, title = {Physical and Vestibular Physical Therapy Referrals in People With Alzheimer Disease.}, journal = {Alzheimer disease and associated disorders}, volume = {}, number = {}, pages = {}, doi = {10.1097/WAD.0000000000000390}, pmid = {32467425}, issn = {1546-4156}, abstract = {People with Alzheimer disease (AD) are at increased risk of falls and disproportionately burdened with vestibular impairment compared with healthy older adults. Although physical therapy (PT) and vestibular physical therapy (VPT) are effective rehabilitation interventions in improving balance and fall risk, referral patterns for these services in the AD population are understudied. A retrospective chart review was conducted of patients seen for primary AD care at a tertiary AD referral center to investigate the frequency of rehabilitation referrals. Of the 801 people with AD seen for AD care in 1 year, 48 individuals (6.0%) were referred to PT and 5 individuals (0.6%) to VPT. People with AD appear to receive very infrequent PT and VPT referrals, despite the potentially large number of people with AD who could benefit from PT and VPT services to improve their balance and vestibular function.}, } @article {pmid32467230, year = {2020}, author = {Gotoh, N and Saito, Y and Hata, S and Saito, H and Ojima, D and Murayama, C and Shigeta, M and Abe, T and Konno, D and Matsuzaki, F and Suzuki, T and Yamamoto, T}, title = {Amyloidogenic processing of amyloid β protein precursor (APP) is enhanced in the brains of Alcadein α-deficient mice.}, journal = {The Journal of biological chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1074/jbc.RA119.012386}, pmid = {32467230}, issn = {1083-351X}, abstract = {Alzheimer's disease (AD) is a very common neurodegenerative disorder, chiefly caused by increased production of neurotoxic amyloid-β (Aβ) peptide generated from proteolytic cleavage of amyloid β protein precursor (APP). Except for familial AD arising from mutations in the APP and presenilins (PSENs) genes, the molecular mechanisms regulating the amyloidogenic processing of APP are largely unclear. Alcadein α/calsyntenin1 (ALCα/CLSTN1) is a neuronal type I transmembrane protein that forms a complex with APP, mediated by the neuronal adaptor protein X11-like (X11L or MINT2). Formation of the ALCα-X11L-APP tripartite complex suppresses Aβ generation in vitro, and X11L-deficient mice exhibit enhanced amyloidogenic processing of endogenous APP. However, the role of ALCα in APP metabolism in vivo remains unclear. Here, by generating ALCα-deficient mice and using immunohistochemistry, immunoblotting, and co-immunoprecipitation analyses, we verified the role of ALCα in the suppression of amyloidogenic processing of endogenous APP in vivo We observed that ALCα deficiency attenuates the association of X11L with APP, significantly enhances amyloidogenic β-site cleavage of APP especially in endosomes, and increases the generation of endogenous Aβ in the brain. Furthermore, we noted amyloid plaque formation in the brains of human APP-transgenic mice in an ALCα-deficient background. These results unveil a potential role of ALCα in protecting cerebral neurons from Aβ-dependent pathogenicity 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}, 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 {pmid32463939, year = {2020}, author = {Amici, M and Lee, Y and Pope, RJP and Bradley, CA and Cole, A and Collingridge, GL}, title = {GSK-3β regulates the synaptic expression of NMDA receptors via phosphorylation of phosphatidylinositol 4 kinase type IIα.}, journal = {The European journal of neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1111/ejn.14841}, pmid = {32463939}, issn = {1460-9568}, abstract = {Deregulation of GSK-3β is strongly implicated in a variety of serious brain conditions, such as Alzheimer disease, bipolar disorder and schizophrenia. To understand how GSK-3β becomes dysregulated in these conditions it is important to understand its physiological functions in the central nervous system. In this context, GSK-3β plays a role in the induction of NMDA receptor-dependent long-term depression (LTD) and several substrates for GSK-3β have been identified in this form of synaptic plasticity, including KLC-2, PSD-95 and tau. Stabilization of NMDA receptors at synapses has also been shown to involve GSK-3β, but the substrates involved are currently unknown. Recent work has identified phosphatidylinositol 4 kinase type IIα (PI4KIIα) as a neuronal GSK-3β substrate that can potentially regulate the surface expression of AMPA receptors. In the present study, we investigated the synaptic role of PI4KIIα in organotypic rat hippocampal slices. We found that knockdown of PI4KIIα has no effect on synaptic AMPA receptor-mediated synaptic transmission but substantially reduces NMDA receptor-mediated synaptic transmission. Furthermore, the ability of the selective GSK-3β inhibitor, CT99021, to reduce the amplitude of NMDA receptor-mediated currents was occluded in shRNA-PI4KIIα transfected neurons. The effects of knocking down PI4KIIα were fully rescued by a shRNA-resistant wild type construct, but not by a mutant construct that cannot be phosphorylated by GSK-3β. These data suggest that GSK-3β phosphorylates PI4KIIα to stabilize NMDA receptors at the synapse.}, } @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}, 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 {pmid32463072, year = {2020}, author = {Wesselman, LMP and Schild, AK and Hooghiemstra, AM and Meiberth, D and Drijver, AJ and Leeuwenstijn-Koopman, MV and Prins, ND and Brennan, S and Scheltens, P and Jessen, F and van der Flier, WM and Sikkes, SAM}, title = {Targeting Lifestyle Behavior to Improve Brain Health: User-Experiences of an Online Program for Individuals with Subjective Cognitive Decline.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {7}, number = {3}, pages = {184-194}, doi = {10.14283/jpad.2020.9}, pmid = {32463072}, issn = {2426-0266}, abstract = {BACKGROUND: Online programs targeting lifestyle have the potential to benefit brain health. We aimed to develop such a program for individuals with subjective cognitive decline (SCD). These individuals were reported to be at increased risk for dementia, and report both an intrinsic need for brain health information and motivation to participate in prevention strategies. Co-creation and user-evaluation benefits the adherence to and acceptance of online programs. Previously, we developed a prototype of the online program in co-creation with the users .

OBJECTIVES: We now aimed to evaluate the user-experiences of our online lifestyle program for brain health.

DESIGN: 30-day user test; multi-method.

SETTING: Participants were recruited in a memory clinic and (online) research registries in the Netherlands (Alzheimer Center Amsterdam) and Germany (Center for memory disorders, Cologne).

PARTICIPANTS: Individuals with SCD (N=137, 65±9y, 57% female).

MEASUREMENTS: We assessed user-experiences quantitatively with rating daily advices and usefulness, satisfaction and ease of use questionnaires as well as qualitatively using telephone interviews.

RESULTS: Quantitative data showed that daily advices were rated moderately useful (3.5 ±1.5, range 1-5 points). Participants (n=101, 78%) gave moderate ratings on the programs' usability (3.7±1.3, max 7), ease of learning (3.6±1.9) and satisfaction (4.0±1.5), and marginal ratings on the overall usability (63.7±19.0, max 100). Qualitative data collected during telephone interviews showed that participants highly appreciated the content of the program. They elaborated that lower ratings of the program were mainly due to technical issues that hindered a smooth walk through. Participants reported that the program increased awareness of lifestyle factors related to brain health.

CONCLUSIONS: Overall user-experience of the online lifestyle program was moderate to positive. Qualitative data showed that content was appreciated and that flawless, easy access technique is essential. The heterogeneity in ratings of program content and in program use highlights the need for personalization. These findings support the use of online self-applied lifestyle programs when aiming to reach large groups of motivated at-risk individuals for brain health promotion.}, } @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 = {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 ; }, 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 {pmid32457323, year = {2020}, author = {Kalovyrna, N and Apokotou, O and Boulekou, S and Paouri, E and Boutou, A and Georgopoulos, S}, title = {A 3'UTR modification of the TNF-α mouse gene increases peripheral TNF-α and modulates the Alzheimer-like phenotype in 5XFAD mice.}, journal = {Scientific reports}, volume = {10}, number = {1}, pages = {8670}, pmid = {32457323}, issn = {2045-2322}, abstract = {Tumor necrosis factor-α (TNF-α) is a pro-inflammatory cytokine, involved in Alzheimer's disease pathogenesis. Anti-TNF-α therapeutic approaches currently used in autoimmune diseases have been proposed as a therapeutic strategy in AD. We have previously examined the role of TNF-α and anti-TNF-α drugs in AD, using 5XFAD mice, and we have found a significant role for peripheral TNF-α in brain inflammation. Here we investigated the role of mouse TNF-α on the AD-like phenotype of 5XFAD mice using a knock-in mouse with deletion of the 3'UTR of the endogenous TNF-α (TNFΔARE/+) that develops rheumatoid arthritis and Crohn's disease. 5XFAD/TNFΔARE/+ mice showed significantly decreased amyloid deposition. Interestingly, microglia but not astrocytes were activated in 5XFAD/ TNFΔARE/+ brains. This microglial activation was associated with increased infiltrating peripheral leukocytes and perivascular macrophages and synaptic degeneration. APP levels and APP processing enzymes involved in Aβ production remained unchanged, suggesting that the reduced amyloid burden can be attributed to the increased microglial and perivascular macrophage activation caused by TNF-α. Peripheral TNF-α levels were increased while brain TNF-α remained the same. These data provide further evidence for peripheral TNF-α as a mediator of inflammation between the periphery and the brain.}, } @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}, doi = {10.1212/WNL.0000000000009582}, pmid = {32457210}, issn = {1526-632X}, 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 {pmid32455936, year = {2020}, author = {Mahomoodally, MF and Picot-Allain, MCN and Zengin, G and Llorent-Martínez, EJ and Abdullah, HH and Ak, G and Senkardes, I and Chiavaroli, A and Menghini, L and Recinella, L and Brunetti, L and Leone, S and Orlando, G and Ferrante, C}, title = {Phytochemical Analysis, Network Pharmacology and in Silico Investigations on Anacamptis pyramidalis Tuber Extracts.}, journal = {Molecules (Basel, Switzerland)}, volume = {25}, number = {10}, pages = {}, pmid = {32455936}, issn = {1420-3049}, abstract = {Anacamptis pyramidalis (L.) Rich. forms part of the Orchidaceae family that is highlyvalued for its horticultural as well as therapeutic benefits. The present study set out to investigatethe inhibitory activity of A. pyramidalis tubers against key biological targets for the management oftype 2 diabetes, Alzheimer disease, and skin hyperpigmentation. In addition, the antioxidantpotential of the extracts was also assessed using multiple methods. The detailed phytochemicalprofiles of the extracts were determined using high-performance liquid chromatography. Based onqualitative phytochemical fingerprint, a network pharmacology analysis was conducted as well.Parishin was identified from the water extract only, whereas gastrodin and caffeic acid derivativeswere present in the methanol extract. The methanol extract exhibited high inhibitory activityagainst tyrosinase (69.69 mg kojic acid equivalent/g extract), α-amylase (15.76 mg acarboseequivalent/g extract), and α-glucosidase (20.07 mg acarbose equivalent/g extract). Similarly, themethanol extract showed highest antioxidant potential (22.12, 44.23, 45.56, and 29.38 mg Troloxequivalent/g extract, for 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), CUPric Reducing Antioxidant Capacity (CUPRAC),and Ferric Reducing Antioxidant Power (FRAP) assays, respectively). Finally, the results ofnetwork pharmacology analysis, besides corroborating traditional uses of plant extracts in themanagement of cold and flu, confirmed a direct involvement of identified phytochemicals in theobserved enzyme inhibitory effects, especially against tyrosinase, α-amylase, and α-glucosidase.Furthermore, based on the results of both colorimetric assays and network pharmacology analysis&nbsp;related to the activity of A. pyramidalis extracts and identified phytocompounds on enzymesinvolved in type 2 diabetes, a docking study was conducted in order to investigate the putativeinteractions of oxo-dihydroxy octadecenoic acid trihydroxy octadecenoic acid against aldosereductase, peroxisome proliferator-activated receptor (PPAR)-α, dipeptidyl peptidase (DPP)-IV,and α-glucosidase. Docking analysis suggested the inhibitory activity of these compounds againstthe aforementioned enzymes, with a better inhibitory profile shown by oxo-dihydroxyoctadecenoic acid. Overall, the present findings supported the rationale for the use of A.pyramidalis as source of bioactive metabolites and highlight, today more than ever, for the strongnecessity of linkage strategy between wild resource valorization and conservation policy.}, } @article {pmid32455806, year = {2020}, author = {Cascajares, M and Alcayde, A and Garrido-Cardenas, JA and Manzano-Agugliaro, F}, title = {The Contribution of Spanish Science to Patents: Medicine as Case of Study.}, journal = {International journal of environmental research and public health}, volume = {17}, number = {10}, pages = {}, pmid = {32455806}, issn = {1660-4601}, abstract = {Investments in research and development (R&D) and innovation are expensive, and one wishes to be assured that there is positive feedback and to receive guidance on how to direct investments in the future. The social or economic benefits of investments in R&D are of particular interest to policymakers. In this regard, public expense in research, especially through universities, is sometimes being questioned. This paper establishes a measure of how research in Spain, and specifically in its universities, is involved. In this study, we have analyzed all the literature cited in the period 1998-2018 produced by Spanish institutions and which has been cited in at least one international patent, obtaining more than 40,000 publications from more than 160,000 different authors. The data have been surprisingly positive, showing that practically all public universities contribute to this subject and that there is a great deal of international collaboration, both in terms of the number of countries with which they collaborate and the prestige of the institutions involved. Regarding the specific scientific fields in which this collaboration is most relevant, biochemistry, genetics and molecular biology, and medicine together account for almost 40% of the total works. The topics most used by these publications were those of diseases or medical problems such as: Neoplams, Carcinoma, Alzheimer Disease, or human immunodeficiency virus (HIV-1). Oncology was according to the All Science Journal Classification (ASJC) the leading and central issue. Therefore, although the result of basic research is difficult to quantify, when it is observed that there is a return in fields such as medicine or global health, it can be said that it is well employed. In terms of journals from a purely bibliometric point of view, it has been observed that some journals do not have a great impact or relative position within their categories, but they do have a great relevance in this area of patent support. Therefore, it would be worthwhile to set up a rank for scientific journals based on the citations of patents, so the percentage of articles cited in patents with Field-Weighted Citation Impact (FWCI) >1, and as an indicator of scientific transfer from universities or research centres, the transference index in patents (TIP) is also proposed.}, } @article {pmid32454771, year = {2020}, author = {Nabil-Adam, A and Shreadah, MA and El Moneam, NMA and El-Assar, SA}, title = {Various In Vitro Bioactivities of Secondary Metabolites Isolated from the Sponge Hyrtios aff. Erectus from the Red Sea Coast of Egypt.}, journal = {Turkish journal of pharmaceutical sciences}, volume = {17}, number = {2}, pages = {127-135}, pmid = {32454771}, issn = {2148-6247}, abstract = {Objectives: The present study revealed the presence of bioactive constituents in Hyrtios aff. erectus sponge (HES) extract collected from the Red Sea using skin and scuba diving.

Materials and Methods: Cytotoxicity was tested against hepatocellular carcinoma cell lines as a prescreening test.

Results: The HES extract had high contents of total phenolic compounds (0.061 mg/g), flavonoids (0.2839 mg/g), and carotenoids (1.976 mg/g). Moreover, the HES extract showed high antioxidant capacity with 93.0% and 99% at 1 mg using 2.2'-Diphenyl-α-picrylhydrazyl and 2.2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid), respectively. Cytotoxic activity against cancerous cell lines showed that the HES extract could inhibit cell growth effectively with IC50=47.5 μg/mL. Furthermore, anticancer activity using protein tyrosine kinase and sphingosine kinase 1 inhibitor screening assays resulted in 71.66% and 85.21% inhibition activity, respectively. The anti-inflammatory assays showed that the inhibition activity against cyclooxygenase (COX1), COX2, interleukin-6, and tumor necrosis factor-α was 71.82%, 81.13%, 80.89%, and 59.74%, respectively. At the same time, the anti-Alzheimer results using acetylcholine inhibition assay showed high activity at 1 mg with 83.51%. Additionally, the antiviral activity using the reverse transcriptase inhibition assay was 91.70%.

Conclusion: This marine sponge isolated from the Red Sea showed tremendous activity against many diseases and it is considered an excellent source for bioactive pharmaceutical compounds.}, } @article {pmid32454411, year = {2020}, author = {Hwang, TW and Kim, EJ and Kim, D and Jeong, JY and Kim, GH and Lim, K and Moon, M and Yoon, KA and Choi, DE and Kim, JJ}, title = {Fat-1 expression enhance hippocampal memory in scopolamine-induced amnesia.}, journal = {The Journal of nutritional biochemistry}, volume = {82}, number = {}, pages = {108394}, doi = {10.1016/j.jnutbio.2020.108394}, pmid = {32454411}, issn = {1873-4847}, abstract = {Omega-3 polyunsaturated fatty acids (PUFA) are critical for optimal brain health and are involved in psychiatric and neurological ailments. Here, we report the effects of higher endogenous omega-3 PUFA on memory impairment in the hippocampus by studying mice with transgenic expression of the fat-1 gene that converts omega-6 to omega-3 PUFA. We performed Y-maze and passive avoidance tests to evaluate the memory function of fat-1 mice treated with scopolamine. Fat-1 mice showed induced alternation in the Y-maze test and increased latency in the passive avoidance test. The effects of scopolamine on hippocampal neurogenesis were confirmed by increases in the number of Ki-67- and DCX-positive cells in the fat-1 mice. Western blotting revealed increased brain-derived neurotrophic factor (BDNF) and phosphorylated cAMP response element-binding protein levels, and lower scopolamine-induced apoptosis based on the cleaved-caspase 3 protein level in fat-1 mice. These findings suggest that higher endogenous omega-3 PUFA prevented granular cell loss, increased BDNF signaling, and decreased apoptosis signaling in scopolamine-treated fat-1 mice. These processes may underlie granular cell survival and suggest potential therapeutic targets for memory impairment.}, } @article {pmid32453744, year = {2020}, author = {Sil, S and Hu, G and Liao, K and Niu, F and Callen, S and Periyasamy, P and Fox, HS and Buch, S}, title = {HIV-1 Tat-mediated astrocytic amyloidosis involves the HIF-1α/lncRNA BACE1-AS axis.}, journal = {PLoS biology}, volume = {18}, number = {5}, pages = {e3000660}, pmid = {32453744}, issn = {1545-7885}, abstract = {Increased life expectancy of patients diagnosed with HIV in the current era of antiretroviral therapy is unfortunately accompanied with the prevalence of HIV-associated neurocognitive disorders (HANDs) and risk of comorbidities such as Alzheimer-like pathology. HIV-1 transactivator of transcription (Tat) protein has been shown to induce the production of toxic neuronal amyloid protein and also enhance neurotoxicity. The contribution of astrocytes in Tat-mediated amyloidosis remains an enigma. We report here, in simian immunodeficiency virus (SIV)+ rhesus macaques and patients diagnosed with HIV, brain region-specific up-regulation of amyloid precursor protein (APP) and Aβ (40 and 42) in astrocytes. In addition, we find increased expression of β-site cleaving enzyme (BACE1), APP, and Aβ in human primary astrocytes (HPAs) exposed to Tat. Mechanisms involved up-regulation of hypoxia-inducible factor (HIF-1α), its translocation and binding to the long noncoding RNA (lncRNA) BACE1-antisense transcript (BACE1-AS), resulting, in turn, in the formation of the BACE1-AS/BACE1 RNA complex, subsequently leading to increased BACE1 protein, and activity and generation of Aβ-42. Gene silencing approaches confirmed the regulatory role of HIF-1α in BACE1-AS/BACE1 in Tat-mediated amyloidosis. This is the first report implicating the role of the HIF-1α/lncRNABACE1-AS/BACE1 axis in Tat-mediated induction of astrocytic amyloidosis, which could be targeted as adjunctive therapies for HAND-associated Alzheimer-like comorbidity.}, } @article {pmid32452861, year = {2020}, author = {Yu, L and Schneider, JA and Kapasi, A and Bennett, DA and Boyle, PA}, title = {Limbic-predominant Age-related TDP-43 Encephalopathy and Distinct Longitudinal Profiles of Domain-specific Literacy.}, journal = {Alzheimer disease and associated disorders}, volume = {}, number = {}, pages = {}, doi = {10.1097/WAD.0000000000000389}, pmid = {32452861}, issn = {1546-4156}, abstract = {PURPOSE: Emerging evidence suggests that limbic-predominant age-related TAR DNA-binding protein-43 (TDP-43) encephalopathy impacts domain-specific literacy, a complex ability not assessed in traditional cognitive evaluations. We examined longitudinal profiles of financial and health literacy in relation to limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC).

PARTICIPANTS: A total of 275 community-dwelling older persons who had completed annual literacy assessments, died and undergone brain autopsy.

METHODS: Financial and health literacy was assessed using a 32-item instrument. Latent class mixed effects models identified groups of individuals with distinct longitudinal literacy profiles. Regression models examined group differences in 9 common age-related neuropathologies assessed via uniform structured neuropathologic evaluations.

RESULTS: Two distinct literacy profiles emerged. The first group (N=121, 44%) had higher level of literacy at baseline, slower decline and less variabilities over time. The second group (N=154, 56%) had lower level of literacy at baseline, faster decline, and greater variabilities. Individuals from the latter group were older, with fewer years of education and more female. They also had higher burdens of Alzheimer disease and LATE-NC. The group association with Alzheimer disease was attenuated and no longer significant after controlling for cognition. By contrast, the association with LATE-NC persisted.

CONCLUSION: Limbic-predominant age-related TDP-43 encephalopathy is uniquely associated with distinct longitudinal profiles of financial and health literacy in old age.}, } @article {pmid32452382, year = {2020}, author = {Bruyère, J and Abada, YS and Vitet, H and Fontaine, G and Deloulme, JC and Cès, A and Denarier, E and Pernet-Gallay, K and Andrieux, A and Humbert, S and Potier, MC and Delatour, B and Saudou, F}, title = {Presynaptic APP levels and synaptic homeostasis are regulated by Akt phosphorylation of huntingtin.}, journal = {eLife}, volume = {9}, number = {}, pages = {}, pmid = {32452382}, issn = {2050-084X}, support = {ANR-12-MALZ-0004 HuntAbeta//Agence Nationale de la Recherche/ ; ANR-15-IDEX-02 NeuroCoG//Agence Nationale de la Recherche/ ; ANR-10-IAIHU-06//Agence Nationale de la Recherche/ ; DEQ20170336752//Fondation pour la Recherche Médicale/ ; FDT201904008035//Fondation pour la Recherche Médicale/ ; DEI20151234418//Fondation pour la Recherche Médicale/ ; AGEMED//INSERM/ ; ANR-14-CE35-0027-01 PASSAGE//Agence Nationale de la Recherche/ ; AGEMED//Inserm/ ; }, abstract = {Studies have suggested that amyloid precursor protein (APP) regulates synaptic homeostasis, but the evidence has not been consistent. In particular, signaling pathways controlling APP transport to the synapse in axons and dendrites remain to be identified. Having previously shown that Huntingtin (HTT), the scaffolding protein involved in Huntington's disease, regulates neuritic transport of APP, we used a microfluidic corticocortical neuronal network-on-a-chip to examine APP transport and localization to the pre- and post-synaptic compartments. We found that HTT, upon phosphorylation by the Ser/Thr kinase Akt, regulates APP transport in axons but not dendrites. Expression of an unphosphorylatable HTT decreased axonal anterograde transport of APP, reduced presynaptic APP levels, and increased synaptic density. Ablating in vivo HTT phosphorylation in APPPS1 mice, which overexpress APP, reduced presynaptic APP levels, restored synapse number and improved learning and memory. The Akt-HTT pathway and axonal transport of APP thus regulate APP presynaptic levels and synapse homeostasis.}, } @article {pmid32451632, year = {2020}, author = {Yonezawa, K and Kusumoto, Y and Kanchi, N and Kinoshita, H and Kanegae, S and Yamaguchi, N and Ozawa, H}, title = {Recent trends in mental illness and omega-3 fatty acids.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {}, number = {}, pages = {}, doi = {10.1007/s00702-020-02212-z}, pmid = {32451632}, issn = {1435-1463}, abstract = {Although it is clear that nutrition affects physical and metabolic functions in humans, the importance of nutrition in mental illness has often been overlooked. Following a report by Hibbeln (Lancet 351:1213, 1998) published in The Lancet, which suggested that depression rates and fish consumption were inversely correlated, the relationships between a variety of nutritional/epidemiological treatments and neuropsychiatric disorders have received increased attention. In particular, many studies have been conducted on the omega-3 fatty acid mechanism of action in pathophysiological aspects of various neuropsychiatric disorders. Furthermore, many clinical studies have also been conducted on the effects of omega-3 replacement therapy. Therefore, this article reports recent trends in, and perspectives on, the use of omega-3 fatty acids to treat the five psychiatric disorders: schizophrenia (a delusion of the psychotic zone), depression and other mood disorders, attention deficit hyperactivity disorder (a developmental disorder), post-traumatic stress disorder (psychological trauma after the disaster), and Alzheimer-type dementia.}, } @article {pmid32450739, year = {2020}, author = {Ou, YN and Tan, CC and Shen, XN and Xu, W and Hou, XH and Dong, Q and Tan, L and Yu, JT}, title = {Blood Pressure and Risks of Cognitive Impairment and Dementia: A Systematic Review and Meta-Analysis of 209 Prospective Studies.}, journal = {Hypertension (Dallas, Tex. : 1979)}, volume = {76}, number = {1}, pages = {217-225}, doi = {10.1161/HYPERTENSIONAHA.120.14993}, pmid = {32450739}, issn = {1524-4563}, abstract = {Controversies persist regarding the association between blood pressure (BP) and the risks of cognitive impairment and dementia due to inconsistent definitions of BP exposure and varying population characteristics. Here, we searched PubMed and performed a meta-analysis of the influence of BP exposure on the risks of cognitive disorders in prospective studies. Dose-response analyses were performed to illustrate the existence of linear/nonlinear relationships. The credibility of each meta-analysis was evaluated according to the risk of bias, inconsistency, and imprecision. Of the 31 628 citations, 209 were included in our systematic review, among which 136 were eligible for the meta-analysis. Overall, stronger associations were found in midlife than late-life. Moderate-quality evidence indicated that midlife hypertension was related to a 1.19- to 1.55-fold excess risk of cognitive disorders. Dose-response analyses of 5 studies indicated that midlife systolic BP >130 mm Hg was associated with an increased risk of cognitive disorders. With regard to BP exposure in late-life, high systolic BP, low diastolic BP, excessive BP variability, and orthostatic hypotension were all associated with an increased dementia risk. Encouragingly, the use of antihypertensive medications exhibited a 21% reduction in dementia risk. The U-shaped dose-response curve indicated that the protective window of diastolic BP level was between 90 and 100 mm Hg for low risk of Alzheimer disease. The relationships between BP variables and cognitive disorders are age- and BP type-dependent. Antihypertensive medications were associated with a reduced risk of dementia. However, the optimal dose, duration, and type for preventing cognitive disorders warrant further investigation.}, } @article {pmid32450287, year = {2020}, author = {Abo-Youssef, AM and Khallaf, WA and Khattab, MM and Messiha, BAS}, title = {The anti-Alzheimer effect of telmisartan in a hyperglycemic ovariectomized rat model; role of central angiotensin and estrogen receptors.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {142}, number = {}, pages = {111441}, doi = {10.1016/j.fct.2020.111441}, pmid = {32450287}, issn = {1873-6351}, abstract = {The central renin angiotensin system (RAS) is implicated in Alzheimer's disease (AD). Here, induction of experimental AD simulation was performed by D-galactose (D-Gal) injection to ovariectomized (OVX) rats fed on high fat high fructose diet (HFFD). Telmisartan administration to OVX/HFFD/D-Gal rats lowered the expression of hippocampal angiotensin 1 and 2 receptors and glucose transporter 2 in addition to lowering of the peripheral and central glucose levels. Furthermore, it improved cognitive impairment and suppressed hippocampal amyloidogenic markers including amyloid-beta level, phosphorylated tau protein and beta site amyloid precursor protein cleaving enzyme 1 expression, while elevated levels of insulin degrading enzyme and recovered permeability of blood brain barrier (BBB). In addition, it inhibited hippocampal oxido-nitrosative stress as well as neuroinflammatory and apoptotic biomarkers. Telmisartan improved memory and cognitive impairment as shown in the behavioral Morris water maze, Y-maze, novel object recognition and open field tests in addition to amelioration of depressive like behavior as shown in forced swimming test. Histopathological examination of brain and immune expression of glial fibrillary acidic protein were also improved together with astrogliosis improvement. In conclusion, telmisartan improved memory and cognitive impairment, recovered amyloidogenesis-hyperglycemic axis, astrogliosis, integrity of BBB, memory deficit and oxidonitrosative stress induced in OVX/HFFD/D-Gal rats.}, } @article {pmid32450052, year = {2020}, author = {Hossain, MI and Marcus, JM and Lee, JH and Garcia, PL and Singh, V and Shacka, JJ and Zhang, J and Gropen, TI and Falany, CN and Andrabi, SA}, title = {Restoration of CTSD (cathepsin D) and lysosomal function in stroke is neuroprotective.}, journal = {Autophagy}, volume = {}, number = {}, pages = {1-19}, doi = {10.1080/15548627.2020.1761219}, pmid = {32450052}, issn = {1554-8635}, abstract = {Stroke is a leading cause of death and disability. The pathophysiological mechanisms associated with stroke are very complex and not fully understood. Lysosomal function has a vital physiological function in the maintenance of cellular homeostasis. In neurons, CTSD (cathepsin D) is an essential protease involved in the regulation of proteolytic activity of the lysosomes. Loss of CTSD leads to lysosomal dysfunction and accumulation of different cellular proteins implicated in neurodegenerative diseases. In cerebral ischemia, the role of CTSD and lysosomal function is not clearly defined. We used oxygen-glucose deprivation (OGD) in mouse cortical neurons and the middle cerebral artery occlusion (MCAO) model of stroke to assess the role of CTSD in stroke pathophysiology. Our results show a time-dependent decrease in CTSD protein levels and activity in the mouse brain after stroke and neurons following OGD, with concurrent defects in lysosomal function. We found that shRNA-mediated knockdown of CTSD in neurons is sufficient to cause lysosomal dysfunction. CTSD knockdown further aggravates lysosomal dysfunction and cell death in OGD-exposed neurons. Restoration of CTSD protein levels via lentiviral transduction increases CTSD activity in neurons and, thus, renders resistance to OGD-mediated defects in lysosomal function and cell death. This study indicates that CTSD-dependent lysosomal function is critical for maintaining neuronal survival in cerebral ischemia; thus, strategies focused on maintaining CTSD function in neurons are potentially novel therapeutic approaches to prevent neuronal death in stroke.

ABBREVIATIONS: 3-MA: 3-methyladenine; ACTB: actin beta; AD: Alzheimer disease; ALS: amyotrophic lateral sclerosis; CQ: chloroquine; CTSB: cathepsin B; CTSD: cathepsin D; CTSL: cathepsin L; FTD: frontotemporal dementia, HD: Huntington disease; LAMP1: lysosomal associated membrane protein 1; LSD: lysosomal storage disease; MCAO: middle cerebral artery occlusion; OGD: oxygen glucose deprivation; OGR: oxygen glucose resupply; PD: Parkinson disease; SQSMT1: sequestosome 1; TCA: trichloroacetic acid; TTC: triphenyl tetrazolium chloride.}, } @article {pmid32449861, year = {2020}, author = {Huwait, EA and Baghallab, IM and Glabe, CG and Abulnaja, KO and Kumosani, TA and Moselhy, SS}, title = {Identification of amyloid antibodies for Alzheimer disease - immunotherapy.}, journal = {Archives of physiology and biochemistry}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/13813455.2020.1767147}, pmid = {32449861}, issn = {1744-4160}, abstract = {The current study identified the specific antibodies that recognise amyloid protein for Alzheimer disease - immunotherapy. The immune-selection of random sequences from a phage display library and sequencing to obtain the random 12 amino acids peptide library for each antibody, and then we analysed these peptides for unique and common sequences, relation to Aβ42 sequence and shape and pattern of the amino acid reaction to the antibody to predict the epitopes. Data obtained for 4G8 showed that, the sequence segment related to the putative epitope of 4G8 was LVFFAED. Nine of the ten top sequences contain the sequence RHD corresponding to the Aβ sequence from residues 5-7. Peptide 7 has the sequence IRYDTGSYHIH, which has a RYD. It was concluded that, 4G8 and 6E10 can tolerate the binding the sequences that explain it is able to recognise amyloid aggregates.}, } @article {pmid32449110, year = {2020}, author = {Sohara, K and Kiriyama, T and Mizumura, S and Ishiwata, A and Yamazaki, M and Kimura, K and Kumita, SI}, title = {Diagnostic utility and characteristics of CT-based attenuation correction in brain perfusion SPECT/CT in predicting the exacerbation of Alzheimer changes from mild cognitive impairment utilizing voxel-based statistical analysis in comparison with Chang's method.}, journal = {Annals of nuclear medicine}, volume = {}, number = {}, pages = {}, doi = {10.1007/s12149-020-01477-4}, pmid = {32449110}, issn = {1864-6433}, abstract = {OBJECTIVE: We examined the diagnostic value of brain perfusion single-photon emission computed tomography (SPECT) using voxel-based statistical analysis with CT-based attenuation correction (CT-AC) by comparing it to that with Chang's AC in mild cognitive impairment (MCI) patients and attempted to locate brain areas that are good indicators predicting the progression of MCI.

METHODS: Twenty-six individuals matched for age, educational background and initial Mini-Mental State Examination (MMSE) score of more than 24 underwent SPECT with N-isopropyl-4-[123I]iodoamphetamine and were assigned to 2 groups: the stable MCI (S-MCI) group comprising 11 subjects who maintained their MMSE score (mean 27.0) during at least a 1-year follow-up period (mean 37.2 months) and the progressive MCI (P-MCI) group comprising 15 subjects whose MMSE scores decreased by 3 or more points (from 26.4 to 21.4, mean). The diagnostic values of the two AC methods for discriminating P-MCI from S-MCI were compared using voxel-based statistical analysis in the lobe (Level 2) and lobule/gyrus levels (Level 3).

RESULTS: Receiver operating characteristic analysis revealed that the area under the curve (AUC) was higher with CT-AC than with Chang's AC in the left temporal and limbic lobes in Level 2. In Level 3, the AUC in the left middle temporal gyrus was higher with CT-AC (0.852) than with Chang's AC (0.827). There were differences between the gyri/lobules that showed higher AUCs with CT-AC and those that showed higher AUCs with Chang's AC. When the gyri with the 4 highest AUCs were combined, AUC (0.897) and accuracy (84.6%) were better with CT-AC than with Chang's AC (0.806 and 80.8%). Surprisingly, the AUCs in the posterior cingulate gyrus and precuneus, excluding the AUC in the right precuneus with Chang's AC (0.715), were no more than 0.70 and less useful.

CONCLUSIONS: CT-AC may allow brain perfusion SPECT to reflect more exact neuropathic changes in MCI that would cause progression of early AD. CT-AC in conjunction with voxel-based statistical analysis could possess higher diagnostic accuracy for exacerbation of disease implying early Alzheimer changes in MCI patients, with decreases in cerebral perfusion in the left temporal and limbic lobes representing good indicators.}, } @article {pmid32448977, year = {2020}, author = {Patel, C and Pande, S and Acharya, S}, title = {Potentiation of anti-Alzheimer activity of curcumin by probiotic Lactobacillus rhamnosus UBLR-58 against scopolamine-induced memory impairment in mice.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {}, number = {}, pages = {}, doi = {10.1007/s00210-020-01904-3}, pmid = {32448977}, issn = {1432-1912}, abstract = {Curcumin, a major component of Indian saffron through clinical studies, revealed its neuroprotective effect in neurodegenerative diseases. However, it has not been utilized alone orally due to its low bioavailability. There are certain strategies to overcome the drawbacks such as poor absorption and low aqueous solubility. Many strategies are utilized to increase the systemic availability of curcumin. Among them, the steady intestinal and liver metabolism of curcumin by a curcumin adjuvant (enzyme inhibitor/inducer) is an important and less engrossed strategy for improving the overall systemic bioavailability of curcumin. Here, we assess the effect of probiotic Lactobacillus rhamnosus as a curcumin adjuvant (potentiate the effect of curcumin) in scopolamine-induced dementia in mice. To induce amnesia, scopolamine was used in a mouse model (1 mg/kg, daily for 10 days i.p.). After execution of behavioural tests (Morris water maze test), brains and liver were isolated for further neurochemical and histopathology examination. Our results showed a significant increase in antioxidant enzyme levels in curcumin with a probiotic group compared with curcumin alone. Besides, histopathology study results showed less neuronal damage of curcumin with probiotics as compared with the curcumin and scopolamine alone groups. Additionally, curcumin with probiotics improved memory and cognitive functions in the behavioural study with the significance of p ≤ 0.0001. In conclusion, curcumin with probiotics has greater activity as compared with curcumin alone and reverses the hallmarks of Alzheimer's disease (AD).}, } @article {pmid32448104, year = {2020}, author = {Quntanilla, RA and Tapia-Monsalves, C}, title = {The role of mitochondrial impairment on Alzheimer´s disease neurodegeneration: the Tau connection.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/1570159X18666200525020259}, pmid = {32448104}, issn = {1875-6190}, abstract = {Accumulative evidence has shown that mitochondrial dysfunction plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). Mitochondrial impairment actively contributes to the synaptic and cognitive failure that characterizes AD. The presence of soluble pathological forms of tau like hyperphosphorylated at Ser396 and Ser404 and cleaved at Asp421 by caspase 3, negatively impacts mitochondrial bioenergetics, transport, and morphology in neurons. These adverse effects against mitochondria health will contribute to the synaptic impairment and cognitive decline showed in AD. Current studies suggest that mitochondrial failure induced by pathological tau forms are likely the result of the opening of the mitochondrial permeability transition pore (mPTP). mPTP is a mitochondrial mega-channel that is activated by increases in calcium and is associated with mitochondrial stress and apoptosis. This structure is composed of different proteins, where CypD is considered to be the primary mediator of mPTP activation. Also, new studies suggest that mPTP contributes to A pathology and oxidative stress in AD. Further, inhibition of mPTP through the reduction of CypD expression prevents cognitive and synaptic impairment in AD mouse models. More importantly, tau protein contributes to the physiological regulation of mitochondria through the opening/interaction with mPTP in hippocampal neurons. Therefore, in this paper, we will discuss evidence that suggests an important role of pathological forms of tau against mitochondrial health. Also, we will discuss the possible role of mPTP in the mitochondrial impairment produced by the presence of tau pathology and its impact on synaptic function present in AD.}, } @article {pmid32444542, year = {2020}, author = {Chen, S and Jia, J}, title = {Tenuifolin Attenuates Amyloid-β42-Induced Neuroinflammation in Microglia Through the NF-κB Signaling Pathway.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {}, doi = {10.3233/JAD-200077}, pmid = {32444542}, issn = {1875-8908}, abstract = {BACKGROUND: Inflammation and oxidative stress are believed to play an important role in the pathogenesis of Alzheimer's disease (AD). Tenuifolin (TEN) is a natural neuroprotective compound extracted from Polygala tenuifolia Willd, which may improve cognitive symptoms.

OBJECTIVE: This study was designed to evaluate the protective effect of TEN on inflammatory and oxidative stress induced by amyloid-β (Aβ)42 oligomers in BV2 cells, and to explore the underlying mechanisms.

METHODS: We conducted cell viability assays to estimate drug toxicity and drug effects on cells. Quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assays were performed to detect the release of inflammatory factors. Nitric oxide (NO) assays were used to measure the degree of oxidative stress. Western blot and immunofluorescence analysis were used to explore the influence of TEN on the nuclear factor-κB (NF-κB) pathway.

RESULTS: Pretreatment of BV2 microglial cells with TEN inhibited the release of tumor necrosis factor-α, interleukin-6, and interleukin-1β, alleviated NO-induced oxidative stress by inhibiting the expression of inducible nitric oxide synthase and cyclo-oxygenase-2, and protected SH-SY5Y cells from the toxicity induced by the medium conditioned by BV2 cells previously exposed to Aβ42 oligomers. Moreover, TEN suppressed upstream activators of NF-κB, as well as NF-κB translocation to the nucleus in BV2 microglial cells.

CONCLUSION: This study demonstrates that TEN can protect SH-SY5Y cells from Aβ42 oligomer-induced microglia-mediated inflammation, and oxidative stress by downregulating the NF-κB signaling pathway.}, } @article {pmid32444385, year = {2020}, author = {Rolland, M and Powell, R and Jacquier-Sarlin, M and Boisseau, S and Reynaud-Dulaurier, R and Martinez-Hernandez, J and André, L and Borel, E and Buisson, A and Lanté, F}, title = {Effect of Aβ oligomers on neuronal APP triggers a vicious cycle leading to the propagation of synaptic plasticity alterations to healthy neurons.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1523/JNEUROSCI.2501-19.2020}, pmid = {32444385}, issn = {1529-2401}, abstract = {Alterations of excitatory synaptic function are the strongest correlate to the pathological disturbance of cognitive ability observed in the early stages of Alzheimer disease (AD). This pathological feature is driven by Amyloid-β oligomers (Aβo) and propagates from neuron to neuron. Here, we investigated the mechanism by which Aβo affect the function of synapses and how these alterations propagate to surrounding healthy neurons. We used complementary techniques ranging from electrophysiological recordings and molecular biology to confocal microscopy in primary cortical cultures, acute hippocampal and cortical slices from male Wild type and Amyloid precursor protein knock-out (APP KO) mice to assess the effects of Aβo on glutamatergic transmission, synaptic plasticity and dendritic spine structure. We showed that extracellular application of Aβo reduced glutamatergic synaptic transmission and long-term potentiation. These alterations were not observed in APP KO neurons suggesting that APP expression is required. We demonstrated that Aβo/APP interaction increases the amyloidogenic processing of APP leading to intracellular accumulation of newly produced Aβo. Intracellular Aβo participate in synaptic dysfunctions as evidenced by pharmacological inhibition of APP processing or by intraneuronal infusion of an antibody raised against Aβo. Furthermore, we provide evidence that following APP processing, extracellular release of Aβo mediates the propagation of the synaptic pathology characterized by a decreased spine density of neighboring healthy neurons in an APP-dependent manner. Together, our data unveil a complementary role for Aβo in AD, while intracellular Aβo alters synaptic function, extracellular Aβo promotes a vicious cycle that propagates synaptic pathology from diseased to healthy neurons.Significance statementHere we provide the proof that a vicious cycle between extracellular and intracellular pools of Aβ oligomers (Aβo) is required for the spreading of Alzheimer disease (AD) pathology. We showed that extracellular Aβo propagate excitatory synaptic alterations by promoting amyloid precursor protein (APP) processing. Our results also suggest that subsequently to APP cleavage two pools of Aβo are produced. One pool accumulates inside the cytosol inducing the loss of synaptic plasticity potential. The other pool is released into the extracellular space and contributes to the propagation of the pathology from diseased to healthy neurons. Pharmacological strategies targeting the proteolytic cleavage of APP disrupt the relationship between extra and intracellular Aβ providing therapeutic approach for the disease.}, } @article {pmid32441331, year = {2020}, author = {Smith, TO and Mistry, D and Lee, H and Dosanji, S and Finnegan, S and Fordham, B and Nichols, VP and Sheehan, B and Lamb, SE}, title = {Moderators of Cognitive Outcomes from an Exercise Program in People with Mild to Moderate Dementia.}, journal = {Journal of the American Geriatrics Society}, volume = {}, number = {}, pages = {}, doi = {10.1111/jgs.16552}, pmid = {32441331}, issn = {1532-5415}, support = {09/80/04//Health Technology Assessment Programme/ ; }, abstract = {BACKGROUND/OBJECTIVES: Our aim was to estimate whether baseline participant variables were able to moderate the effect of an exercise intervention on cognition in patients with mild to moderate dementia.

DESIGN: Subgroup analysis of a multicenter pragmatic randomized controlled trial.

SETTING: Community-based gym/rehabilitation centers.

PARTICIPANTS: A total of 494 community-dwelling participants with mild to moderate dementia.

INTERVENTION: Participants were randomized to a moderate- to high-intensity aerobic and strength exercise program or a usual care control group. Experimental group participants attended twice weekly 60- to 90-minute gym sessions for 4 months. Participants were prescribed home exercises for an additional hour per week during the supervised period and 150 minutes each week after the supervised period.

MEASUREMENTS: Multilevel regression model analyses were undertaken to identify individual moderators of cognitive function measured through the Alzheimer Disease Assessment Scale-Cognitive Subscale score at 12 months.

RESULTS: When tested for a formal interaction effect, only cognitive function assessed by the baseline number cancellation test demonstrated a statistically significant interaction effect (-2.7 points; 95% confidence interval = -5.14 to -0.21).

CONCLUSION: People with worse number cancellation test scores may experience greater progression of cognitive decline in response to a moderate- to high-intensity exercise program. Further analyses to examine whether these findings can be replicated in planned sufficiently powered analyses are indicated.}, } @article {pmid32440639, year = {2020}, author = {Hardman, RJ and Meyer, D and Kennedy, G and Macpherson, H and Scholey, AB and Pipingas, A}, title = {Findings of a Pilot Study Investigating the Effects of Mediterranean Diet and Aerobic Exercise on Cognition in Cognitively Healthy Older People Living Independently within Aged-Care Facilities: The Lifestyle Intervention in Independent Living Aged Care (LIILAC) Study.}, journal = {Current developments in nutrition}, volume = {4}, number = {5}, pages = {nzaa077}, pmid = {32440639}, issn = {2475-2991}, abstract = {Background: Cognitive decline and Alzheimer disease are more prevalent in our aging population. Modifiable risk factors, such as diet and sedentary lifestyle, have been proposed as key to potentially ameliorating cognitive decline. Both exercise and Mediterranean diet (MedDiet) have been linked to reduced levels of cardiovascular disease and other comorbidities. Higher levels of exercise and MedDiet adherence may prove to be cognitively protective, both individually and synergistically.

Objectives: The aim was to investigate the effect of a 6-mo program of MedDiet, exercise, and a combination of both, on cognition, mood, and general health in older persons living independently in aged-care communities.

Methods: The Lifestyle Intervention in Independent Living Aged Care (LIILAC) Study (ACTRN12614001133628) involved 102 participants, aged 60-90 y, who were randomly assigned to 1 of 4 intervention groups. Change in overall memory performance was assessed as the primary outcome. Additionally, changes in cognitive task performance, as well as mood, wellness, cardiovascular function, and blood biomarkers, were investigated.

Results: While there was no significant change in overall memory performance, there was a significant improvement in spatial working memory performance in the combined exercise and diet group, relative to controls. This combined intervention group also showed an overall improvement in their emotional state, as assessed by the Depression Anxiety Stress Scale, as did the exercise-only group.

Conclusions: This research indicates that diet and exercise programs have the potential to improve aspects of cognition and mood in an aging population. However, given the lower than optimal sample size and lack of resources to reinforce the interventions during the trial, further larger randomized controlled trials are required to substantiate whether the introduction of diet and exercise programs into independent-living facilities is a viable method to preserve cognitive health in older people. This trial was registered at www.ANZCTR.org.au ACTRN 12614001133628 (LIILAC Study).}, } @article {pmid32439711, year = {2020}, author = {Törnquist, M and Cukalevski, R and Weininger, U and Meisl, G and Knowles, TPJ and Leiding, T and Malmendal, A and Akke, M and Linse, S}, title = {Ultrastructural evidence for self-replication of Alzheimer-associated Aβ42 amyloid along the sides of fibrils.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {117}, number = {21}, pages = {11265-11273}, pmid = {32439711}, issn = {1091-6490}, abstract = {The nucleation of Alzheimer-associated Aβ peptide monomers can be catalyzed by preexisting Aβ fibrils. This leads to autocatalytic amplification of aggregate mass and underlies self-replication and generation of toxic oligomers associated with several neurodegenerative diseases. However, the nature of the interactions between the monomeric species and the fibrils during this key process, and indeed the ultrastructural localization of the interaction sites have remained elusive. Here we used NMR and optical spectroscopy to identify conditions that enable the capture of transient species during the aggregation and secondary nucleation of the Aβ42 peptide. Cryo-electron microscopy (cryo-EM) images show that new aggregates protrude from the entire length of the progenitor fibril. These protrusions are morphologically distinct from the well-ordered fibrils dominating at the end of the aggregation process. The data provide direct evidence that self-replication through secondary nucleation occurs along the sides of fibrils, which become heavily decorated under the current solution conditions (14 µM Aβ42, 20 mM sodium phosphate, 200 µM EDTA, pH 6.8).}, } @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}, 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 {pmid32438605, year = {2020}, author = {Lidón, L and Urrea, L and Llorens, F and Gil, V and Alvarez, I and Diez-Fairen, M and Aguilar, M and Pastor, P and Zerr, I and Alcolea, D and Lleó, A and Vidal, E and Gavín, R and Ferrer, I and Del Rio, JA}, title = {Disease-Specific Changes in Reelin Protein and mRNA in Neurodegenerative Diseases.}, journal = {Cells}, volume = {9}, number = {5}, pages = {}, pmid = {32438605}, issn = {2073-4409}, support = {RTI2018-099773-B-I00//Ministerio de Ciencia e Innovación/International ; SGR2017-648//Agència de Gestió d'Ajuts Universitaris i de Recerca/International ; MDM-2017-0729//Ministerio de Ciencia, Innovación y Universidades/International ; CMED2018-2//Centro de Investigación en red de enfermedades neurodegenerativas (Ciberned)/International ; PI19-00144//Instituto de Salud Carlos III/International ; LCF/PR/HR19/52160007//"la Caixa" Foundation/International ; }, abstract = {Reelin is an extracellular glycoprotein that modulates neuronal function and synaptic plasticity in the adult brain. Decreased levels of Reelin activity have been postulated as a key factor during neurodegeneration in Alzheimer´s disease (AD) and in aging. Thus, changes in levels of full-length Reelin and Reelin fragments have been revealed in cerebrospinal fluid (CSF) and in post-mortem brains samples of AD patients with respect to non-AD patients. However, conflicting studies have reported decreased or unchanged levels of full-length Reelin in AD patients compared to control (nND) cases in post-mortem brains and CSF samples. In addition, a compelling analysis of Reelin levels in neurodegenerative diseases other than AD is missing. In this study, we analyzed brain levels of RELN mRNA and Reelin protein in post-mortem frontal cortex samples from different sporadic AD stages, Parkinson's disease with dementia (PDD), and Creutzfeldt-Jakob disease (sCJD), obtained from five different Biobanks. In addition, we measured Reelin protein levels in CSF samples of patients with mild cognitive impairment (MCI), dementia, or sCJD diagnosis and a group of neurologically healthy cases. The results indicate an increase in RELN mRNA in the frontal cortex of advanced stages of AD and in sCJD(I) compared to controls. This was not observed in PDD and early AD stages. However, Reelin protein levels in frontal cortex samples were unchanged between nND and advanced AD stages and PDD. Nevertheless, they decreased in the CSF of patients with dementia in comparison to those not suffering with dementia and patients with MCI. With respect to sCJD, there was a tendency to increase in brain samples in comparison to nND and to decrease in the CSF with respect to nND. In conclusion, Reelin levels in CSF cannot be considered as a diagnostic biomarker for AD or PDD. However, we feel that the CSF Reelin changes observed between MCI, patients with dementia, and sCJD might be helpful in generating a biomarker signature in prodromal studies of unidentified dementia and sCJD.}, } @article {pmid32434685, year = {2020}, author = {Vicario, A and Cerezo, GH}, title = {[The cognitive-behavioural impact of hypertension].}, journal = {Hipertension y riesgo vascular}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.hipert.2020.04.003}, pmid = {32434685}, issn = {1989-4805}, 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 {pmid32434656, year = {2020}, author = {Aldaz, P and Garjón, J and Beitia, G and Beltrán, I and Librero, J and Ibáñez, B and Arroyo, P and Ariz, MJ}, title = {Association between benzodiazepine use and development of dementia.}, journal = {Medicina clinica}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.medcli.2020.02.006}, pmid = {32434656}, issn = {1578-8989}, abstract = {OBJECTIVE: To evaluate the association between use of benzodiazepines and incident dementia.

METHODS: Analytical prospective nested case-control study for which the Spanish database for pharmacoepidemiological research in primary care (BIFAP) of the Spanish Agency of Medicines and Medical Devices (AEMPS) was used. A total of 15,212 subjects diagnosed with dementia of the Alzheimer type and 62,397 controls were identified. Exposure was retrieved retrospectively with a 3-year lag time before the index date. Adjusted odd ratios (OR) were calculated.

RESULTS: Benzodiazepines use increased the risk of suffering Alzheimer's disease (OR=1.05, 95% CI, 1.01-1.10). No statistical differences were shown between short-acting and long-acting drugs. The risk is more evident with longer exposure times.

CONCLUSIONS: There seems to be a weak association between benzodiazepine use and the development of dementia, the risk increases with greater exposure.}, } @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}, 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}, 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 administered in the correct doses, in the ideal formulation combination, and during the appropriate therapeutic window. The use of some antioxidants is, therefore, still poorly explored for the treatment of neurodegenerative diseases such as Alzheimer's disease.}, } @article {pmid32431629, year = {2020}, author = {Wagner, F and Duering, M and Gesierich, BG and Enzinger, C and Ropele, S and Dal-Bianco, P and Mayer, F and Schmidt, R and Koini, M}, title = {Gray Matter Covariance Networks as Classifiers and Predictors of Cognitive Function in Alzheimer's Disease.}, journal = {Frontiers in psychiatry}, volume = {11}, number = {}, pages = {360}, pmid = {32431629}, issn = {1664-0640}, abstract = {The study of shared variation in gray matter morphology may define neurodegenerative diseases beyond what can be detected from the isolated assessment of regional brain volumes. We, therefore, aimed to (1) identify SCNs (structural covariance networks) that discriminate between Alzheimer's disease (AD) patients and healthy controls (HC), (2) investigate their diagnostic accuracy in comparison and above established markers, and (3) determine if they are associated with cognitive abilities. We applied a random forest algorithm to identify discriminating networks from a set of 20 SCNs. The algorithm was trained on a main sample of 104 AD patients and 104 age-matched HC and was then validated in an independent sample of 28 AD patients and 28 controls from another center. Only two of the 20 SCNs contributed significantly to the discrimination between AD and controls. These were a temporal and a secondary somatosensory SCN. Their diagnostic accuracy was 74% in the original cohort and 80% in the independent samples. The diagnostic accuracy of SCNs was comparable with that of conventional volumetric MRI markers including whole brain volume and hippocampal volume. SCN did not significantly increase diagnostic accuracy beyond that of conventional MRI markers. We found the temporal SCN to be associated with verbal memory at baseline. No other associations with cognitive functions were seen. SCNs failed to predict the course of cognitive decline over an average of 18 months. We conclude that SCNs have diagnostic potential, but the diagnostic information gain beyond conventional MRI markers is limited.}, } @article {pmid32431504, year = {2020}, author = {Chen, Y and Lu, Y and Lee, RJ and Xiang, G}, title = {Nano Encapsulated Curcumin: And Its Potential for Biomedical Applications.}, journal = {International journal of nanomedicine}, volume = {15}, number = {}, pages = {3099-3120}, pmid = {32431504}, issn = {1178-2013}, abstract = {Curcumin, a yellow-colored polyphenol extracted from the rhizome of turmeric root, is commonly used as a spice and nutritional supplement. It exhibits many pharmacological activities such as anti-inflammatory, anti-bacterial, anti-cancer, anti-Alzheimer, and anti-fungal. However, the therapeutic application of curcumin is limited by its extremely low solubility in aqueous buffer, instability in body fluids, and rapid metabolism. Nano delivery system has shown excellent potential to improve the solubility, biocompatibility and therapeutic effect of curcumin. In this review, we focus on the recent development of nano encapsulated curcumin and its potential for biomedical applications.}, } @article {pmid32428558, year = {2020}, author = {Barthet, G and Mulle, C}, title = {Presynaptic failure in Alzheimer's disease.}, journal = {Progress in neurobiology}, volume = {}, number = {}, pages = {101801}, doi = {10.1016/j.pneurobio.2020.101801}, pmid = {32428558}, issn = {1873-5118}, abstract = {Synaptic loss is the best correlate of cognitive deficits in Alzheimer's disease (AD). Extensive experimental evidence also indicates alterations of synaptic properties at the early stages of disease progression, before synapse loss and neuronal degeneration. A majority of studies in mouse models of AD have focused on post-synaptic mechanisms, including impairment of long-term plasticity, spine structure and glutamate receptor-mediated transmission. Here we review the literature indicating that the synaptic pathology in AD includes a strong presynaptic component. We describe the evidence indicating presynaptic physiological functions of the major molecular players in AD. These include the amyloid precursor protein (APP) and the two presenilin (PS) paralogs PS1 or PS2, genetically linked to the early-onset form of AD, in addition to tau which accumulates in a pathological form in the AD brain. Three main mechanisms participating in presynaptic functions are highlighted. APP fragments bind to presynaptic receptors (e.g. nAChRs and GABAB receptors), presenilins control Ca2+ homeostasis and Ca2+-sensors, and tau regulates the localization of presynaptic molecules and synaptic vesicles. We then discuss how impairment of these presynaptic physiological functions can explain or forecast the hallmarks of synaptic impairment and associated dysfunction of neuronal circuits in AD. Beyond the physiological roles of the AD-related proteins, studies in AD brains also support preferential presynaptic alteration. This review features presynaptic failure as a strong component of pathological mechanisms in AD.}, } @article {pmid32427566, year = {2020}, author = {Guo, Y and Yang, F and Hu, F and Li, W and Ruggiano, N and Lee, HY}, title = {Correction: Existing Mobile Phone Apps for Self-Care Management of People With Alzheimer Disease and Related Dementias: Systematic Analysis.}, journal = {JMIR aging}, volume = {3}, number = {1}, pages = {e18754}, doi = {10.2196/18754}, pmid = {32427566}, issn = {2561-7605}, abstract = {[This corrects the article DOI: 10.2196/15290.].}, } @article {pmid32427314, year = {2020}, author = {Barbaresko, J and Lellmann, AW and Schmidt, A and Lehmann, A and Amini, AM and Egert, S and Schlesinger, S and Nöthlings, U}, title = {Dietary Factors and Neurodegenerative Disorders: An Umbrella Review of Meta-Analyses of Prospective Studies.}, journal = {Advances in nutrition (Bethesda, Md.)}, volume = {}, number = {}, pages = {}, doi = {10.1093/advances/nmaa053}, pmid = {32427314}, issn = {2156-5376}, abstract = {Diet has been hypothesized to be associated with neurodegenerative disorders. The aim was to conduct an umbrella review to summarize and evaluate the current evidence of prospective associations between any dietary factors and the incidence of neurodegenerative disorders. We conducted a systematic search in PubMed, Embase, and the Cochrane library up to November 2019 to identify systematic reviews with meta-analyses of prospective studies investigating the association between dietary factors (dietary patterns, foods and beverages, nutrients, and phytochemicals) and neurodegenerative disorders (cognitive decline, cognitive impairment, Alzheimer disease, all-cause dementia, and Parkinson disease). Summary risk ratios (SRRs) and 95% CIs were recalculated using a random effects model. We evaluated the risk of bias of identified meta-analyses and the quality of evidence for all associations. In total, 20 meta-analyses including 98 SRRs were identified. All original meta-analyses were rated as being at high risk of bias. Methodological concerns related mainly to the inappropriate synthesis, assessment, and discussion of the risk of bias of primary studies. For the recalculated meta-analyses, quality of evidence was moderate for inverse associations between higher adherence to the Mediterranean diet (SRR: 0.63; 95% CI: 0.48, 0.82; n = 4 primary studies) and higher fish intake (SRR: 0.72; 95% CI: 0.59, 0.89; n = 6) and Alzheimer disease, as well as for tea consumption and all-cause dementia (SRR: 0.74; 95% CI: 0.63, 0.88; n = 2) and Parkinson disease (SRR per 2 cups/d: 0.69; 95% CI: 0.54, 0.87; n = 5). This umbrella review provides a comprehensive overview of the available evidence on dietary factors and neurodegenerative disorders. The results indicate that the Mediterranean diet, fish, and tea could be inversely associated with neurodegenerative disorders. However, the quality of evidence was generally low, suggesting that further studies are likely to change the overall estimates. Thus, more well-conducted research, also investigating other dietary factors in association with neurodegenerative disorders, is warranted.}, } @article {pmid32426945, year = {2020}, author = {Sasayama, D and Hattori, K and Yokota, Y and Matsumura, R and Teraishi, T and Yoshida, S and Kunugi, H}, title = {Increased apolipoprotein E and decreased TNF-α in the cerebrospinal fluid of nondemented APOE-ε4 carriers.}, journal = {Neuropsychopharmacology reports}, volume = {}, number = {}, pages = {}, doi = {10.1002/npr2.12110}, pmid = {32426945}, issn = {2574-173X}, support = {25253075//Grant-in-Aid for Scientific Research (A) from the Ministry of Education, Science, Sports and Culture,/ ; 17ak0101044h0402//Japan Agency for Medical Research and Development/ ; 27-1//Intramural Research Grant for Neurological and Psychiatric Disorders of National Center of Neurology and Psychiatry/ ; 27-6//Intramural Research Grant for Neurological and Psychiatric Disorders of National Center of Neurology and Psychiatry/ ; 30-3//Intramural Research Grant for Neurological and Psychiatric Disorders of National Center of Neurology and Psychiatry/ ; }, abstract = {AIM: The ε4 allele of apolipoprotein E gene (APOE) is a well-known risk factor of late-onset Alzheimer's disease. However, little is known why this variant confers a risk for Alzheimer's disease. The aim of this study was to examine the influence of the APOE genotype on cerebrospinal fluid (CSF) protein levels.

METHODS: The present study performed a secondary analysis on our previously generated database to compare the CSF levels of 1128 proteins between APOE-ε4 carriers (28 subjects) and noncarriers (104 subjects). All subjects were physically healthy Japanese individuals without dementia.

RESULTS: CSF levels of apoE2, apoE3, and apoE4 were significantly higher (all nominal P < 10 × 10-5 , false discovery rate < 0.001) and those of tumor necrosis factor-α (TNF-α) were significantly lower (nominal P = 1.39 × 10-6 , false discovery rate < 0.001) in APOE-ε4 carriers than in noncarriers. No significant correlation was observed between the CSF levels of TNF-α and any of the apoE proteins.

CONCLUSIONS: Our findings indicate the possible roles of apoE and TNF-α in the pathogenesis of APOE-ε4-associated Alzheimer's disease.}, } @article {pmid32424756, year = {2020}, author = {Niaz, K and Shah, SZA and Khan, F and Bule, M}, title = {Ochratoxin A-induced genotoxic and epigenetic mechanisms lead to Alzheimer disease: its modulation with strategies.}, journal = {Environmental science and pollution research international}, volume = {}, number = {}, pages = {}, doi = {10.1007/s11356-020-08991-y}, pmid = {32424756}, issn = {1614-7499}, abstract = {Ochratoxin A (OTA) is a naturally occurring mycotoxin mostly found in food items including grains and coffee beans. It induces DNA single-strand breaks and has been considered to be carcinogenic. It is recognized as a serious threat to reproductive health both in males and females. OTA is highly nephrotoxic and carcinogenic, and its potency changes evidently between species and sexes. There is a close association between OTA, mutagenicity, carcinogenicity, and genotoxicity, but the underlying mechanisms are not clear. Reports regarding genotoxic effects in relation to OTA which leads to the induction of DNA adduct formation, protein synthesis inhibition, perturbation of cellular energy production, initiation of oxidative stress, induction of apoptosis, influences on mitosis, induction of cell cycle arrest, and interference with cytokine pathways. All these mechanisms are associated with nephrotoxicity, hepatotoxicity, teratotoxicity, immunological toxicity, and neurotoxicity. OTA administration activates various mechanisms such as p38 MAPK, JNKs, and ERKs dysfunctions, BDNF disruption, TH overexpression, caspase-3 and 9 activation, and ERK-1/2 phosphorylation which ultimately lead to Alzheimer disease (AD) progression. The current review will focus on OTA in terms of recent discoveries in the field of molecular biology. The main aim is to investigate the underlying mechanisms of OTA in regard to genotoxicity and epigenetic modulations that lead to AD. Also, we will highlight the strategies for the purpose of attenuating the hazards posed by OTA exposure.}, } @article {pmid32423406, year = {2020}, author = {Xiong, C and Ye, B and Mihailidis, A and Cameron, JI and Astell, A and Nalder, E and Colantonio, A}, title = {Sex and gender differences in technology needs and preferences among informal caregivers of persons with dementia.}, journal = {BMC geriatrics}, volume = {20}, number = {1}, pages = {176}, pmid = {32423406}, issn = {1471-2318}, support = {SGB-155385//Institute of Gender and Health/ ; CGW-126580//Institute of Gender and Health/ ; }, abstract = {BACKGROUND: Dementia is a major public health concern associated with significant caregiver demands and there are technologies available to assist with caregiving. However, there is a paucity of information on caregiver needs and preferences for these technologies, particularly from a sex and gender perspective. To address this gap in research, the objectives of this study are to examine (1) the knowledge of technology, (2) perceived usefulness of technology, (3) feature preferences when installing and using technology and (4) sex and gender influences on technology needs and preferences among family caregivers of persons with dementia (PWD) across North America.

METHODS: A secondary analysis was conducted on an existing cross-sectional survey with family caregivers of PWDs. Respondents were recruited through the Alzheimer Society of Canada, the Victorian Order of Nurses and Adult Day Programs and other Canadian health care provision institutes. Descriptive statistics, bivariate and multivariate analyses were used to describe the study sample, uncover differences between male and female caregivers and examine sex and gender influences on caregivers' technology needs and preferences.

RESULTS: A total of 381 eligible responses were received over a nine month data collection period. The majority of respondents did not know much about and never used any technologies to assist with caregiving. "Being easy to install", "easy to learn how to use" and "cost" were identified as the most important features when purchasing and setting up technology, while "reliability" was identified as the most important feature when using technology. Most respondents were willing to pay up to $500 to acquire individual technologies. Controlling for other socio-demographic variables, female respondents were more likely to have some or more knowledge about technology for caregiving while male respondents were more willing to pay higher amounts for these technologies compared to their female counterparts.

CONCLUSIONS: As one of the first studies of its kind, our findings represent a step towards the incorporation of sex and gender considerations such as cost and reliability in technology design and promotion for caregivers. Future efforts are warranted to establish an in-depth understanding of sex and gender influences in relation to other social and environmental factors.}, } @article {pmid32423230, year = {2020}, author = {Giesers, NK and Wirths, O}, title = {Loss of Hippocampal Calretinin and Parvalbumin Interneurons in the 5XFAD Mouse Model of Alzheimer's Disease.}, journal = {ASN neuro}, volume = {12}, number = {}, pages = {1759091420925356}, pmid = {32423230}, issn = {1759-0914}, abstract = {The deposition of amyloid-β peptides in the form of extracellular plaques and neuronal degeneration belong to the hallmark features of Alzheimer's disease (AD). In addition, impaired calcium homeostasis and altered levels in calcium-binding proteins seem to be associated with the disease process. In this study, calretinin- (CR) and parvalbumin- (PV) positive gamma-aminobutyric acid-producing (GABAergic) interneurons were quantified in different hippocampal subfields of 12-month-old wild-type mice, as well as in the transgenic AD mouse models 5XFAD and Tg4-42. While, in comparison with wild-type mice, CR-positive interneurons were mainly reduced in the CA1 and CA2/3 regions in plaque-bearing 5XFAD mice, PV-positive interneurons were reduced in all analyzed subfields including the dentate gyrus. No reduction in CR- and PV-positive interneuron numbers was detected in the non-plaque-forming Tg4-42 mouse, although this model has been previously demonstrated to harbor a massive loss of CA1 pyramidal neurons. These results provide information about hippocampal interneuron numbers in two relevant AD mouse models, suggesting that interneuron loss in this brain region may be related to extracellular amyloid burden.}, } @article {pmid32422323, year = {2020}, author = {Wahle, T and Sofranko, A and Dekkers, S and Miller, MR and Heusinkveld, HJ and Albrecht, C and Cassee, FR and Schins, RPF}, title = {Evaluation of neurological effects of cerium dioxide nanoparticles doped with different amounts of zirconium following inhalation exposure in mouse models of Alzheimer's and vascular disease.}, journal = {Neurochemistry international}, volume = {}, number = {}, pages = {104755}, doi = {10.1016/j.neuint.2020.104755}, pmid = {32422323}, issn = {1872-9754}, abstract = {Increasing evidence from toxicological and epidemiological studies indicates that the brain is an important target for ambient (ultrafine) particles. Disturbance of redox-homeostasis and inflammation in the brain are proposed as possible mechanisms that can contribute to neurotoxic and neurodegenerative effects. Whether and how engineered nanoparticles (NPs) may cause neurotoxicity and promote neurodegenerative diseases such as Alzheimer´s disease (AD) is largely unstudied. We have assessed the neurological effects of subacute inhalation exposures (4 mg/m3 for 3 h/day, 5 days/week for 4 weeks) to cerium dioxide (CeO2) NPs doped with different amounts of zirconium (Zr, 0%, 27% and 78%), to address the influence of particle redox-activity in the 5xFAD transgenic mouse model of AD. Four weeks post-exposure, effects on behaviour were evaluated and brain tissues were analysed for amyloid-β plaque formation and reactive microglia (Iba-1 staining). Behaviour was also evaluated in concurrently exposed non-transgenic C57BL/6J littermates, as well as in Western diet-fed apolipoprotein E-deficient (ApoE-/-) mice as a model of vascular disease. Markers of inflammation and oxidative stress were evaluated in brain cortex. The brains of the NP-exposed 5xFAD mice revealed no accelerated amyloid-β plaque formation. No significant treatment-related behaviour impairments were observed in the healthy C57BL/6J mice. In the 5xFAD and ApoE-/- models, the NP inhalation exposures did not affect the alternation score in the X-maze indicating absence of spatial working memory deficits. However, following inhalation exposure to the 78% Zr-doped CeO2 NPs changes in forced motor performance (string suspension) and exploratory motor activity (X-maze) were observed in ApoE-/- and 5xFAD mice, respectively. Exposure to the 78% doped NPs also caused increased cortical expression of glial fibrillary acidic protein (GFAP) in the C57BL/6J mice. No significant treatment-related changes neuroinflammation and oxidative stress were observed in the 5xFAD and ApoE-/- mice. Our study findings reveal that subacute inhalation exposure to CeO2 NPs does not accelerate the AD-like phenotype of the 5xFAD model. Further investigation is warranted to unravel whether the redox-activity dependent effects on motor activity as observed in the mouse models of AD and vascular disease result from specific neurotoxic effects of these NPs.}, } @article {pmid32421689, year = {2020}, author = {Xue, M and Sun, FR and Ou, YN and Shen, XN and Li, HQ and Huang, YY and Dong, Q and Tan, L and Yu, JT and , }, title = {Association of cerebrospinal fluid neurogranin levels with cognition and neurodegeneration in Alzheimer's disease.}, journal = {Aging}, volume = {12}, number = {10}, pages = {9365-9379}, doi = {10.18632/aging.103211}, pmid = {32421689}, issn = {1945-4589}, abstract = {Accumulating data suggest cerebrospinal fluid (CSF) neurogranin (Ng) as a potential biomarker for cognitive decline and neurodegeneration in Alzheimer disease (AD). To investigate whether the CSF Ng can be used for diagnosis, prognosis, and monitoring of AD, we examined 111 cognitively normal (CN) controls, 193 mild cognitive impairment (MCI) patients and 95 AD patients in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Correlations were tested between baseline CSF Ng levels and baseline core AD biomarkers and longitudinal glucose metabolism, brain atrophy and cognitive decline. We detected that CSF Ng levels increased with disease severity, and correlated with phosphorylated tau and total tau levels within each diagnostic group. High baseline CSF Ng levels correlated with longitudinal reductions in cortical glucose metabolism within each diagnostic group and hippocampal volume within MCI group during follow-up. In addition, high baseline CSF Ng levels correlated with cognitive decline as reflected by decreased cognitive scale scores. The CSF Ng levels predicted future cognitive impairment (adjusted hazard ratio:3.66, 95%CI: 1.74-7.70, P = 0.001) in CN controls. These data demonstrate that CSF Ng offers diagnostic utility for AD and predicts future cognitive impairment in CN individuals and, therefore, may be a useful addition to the current AD biomarkers.}, } @article {pmid32421658, year = {2020}, author = {Puente-Castro, A and Fernandez-Blanco, E and Pazos, A and Munteanu, CR}, title = {Automatic assessment of Alzheimer's disease diagnosis based on deep learning techniques.}, journal = {Computers in biology and medicine}, volume = {120}, number = {}, pages = {103764}, doi = {10.1016/j.compbiomed.2020.103764}, pmid = {32421658}, issn = {1879-0534}, abstract = {Early detection is crucial to prevent the progression of Alzheimer's disease (AD). Thus, specialists can begin preventive treatment as soon as possible. They demand fast and precise assessment in the diagnosis of AD in the earliest and hardest to detect stages. The main objective of this work is to develop a system that automatically detects the presence of the disease in sagittal magnetic resonance images (MRI), which are not generally used. Sagittal MRIs from ADNI and OASIS data sets were employed. Experiments were conducted using Transfer Learning (TL) techniques in order to achieve more accurate results. There are two main conclusions to be drawn from this work: first, the damages related to AD and its stages can be distinguished in sagittal MRI and, second, the results obtained using DL models with sagittal MRIs are similar to the state-of-the-art, which uses the horizontal-plane MRI. Although sagittal-plane MRIs are not commonly used, this work proved that they were, at least, as effective as MRI from other planes at identifying AD in early stages. This could pave the way for further research. Finally, one should bear in mind that in certain fields, obtaining the examples for a data set can be very expensive. This study proved that DL models could be built in these fields, whereas TL is an essential tool for completing the task with fewer examples.}, } @article {pmid32420373, year = {2020}, author = {Yu, X and Li, Y and Mu, X}, title = {Effect of Quercetin on PC12 Alzheimer's Disease Cell Model Induced by Aβ25-35 and Its Mechanism Based on Sirtuin1/Nrf2/HO-1 Pathway.}, journal = {BioMed research international}, volume = {2020}, number = {}, pages = {8210578}, pmid = {32420373}, issn = {2314-6141}, abstract = {Objective: This study is aimed at studying the effect of quercetin on the Alzheimer disease cell model induced by Aβ25-35 in PC12 cells and its mechanism of action.

Methods: The AD cell model was established by Aβ25-35. Quercetin was used at different concentrations (0, 10, 20, 40, and 80 μmol/L). The morphology of cells was observed, and the effect on cell survival rate was detected by the MTT method. Cell proliferation was detected by the SRB method. The contents of LDH, SOD, MDA, GSH-Px, AChE, CAT, and T-AOC were detected by kits. The expression of sirtuin1/Nrf2/HO-1 was detected by RT-qPCR and Western blot.

Results: PC12 cells in the control group grew quickly and adhered well to the wall, most of which had extended long axons and easily grew into clusters. In the model group, cells were significantly damaged and the number of cells was significantly reduced. It was found that PC12 cells were swollen, rounded, protruding, and retracting, with reduced adherent function and floating phenomenon. Quercetin could increase the survival rate and proliferation rate of PC12 cells; reduce the levels of LDH, AChE, MDA, and HO-1 protein; and increase the levels of SOD, GSH-Px, CAT, T-AOC, sirtuin1, and Nrf2 protein.

Conclusion: Quercetin can increase the survival rate of PC12 injured by Aβ25-35, promote cell proliferation, and antagonize the toxicity of Aβ; it also has certain neuroprotective effects. Therefore, quercetin is expected to become a drug for the treatment of AD.}, } @article {pmid32418629, year = {2020}, author = {Yliranta, A and Jehkonen, M}, title = {Limb and face apraxias in frontotemporal dementia: A systematic scoping review.}, journal = {Cortex; a journal devoted to the study of the nervous system and behavior}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.cortex.2020.03.023}, pmid = {32418629}, issn = {1973-8102}, abstract = {PURPOSE: To investigate the literature for frequencies, profiles and neural correlates of limb and face apraxias in frontotemporal dementia (FTD).

METHOD: The search conducted in Ovid Medline, PsycINFO and Scopus yielded 487 non-duplicate records, and 43 were included in the final analysis.

RESULTS: Apraxias are evident in diverse forms in all clinical variants of FTD within the first four years of the disease. Face apraxia and productive limb apraxia co-occur in the behavioural and nonfluent variants. The logopenic variant resembles Alzheimer's disease in terms of pronounced parietal limb apraxia and absence of face apraxia. The semantic variant exhibits conceptual praxis deficits together with relatively preserved imitation skills. Concerning the genetic variants of FTD, productive limb apraxia is common among carriers of the progranulin gene mutation, and subtle gestural alterations have been documented among carriers of the chromosome 9 open reading frame 72 gene mutation before the expected disease onset. The data on neural correlations suggest that the breakdown of praxis results from bilateral cortical and subcortical damage in FTD and that Alzheimer-type pathology of the cerebrospinal fluid increases the severity of limb apraxia in all of the variants. Face apraxia correlates with degeneration of the medial and superior frontal cortices.

CONCLUSIONS: Each of the clinical variants of FTD exhibits a characteristic profile of apraxias that may support early differentiation between the variants and from Alzheimer's disease. However, the screening procedures developed for stroke populations seem insufficient, and a multifaceted assessment tool is needed. Although valid and practical tests already exist for dementia populations, a concise selection of test items that covers all of the critical domains is called for.}, } @article {pmid32417775, year = {2020}, author = {Amariglio, RE and Buckley, RF and Rabin, JS and Papp, KV and Quiroz, YT and Mormino, EC and Sparks, KP and Johnson, KA and Rentz, DM and Sperling, RA}, title = {Examining Cognitive Decline Across Black and White Participants in the Harvard Aging Brain Study.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {}, doi = {10.3233/JAD-191291}, pmid = {32417775}, issn = {1875-8908}, abstract = {BACKGROUND: Black Americans are approximately twice as likely to develop dementia as compared to White Americans and the magnitude of this disparity is often attributed to a variety of factors that include psychosocial and vascular risk factors. However, less is known about the potential contribution of Alzheimer's disease pathological differences.

OBJECTIVE: To examine potential differences incross-sectional and longitudinal cognitive performance in black and white participants who were clinically normal at baseline.

METHODS: 296 participants (48 African-American/black participants) underwent MRI and amyloid PET at baseline. Linear mixed models were used to examine the main effects of race, years of education, reading ability, Framingham Heart Study cardiovascular risk score (FHS-CVD), white matter hyperintensities (WMH), and amyloid (Aβ) burden on the Preclinical Alzheimer Cognitive Composite-5 (PACC5).

RESULTS: Lower levels of educationalattainment and reading ability were found for blacks compared to whites. By contrast, no differences in FHS-CVD, WMH, or Aβ were found by racial group. Baseline differences in PACC5 score were attenuated after adjusting for educationalfactors, vascular factors, and Aβ, but remained lower for blacks compared to whites (β= -0.24, p = 0.014). Further, blacks demonstrated a faster rate of PACC5 decline longitudinally compared to whites (β = -0.055, p = 0.025) after adjusting for covariates.

CONCLUSION: Accounting for educationalfactors, vascular factors, and Aβ burden diminished, but did not eliminate, racial differences in PACC5 performance longitudinally. Understanding potential differences in longitudinal cognitive outcomes by race may be important for upcoming secondary prevention trials.}, } @article {pmid32417703, year = {2020}, author = {Hallett, M and de Haan, W and Deco, G and Dengler, R and Di Iorio, R and Gallea, C and Gerloff, C and Grefkes, C and Helmich, RC and Kringelbach, ML and Miraglia, F and Rektor, I and Strýček, O and Vecchio, F and Volz, LJ and Wu, T and Rossini, PM}, title = {Human brain connectivity: Clinical applications for clinical neurophysiology.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {131}, number = {7}, pages = {1621-1651}, doi = {10.1016/j.clinph.2020.03.031}, pmid = {32417703}, issn = {1872-8952}, abstract = {This manuscript is the second part of a two-part description of the current status of understanding of the network function of the brain in health and disease. We start with the concept that brain function can be understood only by understanding its networks, how and why information flows in the brain. The first manuscript dealt with methods for network analysis, and the current manuscript focuses on the use of these methods to understand a wide variety of neurological and psychiatric disorders. Disorders considered are neurodegenerative disorders, such as Alzheimer disease and amyotrophic lateral sclerosis, stroke, movement disorders, including essential tremor, Parkinson disease, dystonia and apraxia, epilepsy, psychiatric disorders such as schizophrenia, and phantom limb pain. This state-of-the-art review makes clear the value of networks and brain models for understanding symptoms and signs of disease and can serve as a foundation for further work.}, } @article {pmid32416463, year = {2020}, author = {Ricci, M and Todino, V and Magarelli, M and Montecucco, I and Ruggeri, M and Gerace, C and Blundo, C}, title = {Spect-neuropsychology correlations in very mild Alzheimer's disease and amnesic mild cognitive impairment.}, journal = {Archives of gerontology and geriatrics}, volume = {89}, number = {}, pages = {104085}, doi = {10.1016/j.archger.2020.104085}, pmid = {32416463}, issn = {1872-6976}, abstract = {BACKGROUND: The purpose of this study was to explore the clinical and brain functional abnormalities in patients with mild Alzheimer's Disease (AD) and patients with amnesic Mild Cognitive Impairment (aMCI).

METHODS: we used resting spect-neuropsychology correlations method.

RESULTS: We found that parieto-temporal associative cortex, mainly involving the inferior parietal lobule, posterior cingulate and middle temporal gyrus, is compromised early in AD. These results suggest that the dysfunction in these areas contributes to cognitive decline in the storage of verbal information, drawing abilities and non-verbal abstract reasoning in AD. The aMCI group showed hypoperfusion primarily involving the frontal areas bilaterally, and this correlated with the impairment in free delayed recall on a verbal memory task.

CONCLUSION: Our results underlie the clinical differences between AD and aMCI patients that might reflect the involvement of different degenerative mechanisms in these groups.}, } @article {pmid32416386, year = {2020}, author = {Mai, N and Wu, Y and Zhong, X and Chen, B and Zhang, M and Ning, Y}, title = {Determining the effects of LLD and MCI on brain decline according to machine learning and a structural covariance network analysis.}, journal = {Journal of psychiatric research}, volume = {126}, number = {}, pages = {43-54}, doi = {10.1016/j.jpsychires.2020.04.011}, pmid = {32416386}, issn = {1879-1379}, abstract = {BACKGROUND: Late-life depression (LLD) and mild cognitive impairment (MCI) are risk factors for Alzheimer disease (AD). However, the interactive effect between LLD and MCI in the progression to AD remains unknown. The purpose of this research is to clarify whether this interaction exists and determined the characteristics of the structural change patterns in LLD and MCI.

METHOD: To address this question, a total 225 participants (91 with intact cognitive function (IC), 34 with MCI, 35 with LLD-IC, 47 with LLD-MCI and 18 with AD) were recruited for the current study and their T1 scanning were acquired. Machine learning was applied to estimate the brain's age gap according to grey matter information (thickness and volume was calculated based on the Human Connectome Project Multi-Modal Parcellation version 1.0 and the Desikan atlas). A structural covariance network (SCN) was constructed based on grey matter volume. Rich-club analysis, global network properties and the Jaccard distance were utilized to describe the topological features in each cohort. Their cognitive functions (executive function, processing speed and memory) were evaluated by a full-scale battery of neuropsychological tests.

RESULT: The interactive effect between LLD and MCI was detected through the brain age gap. The estimated age was positively correlated with processing speed and memory in LLD and non-LLD subjects. In the SCN analysis, the rich-club coefficient and global network properties were disrupted in the MCI group, but remained normal in the LLD-IC, LLD-MCI and AD groups. There was a significant discrepancy in brain structural change patterns between the AD and other cohorts by the Jaccard distance.

CONCLUSION: The application of machine learning reflects that synergies between LLD and MCI could increase the risk of developing AD. According to the SCN, the structural coordination was disrupted in MCI and was kept normal in the other cohorts, while the discrepancies in brain structural change patterns appeared in AD. Overall, the brain age gap could be a potential predictor of AD, and the Jaccard distance has the potential to be a new type of SCN analysis indicator.}, } @article {pmid32415390, year = {2020}, author = {Garnier-Crussard, A and Taki, A and Bonnefoy, M and Bar, JY and Krolak-Salmon, P and Cotton, F and Gilbert, T}, title = {Cerebral amyloid angiopathy with focal presentation-about 3 cases.}, journal = {Neuroradiology}, volume = {}, number = {}, pages = {}, doi = {10.1007/s00234-020-02450-8}, pmid = {32415390}, issn = {1432-1920}, abstract = {Cerebral amyloid angiopathy (CAA) is a common cerebrovascular disease involved in ischemic and hemorrhagic strokes, and its progression is correlated to cognitive decline. In vivo diagnosis of CAA is guided by the modified Boston criteria, with the presence of multiple intracerebral hemorrhage or cerebral microbleeds (CMB), or single hemorrhage and cortical superficial siderosis. The diagnosis of CAA is highly dependent on the quality of imaging and the advent of susceptibility-weighted imaging (SWI) sequences has improved sensitivity of MRI to detect hemosiderin deposition and CMB, hallmarks of CAA. We report here 3 clinical cases of patients with Alzheimer's disease and a focal form (i.e., not disseminated) of probable CAA, diagnosed with SWI sequences. Focal CAA may require closer attention and could offer keys in the understanding of both Alzheimer's disease and CAA pathogenesis.}, } @article {pmid32415209, year = {2020}, author = {Holm, H and Nägga, K and Nilsson, ED and Ricci, F and Melander, O and Hansson, O and Bachus, E and Fedorowski, A and Magnusson, M}, title = {High circulating levels of midregional proenkephalin A predict vascular dementia: a population-based prospective study.}, journal = {Scientific reports}, volume = {10}, number = {1}, pages = {8027}, pmid = {32415209}, issn = {2045-2322}, abstract = {Midregional Pro-enkephalin A (MR-PENK A) and N-terminal Protachykinin A (NT-PTA) have been associated with vascular dementia. However, the longitudinal relationship between these biomarkers and incident dementia has not been fully investigated. In the population-based Malmö Preventive Project, circulating levels of MR-PENK A and NT-PTA were determined in a random sample of 5,323 study participants (mean age: 69 ± 6 years) who were followed-up over a period of 4.6 ± 1.6 years. The study sample included 369 patients (7%) who were diagnosed in the same period with dementia. We analyzed relationship of MR-PENK A and NT-PTA with the risk of developing dementia by using multivariable-adjusted Cox regression models adjusted for traditional risk factors. Increased plasma levels of MR-PENK A were associated with higher risk of incident vascular dementia whereas no associations were found with all-cause or Alzheimer dementia. The risk of vascular dementia was mainly conferred by the highest quartile of MR-PENK as compared with lower quartiles. Elevated levels of NT-PTA yielded significant association with all-cause dementia or dementia subtypes. Elevated plasma concentration of MR-PENK A independently predicts vascular dementia in the general population. MR-PENK A may be used as an additional tool for identifying vascular subtype in ambiguous dementia cases.}, } @article {pmid32414946, year = {2020}, author = {Barthel, H and Seibyl, J and Lammertsma, AA and Villemagne, VL and Sabri, O}, title = {Exploiting the Full Potential of Beta-Amyloid and Tau PET Imaging for Drug Efficacy Testing.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {}, number = {}, pages = {}, doi = {10.2967/jnumed.119.228346}, pmid = {32414946}, issn = {1535-5667}, } @article {pmid32413985, year = {2020}, author = {Catalán-García, M and García-García, FJ and Moreno-Lozano, PJ and Alcarraz-Vizán, G and Tort-Merino, A and Milisenda, JC and Cantó-Santos, J and Barcos-Rodríguez, T and Cardellach, F and Lladó, A and Novials, A and Garrabou, G and Grau-Junyent, JM}, title = {Mitochondrial Dysfunction: A Common Hallmark Underlying Comorbidity between sIBM and Other Degenerative and Age-Related Diseases.}, journal = {Journal of clinical medicine}, volume = {9}, number = {5}, pages = {}, pmid = {32413985}, issn = {2077-0383}, support = {PIE14/00061//Integrated Projects of Excellence/ ; PERIS SLT008/18/00061//CERCA programs from the Generalitat de Catalunya/ ; PI1800498//Instituto de Salud Carlos III/ ; PI1800451//Instituto de Salud Carlos III/ ; 2017 SGR 893//Fundación Cellex/ ; PERIS SLT008/18/00061//Departament de Salut, Generalitat de Catalunya/ ; }, abstract = {Sporadic inclusion body myositis (sIBM) is an inflammatory myopathy associated, among others, with mitochondrial dysfunction. Similar molecular features are found in Alzheimer's disease (AD) and Type 2 Diabetes Mellitus (T2DM), underlying potential comorbidity. This study aims to evaluate common clinical and molecular hallmarks among sIBM, AD, and T2DM. Comorbidity with AD was assessed in n = 14 sIBM patients by performing neuropsychological and cognitive tests, cranial magnetic resonance imaging, AD cerebrospinal fluid biomarkers (levels of amyloid beta, total tau, and phosphorylated tau at threonine-181), and genetic apolipoprotein E genotyping. In the same sIBM cohort, comorbidity with T2DM was assessed by collecting anthropometric measures and performing an oral glucose tolerance test and insulin determinations. Results were compared to the standard population and other myositis (n = 7 dermatomyositis and n = 7 polymyositis). Mitochondrial contribution into disease was tested by measurement of oxidative/anaerobic and oxidant/antioxidant balances, respiration fluxes, and enzymatic activities in sIBM fibroblasts subjected to different glucose levels. Comorbidity of sIBM with AD was not detected. Clinically, sIBM patients showed signs of misbalanced glucose homeostasis, similar to other myositis. Such misbalance was further confirmed at the molecular level by the metabolic inability of sIBM fibroblasts to adapt to different glucose conditions. Under the standard condition, sIBM fibroblasts showed decreased respiration (0.71 ± 0.08 vs. 1.06 ± 0.04 nmols O2/min; p = 0.024) and increased anaerobic metabolism (5.76 ± 0.52 vs. 3.79 ± 0.35 mM lactate; p = 0.052). Moreover, when glucose conditions were changed, sIBM fibroblasts presented decreased fold change in mitochondrial enzymatic activities (-12.13 ± 21.86 vs. 199.22 ± 62.52 cytochrome c oxidase/citrate synthase ratio; p = 0.017) and increased oxidative stress per mitochondrial activity (203.76 ± 82.77 vs. -69.55 ± 21.00; p = 0.047), underlying scarce metabolic plasticity. These findings do not demonstrate higher prevalence of AD in sIBM patients, but evidences of prediabetogenic conditions were found. Glucose deregulation in myositis suggests the contribution of lifestyle conditions, such as restricted mobility. Additionally, molecular evidences from sIBM fibroblasts confirm that mitochondrial dysfunction may play a role. Monitoring T2DM development and mitochondrial contribution to disease in myositis patients could set a path for novel therapeutic options.}, } @article {pmid32413735, year = {2020}, author = {Nasseri, B and Zareian, P and Alizade, H}, title = {Apelin attenuates streptozotocin-induced learning and memory impairment by modulating necroptosis signaling pathway.}, journal = {International immunopharmacology}, volume = {84}, number = {}, pages = {106546}, doi = {10.1016/j.intimp.2020.106546}, pmid = {32413735}, issn = {1878-1705}, abstract = {Apelin is a neuropeptide that plays an important role in neuronal protection. In this study, we investigated the effects of apelin intracerebroventricular administration on spatial learning and memory-related behaviors, and necroptosis signaling pathways in the hippocampus of streptozotocin (STZ) -injected rats. Apelin treatment was implemented following STZ-induced dementia for 15 days. After conducting a behavioral test (Morris Water Maze), the cellular and molecular aspects were examined to detect the apelin effect on the necroptosis signaling pathway. We demonstrated that STZ administration significantly slowed down the learning capability. However apelin treatment notably reversed this neuroinflammation induced behavioral impairment. Furthermore, molecular investigations showed that apelin treatment reduced the hippocampal RIP1, RIP3, and TNF-α level. Our results suggest that apelin treatment attenuates STZ-induced dementia. This effect may be mediated by inhibition of the necroptosis signaling pathway which seems to be associated with the ability of apelin to reduce central TNF-α level. This data provides evidence of the neuroprotective effect of apelin on STZ-induced learning and memory impairment and characterize some of the underlying mechanisms.}, } @article {pmid32413539, year = {2020}, author = {Leiteritz, A and Baumanns, S and Wenzel, U}, title = {Amyloid-beta (Aβ1-42)-induced paralysis in Caenorhabditis elegans is reduced through NHR-49/PPARalpha.}, journal = {Neuroscience letters}, volume = {730}, number = {}, pages = {135042}, doi = {10.1016/j.neulet.2020.135042}, pmid = {32413539}, issn = {1872-7972}, abstract = {Alzheimer´s disease is a neurodegenerative disorder characterized by the misfolding and aggregation of amyloid β (Aβ). Agonists of peroxisomal proliferator-activated receptors (PPARs) are discussed as anti-amyloidogenic compounds, e.g. due to their cholesterol-lowering activities. In a previous study we have shown in Caenorhabditis elegans expressing human Aβ in muscle cells, that inhibition of steroid-signaling, by RNAi of respective members of the signaling pathway or by reducing cellular cholesterol uptake, both increases the nuclear translocation of the foxo transcription factor DAF-16 and concomitantly reduces Aβ-induced paralysis. Using RNAi in the present study we show that NHR-49/PPARalpha inhibits steroidal-signaling upstream of DAF-9, a cytochrome P450-dependent enzyme which generates dafachronic acids as ligands for the nuclear hormone receptor DAF-12, and upstream of DAF-12 itself. The NHR-49/PPARalpha agonist fenofibrate reduces Aβ-induced paralysis in dependence on nhr-49 and nuclear translocation of DAF-16. In conclusion, activation of NHR-49/PPARalpha inhibits the steroidal-signaling pathway which increases the nuclear translocation of DAF-16 and inhibits the Aβ-induced phenotype in an Alzheimer model of C. elegans.}, } @article {pmid32413284, year = {2020}, author = {Kibinge, NK and Relton, CL and Gaunt, TR and Richardson, TG}, title = {Characterizing the Causal Pathway for Genetic Variants Associated with Neurological Phenotypes Using Human Brain-Derived Proteome Data.}, journal = {American journal of human genetics}, volume = {106}, number = {6}, pages = {885-892}, pmid = {32413284}, issn = {1537-6605}, abstract = {Leveraging high-dimensional molecular datasets can help us develop mechanistic insight into associations between genetic variants and complex traits. In this study, we integrated human proteome data derived from brain tissue to evaluate whether targeted proteins putatively mediate the effects of genetic variants on seven neurological phenotypes (Alzheimer disease, amyotrophic lateral sclerosis, depression, insomnia, intelligence, neuroticism, and schizophrenia). Applying the principles of Mendelian randomization (MR) systematically across the genome highlighted 43 effects between genetically predicted proteins derived from the dorsolateral prefrontal cortex and these outcomes. Furthermore, genetic colocalization provided evidence that the same causal variant at 12 of these loci was responsible for variation in both protein and neurological phenotype. This included genes such as DCC, which encodes the netrin-1 receptor and has an important role in the development of the nervous system (p = 4.29 × 10-11 with neuroticism), as well as SARM1, which has been previously implicated in axonal degeneration (p = 1.76 × 10-08 with amyotrophic lateral sclerosis). We additionally conducted a phenome-wide MR study for each of these 12 genes to assess potential pleiotropic effects on 700 complex traits and diseases. Our findings suggest that genes such as SNX32, which was initially associated with increased risk of Alzheimer disease, may potentially influence other complex traits in the opposite direction. In contrast, genes such as CTSH (which was also associated with Alzheimer disease) and SARM1 may make worthwhile therapeutic targets because they did not have genetically predicted effects on any of the other phenotypes after correcting for multiple testing.}, } @article {pmid32410494, year = {2020}, author = {Volicer, L}, title = {Importance of Distinguishing Reactive and Proactive Aggression in Dementia Care.}, journal = {Journal of geriatric psychiatry and neurology}, volume = {}, number = {}, pages = {891988720924706}, doi = {10.1177/0891988720924706}, pmid = {32410494}, issn = {0891-9887}, abstract = {Aggressive behavior is one of the most disturbing symptoms of Alzheimer disease and other progressive neurodegenerative dementias. Development of strategies for management of aggressive behaviors in people with dementia is hindered by a lack of recognition that aggression is not a uniform behavioral construct. It is possible to distinguish 2 types of aggression: reactive or impulsive aggression and proactive or premeditated aggression. Research concerning aggressive behaviors in people with dementia is hindered by scales describing behavioral symptoms of dementia which do not distinguish between reactive and proactive aggressions because they do not consider the factors leading to these behaviors. Reactive aggression is caused by lack of understanding, leading to rejection of care, while proactive aggression could be caused by a psychopathic personality, hallucinations or delusions, and other determinants. It is difficult to underestimate the importance of distinguishing reactive and proactive aggressions in people with dementia because there are different strategies that can be used for management of these behaviors. For reactive aggression, delayed treatment, distraction, improved communication, and change in treatment strategy is useful, while antipsychotic medication may be needed for treatment of proactive aggression. Dementia is increasing the risk of both types of aggressions and antidepressant treatment can be helpful. Most importantly, persons exhibiting reactive aggression should not be labeled "aggressors" because this behavior could be caused by unmet persons' needs, pain and poor communication with care providers.}, } @article {pmid32410488, year = {2020}, author = {Radakovic, R and Colville, S and Cranley, D and Starr, JM and Pal, S and Abrahams, S}, title = {Multidimensional Apathy in Behavioral Variant Frontotemporal Dementia, Primary Progressive Aphasia, and Alzheimer Disease.}, journal = {Journal of geriatric psychiatry and neurology}, volume = {}, number = {}, pages = {891988720924716}, doi = {10.1177/0891988720924716}, pmid = {32410488}, issn = {0891-9887}, abstract = {Apathy is prevalent in dementia, such as behavioral variant frontotemporal dementia (bvFTD), primary progressive aphasia (PPA), and Alzheimer disease (AD). As a multidimensional construct, it can be assessed and subsumed under a Dimensional Apathy Framework. A consistent apathy profile in bvFTD and PPA has yet to be established. The aim was to explore apathy profiles and awareness in bvFTD, PPA, and AD. A total of 12 patients with bvFTD, 12 patients with PPA, 28 patients with AD, and 20 matched controls, as well as their informants/carers, were recruited. All participants completed the Dimensional Apathy Scale (DAS), assessing executive, emotional, and initiation apathy subtypes, a 1-dimensional apathy measure, depression measure, and functional and cognitive screens. Apathy subtype awareness was determined through DAS informant/carer and self-rating discrepancy. Apathy profile comparison showed patients with bvFTD had significantly higher emotional apathy than patients with AD (P < .01) and significantly higher apathy over all subtypes than patients with PPA (Ps < .05). Additionally, patients with bvFTD had significantly lower awareness for emotional apathy (P < .01) when compared to patients with AD and PPA. All patient groups had significant global apathy over all subtypes compared to controls. The emergent apathy profile for bvFTD seems to be emotional apathy (indifference or emotional/affective neutrality), with lower self-awareness in this subtype. Further, lower self-awareness for executive apathy (lack of motivation for planning, organization, or attention) differentiates bvFTD from PPA. Future research should investigate the cognitive and neural correlates as well as the practical impact of apathy subtypes.}, } @article {pmid32407731, year = {2020}, author = {Suryadevara, V and Kluppel, M and Monte, FD and Willis, MS}, title = {The Unraveling: Cardiac and Musculoskeletal Defects and Their Role in Common Alzheimer Disease Morbidity and Mortality.}, journal = {The American journal of pathology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ajpath.2020.04.013}, pmid = {32407731}, issn = {1525-2191}, abstract = {Alzheimer disease (AD) is characterized by deterioration of cognitive capabilities, and an estimated 44 million people worldwide are living with the disease. Beyond memory deficits, the most common AD co-morbidities include swallowing defects (muscle), fractures (bone, muscle), and heart failure. The underlying causes of these co-morbidities and their role in AD pathophysiology are currently unknown. This review is the first to summarize the emerging picture of the cardiac and musculoskeletal deficits in human AD. We present the involvement of the heart, characterized by diastolic heart failure, the presence of amyloid deposits, and electrophysiological changes, compared with age-matched control subjects. The characteristic musculoskeletal defects in AD come from recent clinical studies and include potential underlying mechanisms (bone) in animal models. These studies detail a primary muscle weakness (without a loss of muscle mass) in patients with mild cognitive impairment, with progression of cognitive impairment to AD associating with ongoing muscle weakness and the onset of muscle atrophy. We conclude by reviewing the loss of bone density in patients with AD, paralleling the increase in fracture and fall risk in specific populations. These studies paint AD as a systemic disease in broad strokes, which may help elucidate AD pathophysiology and to allow for new ways of thinking about therapeutic interventions, diagnostic biomarkers, and the pathogenesis of this multidisciplinary disease.}, } @article {pmid32405969, year = {2020}, author = {Bhatt, T and Patel, K}, title = {Carotenoids: Potent to Prevent Diseases Review.}, journal = {Natural products and bioprospecting}, volume = {10}, number = {3}, pages = {109-117}, doi = {10.1007/s13659-020-00244-2}, pmid = {32405969}, issn = {2192-2195}, abstract = {Carotenoids are the phytochemicals known for their biological activities. They are found in nature in the form of plants, algae, fungi and in microorganisms. This is the major group having two different structure one with oxygen and without oxygen. The Present article aims to present these molecules as a new therapeutic agent, as it has unrealized efficiency to prevent and reduce the symptoms of many diseases like cancer, neurodegenerative diseases such as Alzheimer, cerebral ischemia, diabetes associated with obesity and hypertension, ophthalmic diseases and many more. It can be utilized in the form of dietary supplement as nutraceutical and pharmaceutical compounds. Yet more research and developing test knowledge is needed to make it available to the humans. In this article its sources, biosynthesis, properties, applicability and commercialization of pigments from naturally produced sources are discussed.}, } @article {pmid32402618, year = {2020}, author = {Formica, C and Bonanno, L and Todaro, A and Marra, A and Alagna, A and Corallo, F and Marino, S and Bramanti, A and De Salvo, S}, title = {The role of mind theory in patients affected by neurodegenerative disorders and impact on caregiver burden.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jocn.2020.05.028}, pmid = {32402618}, issn = {1532-2653}, abstract = {BACKGROUND: Theory of Mind (ToM) is defined as the ability to understand mental and emotional state. This ability is assessed also in neurodegenerative disease. Few studies have investigated the impact that social cognition of patients could have on caregiver burden. The aim of this study was to investigate a possible correlation in level of social cognition impairment between patients with different neurodegenerative disorders and their caregivers with possible impact on caregivers burden.

METHODS: we enrolled 48 patients with dementia divided in different groups: Fronto-Temporal Dementia (FTD), Alzheimer Disease (AD), and Mild Cognitive Impairment (MCI) and also the three groups of their respective caregivers. All subjects were submitted to ToM tests, and the caregiver groups also to Caregiver Burden Inventory (CBI) to evaluate level of burden.

RESULTS: Our results showed that ToM was more impaired in FTD patients and in their caregivers In addition, FTD group showed more impaired performances in tasks related to emotional skills.

CONCLUSIONS: We suggested that ToM impairment of patients are related to ToM impairment of caregivers with differences of scores in caregiver groups. The caregiver difficulties to understand, attribute and describe emotional and mental states of their relatives develop distress and inability in burden management and disorders relative to neurodegenerative disease.}, } @article {pmid32402239, year = {2020}, author = {Kim, JT and Jedrychowski, MP and Wei, W and Fernandez, D and Fischer, CR and Banik, SM and Spiegelman, BM and Long, JZ}, title = {A Plasma Protein Network Regulates PM20D1 and N-Acyl Amino Acid Bioactivity.}, journal = {Cell chemical biology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.chembiol.2020.04.009}, pmid = {32402239}, issn = {2451-9448}, abstract = {N-acyl amino acids are a family of cold-inducible circulating lipids that stimulate thermogenesis. Their biosynthesis is mediated by a secreted enzyme called PM20D1. The extracellular mechanisms that regulate PM20D1 or N-acyl amino acid activity in the complex environment of blood plasma remains unknown. Using quantitative proteomics, here we show that PM20D1 circulates in tight association with both low- and high-density lipoproteins. Lipoprotein particles are powerful co-activators of PM20D1 activity in vitro and N-acyl amino acid biosynthesis in vivo. We also identify serum albumin as a physiologic N-acyl amino acid carrier, which spatially segregates N-acyl amino acids away from their sites of production, confers resistance to hydrolytic degradation, and establishes an equilibrium between thermogenic "free" versus inactive "bound" fractions. These data establish lipoprotein particles as principal extracellular sites of N-acyl amino acid biosynthesis and identify a lipoprotein-albumin network that regulates the activity of a circulating thermogenic lipid family.}, } @article {pmid32402127, year = {2020}, author = {Bersini, S and Arrojo E Drigo, R and Huang, L and Shokhirev, MN and Hetzer, MW}, title = {Transcriptional and Functional Changes of the Human Microvasculature during Physiological Aging and Alzheimer Disease.}, journal = {Advanced biosystems}, volume = {4}, number = {5}, pages = {e2000044}, doi = {10.1002/adbi.202000044}, pmid = {32402127}, issn = {2366-7478}, abstract = {Aging of the circulatory system correlates with the pathogenesis of a large spectrum of diseases. However, it is largely unknown which factors drive the age-dependent or pathological decline of the vasculature and how vascular defects relate to tissue aging. The goal of the study is to design a multianalytical approach to identify how the cellular microenvironment (i.e., fibroblasts) and serum from healthy donors of different ages or Alzheimer disease (AD) patients can modulate the functionality of organ-specific vascular endothelial cells (VECs). Long-living human microvascular networks embedding VECs and fibroblasts from skin biopsies are generated. RNA-seq, secretome analyses, and microfluidic assays demonstrate that fibroblasts from young donors restore the functionality of aged endothelial cells, an effect also achieved by serum from young donors. New biomarkers of vascular aging are validated in human biopsies and it is shown that young serum induces angiopoietin-like-4, which can restore compromised vascular barriers. This strategy is then employed to characterize transcriptional/functional changes induced on the blood-brain barrier by AD serum, demonstrating the importance of PTP4A3 in the regulation of permeability. Features of vascular degeneration during aging and AD are recapitulated, and a tool to identify novel biomarkers that can be exploited to develop future therapeutics modulating vascular function is established.}, } @article {pmid32401067, year = {2020}, author = {Oguz, M and Kalay, E and Akocak, S and Nocentini, A and Lolak, N and Boga, M and Yilmaz, M and Supuran, CT}, title = {Synthesis of calix[4]azacrown substituted sulphonamides with antioxidant, acetylcholinesterase, butyrylcholinesterase, tyrosinase and carbonic anhydrase inhibitory action.}, journal = {Journal of enzyme inhibition and medicinal chemistry}, volume = {35}, number = {1}, pages = {1215-1223}, pmid = {32401067}, issn = {1475-6374}, abstract = {A series of novel calix[4]azacrown substituted sulphonamide Schiff bases was synthesised by the reaction of calix[4]azacrown aldehydes with different substituted primary and secondary sulphonamides. The obtained novel compounds were investigated as inhibitors of six human (h) isoforms of carbonic anhydrases (CA, EC 4.2.1.1). Their antioxidant profile was assayed by various bioanalytical methods. The calix[4]azacrown substituted sulphonamide Schiff bases were also investigated as inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and tyrosinase enzymes, associated with several diseases such as Alzheimer, Parkinson, and pigmentation disorders. The new sulphonamides showed low to moderate inhibition against hCAs, AChE, BChE, and tyrosinase enzymes. However, some of them possessed relevant antioxidant activity, comparable with standard antioxidants used in the study.}, } @article {pmid32400259, year = {2020}, author = {Alexander, CM and Martyr, A and Savage, SA and Morris, RG and Clare, L}, title = {Measuring Awareness in People With Dementia: Results of a Systematic Scoping Review.}, journal = {Journal of geriatric psychiatry and neurology}, volume = {}, number = {}, pages = {891988720924717}, doi = {10.1177/0891988720924717}, pmid = {32400259}, issn = {0891-9887}, abstract = {BACKGROUND: Awareness of the diagnosis or related changes in functioning varies in people with dementia (PwD), with implications for the well-being of PwD and their carers. Measuring awareness in a clinical setting could facilitate tailored support and optimize involvement in personal health and care decisions. This scoping review aimed to identify validated methods of assessing awareness in dementia and appraise their clinical utility.

METHOD: A systematic search was conducted of English-language publications that measured awareness in PwD, in 6 electronic databases. Search terms included dement*, Alzheimer*, Pick disease, and awareness, unawareness, anosognosia, insight, denial, metacognit*, or discrepanc*.

RESULTS: We screened 30,634 articles, finding 345 articles that met our inclusion criteria. We identified 76 measures, most commonly using a discrepancy questionnaire comparing evaluations of function by PwD and an informant. There were 30 awareness measures developed and validated for use in dementia populations but few designed for general clinical use.

CONCLUSIONS: Although we found a range of clinical indications for measuring awareness, there were few studies investigating clinical applications and few tools designed for clinical purposes. Further investigation and development of a person-centered tool could facilitate health and care choices in mild-to-moderate dementia.}, } @article {pmid32400221, year = {2020}, author = {Lanthier, C and Dallemagne, P and Lecoutey, C and Claeysen, S and Rochais, C}, title = {Therapeutic modulators of the serotonin 5-HT4 receptor: a patent review (2014-present).}, journal = {Expert opinion on therapeutic patents}, volume = {}, number = {}, pages = {1-14}, doi = {10.1080/13543776.2020.1767587}, pmid = {32400221}, issn = {1744-7674}, abstract = {INTRODUCTION: Numerous chemotypes have been described over time in order to generate potent and selective 5-HT4R ligands. Both agonists and antagonists have demonstrated their interest in several disease models. This culminates with the FDA approval of tegaserod and prucalopride in the recent years.

AREAS COVERED: This review summarizes the patent applications from 2014 to present, dedicated to the use or the description of novel 5-HT4R modulators. Several novel ligands and scaffolds have been industrially protected mainly in the field of central nervous system (CNS) pathologies as well as gastrointestinal disorders, including the combination with other drugs or for veterinary uses.

EXPERT OPINION: The therapeutic potential of 5-HT4R modulators has been explored for several years in animal models, but also linked to potential safety issues with initial ligands. The current use of prucalopride in humans demonstrates that its toxicity is not linked to the target and that 5-HT4R modulators are safe in humans. Therefore, an important number of studies and patents has continued in the recent years to expand the use of 5-HT4R modulators, not only to treat gastrointestinal disorders, but also for CNS pathologies. This article details current efforts in this development.}, } @article {pmid32398359, year = {2020}, author = {Mattsson-Carlgren, N and Leuzy, A and Janelidze, S and Palmqvist, S and Stomrud, E and Strandberg, O and Smith, R and Hansson, O}, title = {The implications of different approaches to define AT(N) in Alzheimer disease.}, journal = {Neurology}, volume = {94}, number = {21}, pages = {e2233-e2244}, doi = {10.1212/WNL.0000000000009485}, pmid = {32398359}, issn = {1526-632X}, abstract = {OBJECTIVE: To compare different β-amyloid (Aβ), tau, and neurodegeneration (AT[N]) variants within the Swedish BioFINDER studies.

METHODS: A total of 490 participants were classified into AT(N) groups. These include 53 cognitively unimpaired (CU) and 48 cognitively impaired (CI) participants (14 mild cognitive impairment [MCI] and 34 Alzheimer disease [AD] dementia) from BioFINDER-1 and 389 participants from BioFINDER-2 (245 CU and 144 CI [138 MCI and 6 AD dementia]). Biomarkers for A were CSF Aβ42 and amyloid-PET ([18F]flutemetamol); for T, CSF phosphorylated tau (p-tau) and tau PET ([18F]flortaucipir); and for (N), hippocampal volume, temporal cortical thickness, and CSF neurofilament light (NfL). Binarization of biomarkers was achieved using cutoffs defined in other cohorts. The relationship between different AT(N) combinations and cognitive trajectories (longitudinal Mini-Mental State Examination scores) was examined using linear mixed modeling and coefficient of variation.

RESULTS: Among CU participants, A-T-(N)- or A+T-(N)- variants were most common. However, more T+ cases were seen using p-tau than tau PET. Among CI participants, A+T+(N)+ was more common; however, more (N)+ cases were seen for MRI measures relative to CSF NfL. Tau PET best predicted longitudinal cognitive decline in CI and p-tau in CU participants. Among CI participants, continuous T (especially tau PET) and (N) measures improved the prediction of cognitive decline compared to binary measures.

CONCLUSIONS: Our findings show that different AT(N) variants are not interchangeable, and that optimal variants differ by clinical stage. In some cases, dichotomizing biomarkers may result in loss of important prognostic information.}, } @article {pmid32397415, year = {2020}, author = {Turkez, H and Cacciatore, I and Arslan, ME and Fornasari, E and Marinelli, L and Di Stefano, A and Mardinoglu, A}, title = {Histidyl-Proline Diketopiperazine Isomers as Multipotent Anti-Alzheimer Drug Candidates.}, journal = {Biomolecules}, volume = {10}, number = {5}, pages = {}, pmid = {32397415}, issn = {2218-273X}, abstract = {Cyclic dipeptides administered by both parenteral and oral routes are suggested as promising candidates for the treatment of neurodegeneration-related pathologies. In this study, we tested Cyclo (His-Pro) isomers (cHP1-4) for their anti-Alzheimer potential using a differentiated human neuroblastoma cell line (SH-SY5Y) as an Alzheimer's disease (AD) experimental model. The SH-SY5Y cell line was differentiated by the application of all-trans retinoic acid (RA) to obtain mature neuron-like cells. Amyloid-beta 1-42 (Aβ1-42) peptides, the main effector in AD, were administered to the differentiated cell cultures to constitute the in vitro disease model. Next, we performed cell viability analyses 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) release assays) to investigate the neuroprotective concentrations of cyclodipeptides using the in vitro AD model. We evaluated acetylcholinesterase (AChE), α- and β-secretase activities (TACE and BACE1), antioxidant potency, and apoptotic/necrotic properties and performed global gene expression analysis to understand the main mechanism behind the neuroprotective features of cHP1-4. Moreover, we conducted sister chromatid exchange (SCE), micronucleus (MN), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) analyses to evaluate the genotoxic damage potential after applications with cHP1-4 on cultured human lymphocytes. Our results revealed that cHP1-4 isomers provide a different degree of neuroprotection against Aβ1-42-induced cell death on the in vitro AD model. The applications with cHP1-4 isomers altered the activity of AChE but not the activity of TACE and BACE1. Our analysis indicated that the cHP1-4 increased the total antioxidant capacity without altering total oxidative status levels in the cellular AD model and that cHP1-4 modulated the alterations of gene expressions by Aβ1-42 exposure. We also observed that cHP1-4 exhibited noncytotoxic and non-genotoxic features in cultured human whole blood cells. In conclusion, cHP1-4 isomers, especially cHP4, have been explored as novel promising therapeutics against AD.}, } @article {pmid32396777, year = {2020}, author = {Beeri, MS and Uribarri, J and Cai, W and Buchman, AS and Haroutunian, V}, title = {Human Brain and Serum Advanced Glycation End Products are Highly Correlated: Preliminary Results of Their Role in Alzheimer Disease and Type 2 Diabetes.}, journal = {Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists}, volume = {26}, number = {5}, pages = {576-577}, doi = {10.4158/1934-2403-26.5.576}, pmid = {32396777}, issn = {1530-891X}, } @article {pmid32396016, year = {2020}, author = {Namdar Khatibani, M and Mehri, A and Jalaie, S and Dastjerdi Kazemi, M}, title = {Developing Verb Picture Naming Test for Persian adults and determining its psychometric properties.}, journal = {Applied neuropsychology. Adult}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/23279095.2020.1762085}, pmid = {32396016}, issn = {2327-9109}, abstract = {There are a few standardized assessment tools in Persian language. The present study was carried out to develop a Verb Picture Naming Test and assessing its psychometric properties. In this cross-sectional study, a total of 230 verbs were selected based on their frequency, familiarity, age of acquisition, visual complexity, name agreement, image agreement, syllable length, transitivity, and compound or simple verbs. To determine content and face validity, 230 pictures of verbs were given to 15 experts, and then 180 final pictures were divided into original and parallel versions. Both versions of the test were performed on 50 healthy adults and 20 patients with Alzheimer's diseases. Results showed that face and content validity of these versions was more than .85 and .98. Intraclass Correlation Coefficient (ICC) for total scores was equal to .98 (p < .001, 95%CI: .97-.99) and .96 (p < .001, 95%CI: .93-.98). Standard Error of Measurement (SEM) and Smallest Detectable Change (SDC) of total scores were equal to .93 and 2.66 in version1 and 1.27 and 3.12 in version 2, respectively. The two versions of Persian Verb Picture Naming Test were found to be valid and reliable, so the clinicians can use it in clinical settings.}, } @article {pmid32393651, year = {2020}, author = {Howdle, GC and Quidé, Y and Kassem, MS and Johnson, K and Rae, CD and Brew, BJ and Cysique, LA}, title = {Brain amyloid in virally suppressed HIV-associated neurocognitive disorder.}, journal = {Neurology(R) neuroimmunology & neuroinflammation}, volume = {7}, number = {4}, pages = {}, doi = {10.1212/NXI.0000000000000739}, pmid = {32393651}, issn = {2332-7812}, abstract = {OBJECTIVE: To determine whether virally suppressed HIV neuropathogenesis, a chronic neuroinflammatory state, promotes abnormal brain amyloid deposition.

METHODS: A total of 10 men with virally suppressed HIV-associated neurocognitive disorder (HAND), aged 46-68 years, underwent 11C-labeled Pittsburgh compound B PET. Data from the Australian Imaging, Biomarkers and Lifestyle (AIBL), including 39 cognitively normal individuals (aged 60-74 years), 7 individuals with mild cognitive impairment (MCI) (aged 64-71 years), and 11 individuals with Alzheimer disease (AD) (aged 55-74 years), were used as reference. Apart from more women, the AIBL cohort was demographically comparable with the HIV sample. Also, the AIBL PET data did not differ by sex. Cerebellum standardized uptake value ratio amyloid values within 22 regions of interest were estimated. In the HIV sample, apolipoprotein E (APOE) was available in 80%, CSF biomarkers in 60%, and 8-10 years of long-term health outcomes in 100%.

RESULTS: HAND and the AIBL group with no cognitive deficits had similar amyloid deposition, which was lower than that in both the MCI and AD groups. At the individual level, one HAND case showed high amyloid deposition consistent with AD. This case also had a CSF-AD-like profile and an E4/E4 for APOE. Clinically, this case declined over 18 years with mild HAND symptoms first, followed by progressive memory decline 8-9 years after the study PET, then progression to severe dementia within 2-3 years, and lived a further 6 years. Another HAND case showed increased amyloid deposition restricted to the hippocampi. Two other HAND cases showed abnormally decreased amyloid in subcortical areas.

CONCLUSIONS: Relative to cognitively normal older controls, brain amyloid burden does not differ in virally suppressed HAND at the group level. However, individual analyses show that abnormally high and low amyloid burden occur.}, } @article {pmid32393395, year = {2020}, author = {Song, Q and Meng, B and Xu, H and Mao, Z}, title = {The emerging roles of vacuolar-type ATPase-dependent Lysosomal acidification in neurodegenerative diseases.}, journal = {Translational neurodegeneration}, volume = {9}, number = {1}, pages = {17}, pmid = {32393395}, issn = {2047-9158}, support = {R01NS107505/NH/NIH HHS/United States ; R01NS095269/NH/NIH HHS/United States ; }, abstract = {BACKGROUND: Lysosomes digest extracellular material from the endocytic pathway and intracellular material from the autophagic pathway. This process is performed by the resident hydrolytic enzymes activated by the highly acidic pH within the lysosomal lumen. Lysosome pH gradients are mainly maintained by the vacuolar (H+) ATPase (or V-ATPase), which pumps protons into lysosomal lumen by consuming ATP. Dysfunction of V-ATPase affects lysosomal acidification, which disrupts the clearance of substrates and leads to many disorders, including neurodegenerative diseases.

MAIN BODY: As a large multi-subunit complex, the V-ATPase is composed of an integral membrane V0 domain involved in proton translocation and a peripheral V1 domain catalyzing ATP hydrolysis. The canonical functions of V-ATPase rely on its H+-pumping ability in multiple vesicle organelles to regulate endocytic traffic, protein processing and degradation, synaptic vesicle loading, and coupled transport. The other non-canonical effects of the V-ATPase that are not readily attributable to its proton-pumping activity include membrane fusion, pH sensing, amino-acid-induced activation of mTORC1, and scaffolding for protein-protein interaction. In response to various stimuli, V-ATPase complex can reversibly dissociate into V1 and V0 domains and thus close ATP-dependent proton transport. Dysregulation of pH and lysosomal dysfunction have been linked to many human diseases, including neurodegenerative disorders such as Alzheimer disease, Parkinson's disease, amyotrophic lateral sclerosis as well as neurodegenerative lysosomal storage disorders.

CONCLUSION: V-ATPase complex is a universal proton pump and plays an important role in lysosome acidification in all types of cells. Since V-ATPase dysfunction contributes to the pathogenesis of multiple neurodegenerative diseases, further understanding the mechanisms that regulate the canonical and non-canonical functions of V-ATPase will reveal molecular details of disease process and help assess V-ATPase or molecules related to its regulation as therapeutic targets.}, } @article {pmid32392471, year = {2020}, author = {Sauerbeck, AD and Gangolli, M and Reitz, SJ and Salyards, MH and Kim, SH and Hemingway, C and Gratuze, M and Makkapati, T and Kerschensteiner, M and Holtzman, DM and Brody, DL and Kummer, TT}, title = {SEQUIN Multiscale Imaging of Mammalian Central Synapses Reveals Loss of Synaptic Connectivity Resulting from Diffuse Traumatic Brain Injury.}, journal = {Neuron}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neuron.2020.04.012}, pmid = {32392471}, issn = {1097-4199}, abstract = {The brain's complex microconnectivity underlies its computational abilities and vulnerability to injury and disease. It has been challenging to illuminate the features of this synaptic network due to the small size and dense packing of its elements. Here, we describe a rapid, accessible super-resolution imaging and analysis workflow-SEQUIN-that quantifies central synapses in human tissue and animal models, characterizes their nanostructural and molecular features, and enables volumetric imaging of mesoscale synaptic networks without the production of large histological arrays. Using SEQUIN, we identify cortical synapse loss resulting from diffuse traumatic brain injury, a highly prevalent connectional disorder. Similar synapse loss is observed in three murine models of Alzheimer-related neurodegeneration, where SEQUIN mesoscale mapping identifies regional synaptic vulnerability. These results establish an easily implemented and robust nano-to-mesoscale synapse quantification and characterization method. They furthermore identify a shared mechanism-synaptopathy-between Alzheimer neurodegeneration and its best-established epigenetic risk factor, brain trauma.}, } @article {pmid32391858, year = {2020}, author = {Leuzy, A and Smith, R and Ossenkoppele, R and Santillo, A and Borroni, E and Klein, G and Ohlsson, T and Jögi, J and Palmqvist, S and Mattsson-Carlgren, N and Strandberg, O and Stomrud, E and Hansson, O}, title = {Diagnostic Performance of RO948 F 18 Tau Positron Emission Tomography in the Differentiation of Alzheimer Disease From Other Neurodegenerative Disorders.}, journal = {JAMA neurology}, volume = {}, number = {}, pages = {}, pmid = {32391858}, issn = {2168-6157}, abstract = {Importance: The diagnostic performance of second-generation tau positron emission tomographic (PET) tracers is not yet known.

Objective: To examine the novel tau PET tracer RO948 F 18 ([18F]RO948) performance in discriminating Alzheimer disease (AD) from non-AD neurodegenerative disorders.

In this diagnostic study, 613 participants in the Swedish BioFINDER-2 study were consecutively enrolled in a prospective cross-sectional study from September 4, 2017, to August 28, 2019. Participants included 257 cognitively unimpaired controls, 154 patients with mild cognitive impairment, 100 patients with AD dementia, and 102 with non-AD neurodegenerative disorders. Evaluation included a comparison of tau PET tracer [18F]RO948 with magnetic resonance imaging (MRI) and cerebrospinal fluid and a head-to-head comparison between [18F]RO948 and flortaucipir F 18 ([18F]flortaucipir) in patients with semantic variant primary progressive aphasia (svPPA).

Exposures: [18F]RO948 (all patients) and [18F]flortaucipir (3 patients with svPPA) tau PET; MRI (hippocampal volume, composite temporal lobe cortical thickness, whole-brain cortical thickness) and cerebrospinal fluid measures (p-tau181 and amyloid Aβ42 and Aβ40 ratio[Aβ42/Aβ40], and Aβ42/p-tau181 ratio).

Main Outcomes and Measures: Standard uptake value ratios (SUVRs) in 4 predefined regions of interest (ROIs) reflecting Braak staging scheme for tau pathology and encompass I-II (entorhinal cortex), III-IV (inferior/middle temporal, fusiform gyrus, parahippocampal cortex, and amygdala), I-IV, and V-VI (widespread neocortical areas), area under the receiver operating characteristic curve (AUC) values, and subtraction images between [18F]RO948 and [18F]flortaucipir.

Results: Diagnostic groups among the 613 participants included cognitively unimpaired (mean [SD] age, 65.8 [12.1] years; 117 men [46%]), mild cognitive impairment (age, 70.8 [8.3] years; 82 men [53%]), AD dementia (age, 73.5 [6.7] years; 57 men [57%]), and non-AD disorders (age, 70.5 [8.6] years; 41 men [40%]). Retention of [18F]RO948 was higher in AD dementia compared with all other diagnostic groups. [18F]RO948 could distinguish patients with AD dementia from individuals without cognitive impairment and those with non-AD disorders, and the highest AUC was obtained using the I-IV ROI (AUC = 0.98; 95% CI, 0.96-0.99 for AD vs no cognitive impairment and AUC = 0.97; 95% CI, 0.95-0.99 for AD vs non-AD disorders), which outperformed MRI (highest AUC = 0.91 for AD vs no cognitive impairment using whole-brain thickness, and AUC = 0.80 for AD vs non-AD disorders using temporal lobe thickness) and cerebrospinal fluid measures (highest AUC = 0.94 for AD vs no cognitive impairment using Aβ42/p-tau181, and AUC = 0.93 for AD vs non-AD disorders using Aβ42/Aβ40). Generally, tau PET positivity using [18F]RO948 was observed only in Aβ-positive cases or in MAPT R406W mutation carriers. Retention of [18F]RO948 was not pronounced in patients with svPPA, and head-to-head comparison revealed lower temporal lobe uptake than with [18F]flortaucipir.

Conclusions and Relevance: In this study, elevated [18F]RO948 SUVRs were most often seen among Aβ-positive cases, which suggests that [18F]RO948 has high specificity for AD-type tau and highlights its potential as a diagnostic marker in the differential diagnosis of AD.}, } @article {pmid32390791, year = {2020}, author = {Cai, C and Huang, C and Yang, C and Lu, H and Hong, X and Ren, F and Hong, D and Ng, E}, title = {Altered Patterns of Functional Connectivity and Causal Connectivity in Salience Subnetwork of Subjective Cognitive Decline and Amnestic Mild Cognitive Impairment.}, journal = {Frontiers in neuroscience}, volume = {14}, number = {}, pages = {288}, pmid = {32390791}, issn = {1662-4548}, abstract = {The subjective cognitive decline (SCD) may last for decades prior to the onset of dementia and has been proposed as a risk population for development to amnestic mild cognitive impairment (aMCI) and Alzheimer disease (AD). Disruptions of functional connectivity and causal connectivity (CC) in the salience network (SN) are generally perceived as prominent hallmarks of the preclinical AD. Nevertheless, the alterations in anterior SN (aSN), and posterior SN (pSN) remain unclear. Here, we hypothesized that both the functional connectivity (FC) and CC of the SN subnetworks, comprising aSN and pSN, were distinct disruptive in the SCD and aMCI. We utilized resting-state functional magnetic resonance imaging to investigate the altered FC and CC of the SN subnetworks in 28 healthy controls, 23 SCD subjects, and 29 aMCI subjects. In terms of altered patterns of FC in SN subnetworks, aSN connected to the whole brain was significantly increased in the left orbital superior frontal gyrus, left insula lobule, right caudate lobule, and left rolandic operculum gyrus (ROG), whereas decreased FC was found in the left cerebellum superior lobule and left middle temporal gyrus when compared with the HC group. Notably, no prominent statistical differences were obtained in pSN. For altered patterns of CC in SN subnetworks, compared to the HC group, the aberrant connections in aMCI group were separately involved in the right cerebellum inferior lobule (CIL), right supplementary motor area (SMA), and left ROG, whereas the SCD group exhibited more regions of aberrant connection, comprising the right superior parietal lobule, right CIL, left inferior parietal lobule, left post-central gyrus (PG), and right angular gyrus. Especially, SCD group showed increased CC in the right CIL and left PG, whereas the aMCI group showed decreased CC in the left pre-cuneus, corpus callosum, and right SMA when compared to the SCD group. Collectively, our results suggest that analyzing the altered FC and CC observed in SN subnetworks, served as impressible neuroimaging biomarkers, may supply novel insights for designing preclinical interventions in the preclinical stages of AD.}, } @article {pmid32390545, year = {2020}, author = {Kurth, S and Wojtasik, V and Lekeu, F and Quittre, A and Olivier, C and Godichard, V and Bastin, C and Salmon, E}, title = {Efficacy of Cognitive Rehabilitation Versus Usual Treatment at Home in Patients With Early Stages of Alzheimer Disease.}, journal = {Journal of geriatric psychiatry and neurology}, volume = {}, number = {}, pages = {891988720924721}, doi = {10.1177/0891988720924721}, pmid = {32390545}, issn = {0891-9887}, abstract = {INTRODUCTION: Assessing the benefit of cognitive rehabilitation (CR) remains difficult.

METHOD: An observational study was conducted in 33 patients with early-stage Alzheimer disease and their caregiver included in a clinical CR program at home, compared to 17 patients who received usual treatment. Evaluation of patient's dependence and objective and subjective caregiver's burden was performed by the caregiver with a research tool focusing on impairment in daily activities related to cognitive deficits.

RESULTS: Repeated measures analysis of variance showed a time by group interaction (P < .05), with decreased patient's dependence for adapted activities at 1 year in the CR group. Lawton scale for daily activities showed also a time by group interaction (P < .05), with increased dependence at 1 year in the control group. There was a significant decrease in Mini-Mental State Examination scores in both groups at 1-year follow-up (P < .05). Concerning caregiver's subjective burden, there was a trend for the time by group interaction (P = .07), and post hoc Tukey test showed that subjective burden was decreased in the CR group (P < .05). This was confirmed by nonparametric Mann-Whitney analysis on differences between follow-up and baseline evaluation (P < .05).

CONCLUSION: This observational study in a clinical setting is in line with the benefit of CR reported in recent randomized controlled trials. The benefit obtained for adapted daily activities remained after 1 year, even if global cognition declined. Moreover, caregiver's subjective burden related to all relevant daily activities evaluated within the CR program was decreased after 1 year in our clinical setting.}, } @article {pmid32388561, year = {2020}, author = {Oakley, DH and Chung, M and Klickstein, N and Commins, C and Hyman, BT and Frosch, MP}, title = {The Alzheimer Disease-Causing Presenilin-1 L435F Mutation Causes Increased Production of Soluble Aβ43 Species in Patient-Derived iPSC-Neurons, Closely Mimicking Matched Patient Brain Tissue.}, journal = {Journal of neuropathology and experimental neurology}, volume = {79}, number = {6}, pages = {592-604}, pmid = {32388561}, issn = {1554-6578}, support = {P30 AG062421/AG/NIA NIH HHS/United States ; }, abstract = {Familial Alzheimer disease-causing mutations in Presenilin 1 (PSEN1) are generally thought to shift the processing of APP toward longer, more amyloidogenic Aβ fragments. However, certain PSEN1 mutations cause severe reduction in gamma secretase function when expressed in the homozygous state, thus challenging the amyloid hypothesis. We sought to evaluate the effects of one such mutation, PSEN1 L435F, in more physiologic conditions and genetic contexts by using human induced pluripotent stem cell (iPSC)-derived neurons from an individual with familial AD (fAD) linked to the PSEN1 L435F mutation, and compared the biochemical phenotype of the iPS-derived neurons with brain tissue obtained at autopsy from the same patient. Our results demonstrate that in the endogenous heterozygous state, the PSEN1 L435F mutation causes a large increase in soluble Aβ43 but does not change the overall levels of soluble Aβ40 or Aβ42 when compared with control iPSC-neurons. Increased pathologically phosphorylated tau species were also observed in PSEN1-mutant iPSC-neurons. Concordant changes in Aβ species were present in autopsy brain tissue from the same patient. Finally, the feasibility of using Aβ43 immunohistochemistry of brain tissue to identify fAD cases was evaluated in a limited autopsy case series with the finding that strong Aβ43 staining occurred only in fAD cases.}, } @article {pmid32388335, year = {2020}, author = {Delpak, A and Talebi, M}, title = {On the impact of age, gender and educational level on cognitive function in Alzheimer's disease: A quantitative approach.}, journal = {Archives of gerontology and geriatrics}, volume = {89}, number = {}, pages = {104090}, doi = {10.1016/j.archger.2020.104090}, pmid = {32388335}, issn = {1872-6976}, abstract = {BACKGROUND: The Mini-Mental State Examination (MMSE) test is a brief and useful tool widely utilized to measure dementia severity. The effects of education, age and gender on the total MMSE scores are less well-understood. Also, there are few studies about cognitive domains involvement in Alzheimer's disease and the effects of demographic factors on it. The aim of this study is to assess the relationship between seven areas of cognitive function in the MMSE test with age, gender and education level.

METHODS: In this study, 182 patients with Alzheimer (125 women and 57 men) were evaluated. We investigated the impact of age, sex and education on total score of MMSE and each areas of cognitive function. The results were analyzed by MATLAB software.

RESULTS: The most cognitive domain that was impaired in the MMSE test was orientation to time. Moreover, the most involved cognitive areas based on age, gender and educational level were recall, orientation to place and language, respectively.

CONCLUSION: We found that there were meaningful correlations between the demographic factors and subsets of the MMSE score.}, } @article {pmid32387717, year = {2020}, author = {Doulah, A and Mahmoodi, G and Pourmahdi Borujeni, M}, title = {Evaluation of the pre-treatment effect of Centella asiatica medicinal plants on long-term potentiation (LTP) in rat model of Alzheimer's disease.}, journal = {Neuroscience letters}, volume = {729}, number = {}, pages = {135026}, doi = {10.1016/j.neulet.2020.135026}, pmid = {32387717}, issn = {1872-7972}, abstract = {The present study was aimed to investigate the pre-treatment effect of Centella asiatica (CeA) extract on long-term potentiation (LTP) in a rat model of Alzheimer's disease (AD). A total of 32 male Wistar rats weighing 380 ± 30 g were randomly divided into four groups (n = 8). Group 1 (C: Control): the control group. Group 2 (L: Lesion): The nucleus basalis of Meynert (NBM) of rats' brain was bilaterally destroyed by injection of Ibotenic acid. Group 3 (CeA): Animals in this group received the CeA leaf extract for only a period of six weeks. Group 4 (CeA + L): The NBM of rats was destroyed by Ibotenic acid after six weeks of a diet containing the CeA leaf extract. In all groups, LTP was recorded using the electrophysiological technique and fEPSP after high frequency stimulation (HFS). The results showed that the slope and amplitude of PS as well as the sub-curve level significantly increased in the CeA + L group compared with the L and CeA groups. The CeA extract improved and strengthened the slope, amplitude and sub-curve surface of cumulative waves in animals with NBM lesion. The results showed that administration CeA extract for six weeks before induction of NBM lesion and induction of Alzheimer could enhance memory. In other words, the CeA extract had a preventive or protective role. The present study showed that CeA had a protective role for neurons among rats with NBM lesion.}, } @article {pmid32387399, year = {2020}, author = {Sodero, AO and Barrantes, FJ}, title = {Pleiotropic effects of statins on brain cells.}, journal = {Biochimica et biophysica acta. Biomembranes}, volume = {1862}, number = {9}, pages = {183340}, doi = {10.1016/j.bbamem.2020.183340}, pmid = {32387399}, issn = {1879-2642}, abstract = {Starting with cholesterol homeostasis, the first part of the review addresses various aspects of cholesterol metabolism in neuronal and glial cells and the mutual crosstalk between the two cell types, particularly the transport of cholesterol from its site of synthesis to its target loci in neuronal cells, discussing the multiple mechanistic aspects and transporter systems involved. Statins are next analyzed from the point of view of their chemical structure and its impingement on their pharmacological properties and permeability through cell membranes and the blood-brain barrier in particular. The following section then discusses the transcriptional effects of statins and the changes they induce in brain cell genes associated with a variety of processes, including cell growth, signaling and trafficking, uptake and synthesis of cholesterol. We review the effects of statins at the cellular level, analyzing their impact on the cholesterol composition of the nerve and glial cell plasmalemma, neurotransmitter receptor mobilization, myelination, dendritic arborization of neurons, synaptic vesicle release, and cell viability. Finally, the role of statins in disease is exemplified by Alzheimer and Parkinson diseases and some forms of epilepsy, both in animal models and in the human form of these pathologies.}, } @article {pmid32384591, year = {2020}, author = {Cabinio, M and Rossetto, F and Isernia, S and Saibene, FL and Di Cesare, M and Borgnis, F and Pazzi, S and Migliazza, T and Alberoni, M and Blasi, V and Baglio, F}, title = {The Use of a Virtual Reality Platform for the Assessment of the Memory Decline and the Hippocampal Neural Injury in Subjects with Mild Cognitive Impairment: The Validity of Smart Aging Serious Game (SASG).}, journal = {Journal of clinical medicine}, volume = {9}, number = {5}, pages = {}, pmid = {32384591}, issn = {2077-0383}, support = {Ricerca Corrente 2018-2020//Ministero della Salute/ ; }, abstract = {Due to the lack of pharmacological treatment for dementia, timely detection of subjects at risk can be of seminal importance for preemptive rehabilitation interventions. The aim of the study was to determine the usability of the smart aging serious game (SASG), a virtual reality platform, in assessing the cognitive profile of an amnestic mild cognitive impairment (aMCI) population, its validity in discriminating aMCI from healthy controls (HC), and in detecting hippocampal degeneration, a biomarker of clinical progression towards dementia. Thirty-six aMCI and 107 HC subjects were recruited and administered the SASG together with a neuropsychological evaluation. All aMCI and 30 HC subjects performed also an MRI for hippocampal volume measurement. Results showed good usability of the SASG despite the low familiarity with technology in both groups. ROC curve analyses showed similar discriminating abilities for SASG and gold standard tests, and a greater discrimination ability compared to non-specific neuropsychological tests. Finally, linear regression analysis revealed that the SASG outperformed the Montreal cognitive assessment test (MoCA) in the ability to detect neuronal degeneration in the hippocampus on the right side. These data show that SASG is an ecological task, that can be considered a digital biomarker providing objective and clinically meaningful data about the cognitive profile of aMCI subjects.}, } @article {pmid32384286, year = {2020}, author = {Thaut, MH and Fischer, CE and Leggieri, M and Vuong, V and Churchill, NW and Fornazzari, LR and Schweizer, TA}, title = {Neural Basis of Long-term Musical Memory in Cognitively Impaired Older Persons.}, journal = {Alzheimer disease and associated disorders}, volume = {}, number = {}, pages = {}, doi = {10.1097/WAD.0000000000000382}, pmid = {32384286}, issn = {1546-4156}, abstract = {OBJECTIVE: The objective of this study was to determine whether exposure to long-known music would evoke more extensive activation of brain regions minimally affected by Alzheimer disease (AD) pathology and outside traditional memory networks using a functional magnetic resonance imaging paradigm involving listening to long-known and recently-learned music in older adults with cognitive impairment to provide insight into mechanisms of long-term musical memory preservation in cognitively impaired older persons.

METHODS: Seventeen subjects with a diagnosis of mild AD or mild cognitive impairment were recruited for this study. Subjects were scanned using functional magnetic resonance imaging while they performed a music listening task, which included short clips of personally selected music from the patient's past and newly-composed music heard for the first time 60 minutes before scanning. From this task, we obtained group-level maps comparing brain areas associated with long-known and recently-heard music in all subjects.

RESULTS: Exposure to long-known music preferentially activated brain regions including the medial prefrontal cortex, precuneus, anterior insula, basal ganglia, hippocampus, amygdala, and cerebellum relative to recently-heard music. These areas are involved in autobiographical memory and associated emotional responses. In addition, they are minimally affected by early stage AD pathology, thus providing a neural basis for long-known musical memory survival.

CONCLUSIONS: Long-known music activates a bilateral network of prefrontal, emotional, motor, auditory, and subcortical regions (cerebellum, putamen, limbic structures). This extensive activation, relative to recently-heard music, may offer structural and functional clues as to why long-term musical memory appears to be relatively preserved among cognitively impaired older persons.}, } @article {pmid32384285, year = {2020}, author = {Kitamura, J and Nagai, M and Ueno, H and Ohshita, T and Kikumoto, M and Toko, M and Kato, M and Dote, K and Yamashita, H and Kario, K}, title = {The Insular Cortex, Alzheimer Disease Pathology, and Their Effects on Blood Pressure Variability.}, journal = {Alzheimer disease and associated disorders}, volume = {}, number = {}, pages = {}, doi = {10.1097/WAD.0000000000000340}, pmid = {32384285}, issn = {1546-4156}, abstract = {Recent findings indicate that the human cardiovascular system is regulated by a cortical network comprised of the insular cortex (Ic), anterior cingulate gyrus, and amygdala which is necessary for the regulation of the central autonomic network system. Alzheimer disease (AD) affects the Ic at a preclinical stage. The pathology of AD at the Ic is suggested to predispose the cardiovascular system to detrimental changes such as increased blood pressure variability (BPV). In this review article, we focus on the physiology of the Ic in the relationship between the central autonomic network and BPV. We provide a summary of the published evidence regarding the relationship between Ic damage and exaggerated BPV in the context of AD pathology.}, } @article {pmid32384189, year = {2020}, author = {Sun, C and Gao, M and Wang, F and Yun, Y and Sun, Q and Guo, R and Yan, C and Sun, X and Li, Y}, title = {Serum metabolomic profiling in patients with Alzheimer Disease and Amnestic Mild Cognitive Impairment by GC/MS.}, journal = {Biomedical chromatography : BMC}, volume = {}, number = {}, pages = {e4875}, doi = {10.1002/bmc.4875}, pmid = {32384189}, issn = {1099-0801}, abstract = {OBJECTIVES: The aim of this study is to characterize the serum metabolic profiles of patients with Alzheimer Disease (AD) and Amnestic Mild Cognitive Impairment (AMCI) using metabolomics based on GC/MS.

METHODS: Serum samples were collected from patients with AD (n=30), AMCI (n=32), and normal healthy controls (NOR, n=40). Metabolite profiles were performed with gas chromatography-mass spectrometry (GC/MS) in conjunction with multivariate statistical analysis, and possible biomarker metabolites were identified.

RESULTS: 31 kinds of endogenous metabolites could be identified simultaneously. 11 components were chosen as biomarker metabolites between AD and NOR groups, and these metabolites were closely related to 7 biological pathways: arginine and proline metabolism, phenylalanine metabolism, beta-alanine metabolism, primary bile acid synthesis, glutathione metabolism, starch and sucrose metabolism and steroid hormone biosynthesis. Meanwhile,10 components were chosen as biomarker metabolites between AMCI and NOR groups and 7 biological pathways were closely related: arginine and proline metabolism, phenylalanine metabolism, citrate cycle, alanine, aspartate and glutamate metabolism, taurine and hypotaurine metabolism, starch and sucrose metabolism, and steroid hormone biosynthesis.

CONCLUSIONS: Our study distinguished serum metabotypes between AD, AMCI and NOR patients successfully. The implementation of this metabolomic strategy may help to develop biochemical insight into the metabolic alterations in AD/AMCI and will be helpful for the further understanding of pathogenesis.}, } @article {pmid32383552, year = {2020}, author = {Vinueza-Veloz, MF and Martín-Román, C and Robalino-Valdivieso, MP and White, T and Kushner, SA and De Zeeuw, CI}, title = {Genetic risk for Alzheimer disease in children: Evidence from early-life IQ and brain white-matter microstructure.}, journal = {Genes, brain, and behavior}, volume = {}, number = {}, pages = {}, doi = {10.1111/gbb.12656}, pmid = {32383552}, issn = {1601-183X}, support = {//Dutch Organization for Medical Sciences, Life Sciences, Social and Behavioral Sciences/ ; //ERC-adv/ ; //ERC-POC/ ; //Secretaría de Educación Superior, Ciencia, Tecnología e Innovación/ ; //Ministry of Health/ ; //Netherlands Organization for Scientific Research/ ; //Health Research/ ; //Erasmus University Rotterdam/ ; //Erasmus MC/ ; }, abstract = {It remains unclear whether the genetic risk for late-onset Alzheimer disease (AD) is linked to premorbid individual differences in general cognitive ability and brain structure. The objective of the present study was to determine whether the genetic risk of late-onset AD is related to premorbid individual differences in intelligence quotient (IQ) and characteristics of the cerebral white-matter in children. The study sample included children of the Generation R Study from Rotterdam, The Netherlands. IQ was measured using a well-validated Dutch nonverbal IQ test (n = 1908) at ages 5 to 9 years. White-matter microstructure was assessed by measuring fractional anisotropy (FA) of white-matter tracts using diffusion tensor imaging (DTI) (n = 919) at ages 9 to 12 years. Genetic risk was quantified using three biologically defined genetic risk scores (GRSs) hypothesized to be related to the pathophysiology of late-onset AD: immune response, cholesterol/lipid metabolism and endocytosis. Higher genetic risk for late-onset AD that included genes associated with immune responsivity had a negative influence on cognition and cerebral white-matter microstructure. For each unit increase in the immune response GRS, IQ decreased by 0.259 SD (95% CI [-0.500, -0.017]). For each unit increase in the immune response GRS, global FA decreased by 0.373 SD (95% CI [-0.721, -0.026]). Neither cholesterol/lipid metabolism nor endocytosis GRSs were associated with IQ or cerebral white-matter microstructure. Our findings suggest that elevated genetic risk for late-onset AD may in part be manifest during childhood neurodevelopment through alterations in immune responsivity.}, } @article {pmid32383521, year = {2020}, author = {Attia, H and Albuhayri, S and Alaraidh, S and Alotaibi, A and Yacoub, H and Mohamad, R and Al-Amin, M}, title = {Biotin, coenzyme Q10, and their combination ameliorate aluminium chloride-induced Alzheimer's disease via attenuating neuroinflammation and improving brain insulin signaling.}, journal = {Journal of biochemical and molecular toxicology}, volume = {}, number = {}, pages = {e22519}, doi = {10.1002/jbt.22519}, pmid = {32383521}, issn = {1099-0461}, support = {URSP-4-19-23//Deanship of Scientific Research at King Saud University, Undergraduate Student's Research Support Program/ ; }, abstract = {Insulin is important for brain function and neuronal survival. Insulin signaling is initiated by the phosphorylation of insulin receptor substrate-1 (IRS-1) at tyrosine (pTyr) residue. However, IRS-1 is inhibited by phosphorylation at serine (pSer). In Alzheimer's disease (AD), oxidative stress and accumulation of amyloid beta (Aβ) induce neuroinflammation, which augments pSer-IRS-1 and reduces pTyr-IRS-1 disturbing insulin signaling pathway. Coenzyme Q10 (CoQ10) and biotin possess antioxidant and anti-inflammatory properties, and, in this study, their impact on insulin signaling is investigated in an aluminium chloride (AlCl3) model of AD. AD was induced by oral administration of AlCl3 (75 mg/kg) for 60 days. Biotin (2 mg/kg), CoQ10 (10 mg/kg), and their combination were supplemented concomitantly with AlCl3 for 60 days. Memory test and histological examination were performed. Brain levels of lipid peroxides, antioxidants (reduced glutathione and superoxide dismutase), inflammatory markers (tumor necrosis factor-α, interleukin-6 [IL-6], IL-1, and nuclear factor κB), and phosphorylated Akt (survival kinase) as well as protein levels of Aβ, IRS-1 (pTyr and pSer), and caspase-3 (apoptotic marker) were determined. AlCl3 resulted in impaired memory, significant increase in Aβ, lipid peroxides, inflammatory markers, caspase-3, and pSer-IRS-1, with significant reduction of the antioxidants, pTyr-IRS-1, and p-Akt reflecting Aβ-induced inflammation and defective insulin signaling. Histological examination revealed focal aggregations of inflammatory cells and neuronal degeneration. The biochemical deviations and histological changes were attenuated by the concomitant treatment with biotin and, to greater extent, with CoQ10 and the combination. In conclusion, biotin and CoQ10 could protect against AD via attenuating inflammatory response and enhancing insulin signaling.}, } @article {pmid32383491, year = {2020}, author = {Rouch, I and Padovan, C and Boublay, N and Pongan, E and Laurent, B and Trombert-Paviot, B and Krolak-Salmon, P and Dorey, JM}, title = {Association between executive function and the evolution of behavioral disorders in Alzheimer's disease.}, journal = {International journal of geriatric psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1002/gps.5327}, pmid = {32383491}, issn = {1099-1166}, abstract = {OBJECTIVE: This study was aimed at evaluating the association between cognitive functioning and the occurrence of Behavioral and Psychological Symptoms of Dementia (BPSD) in patients with Alzheimer's disease (AD).

METHODS/DESIGN: The population is derived from the PACO cohort, including 237 patients with prodromal or mild AD. A neuropsychological tests battery exploring verbal and visual memory, language, attention and executive functions was performed at baseline. BPSD were assessed at 6, 12 and 18-month follow-up with Neuropsychiatric Inventory (NPI).

RESULTS: Lower baseline performance on Stroop test interference score was associated with higher subsequent overall NPI scores (P = 0.006), sub-scores of anxiety/depression (P = 0.03) and apathy inventory (P = 0.01). Conversely, other executive functions, verbal or visual memory and language performances were not associated with a higher risk of BPSD.

CONCLUSION: Our results suggest that poorer inhibition performance would be associated with a higher risk of 18-month BPSD occurrence, including anxiety, depression and apathy. A better knowledge of the predictive factors of the BPSDs would make it possible to better identify the patients at risk, to propose preventive strategies and an earlier adapted care.}, } @article {pmid32383387, year = {2020}, author = {He, M and Stevenson, JM and Zhang, Y and Hernandez, I}, title = {Risk Factors for Cardiovascular Events in Patients on Antidementia Medications.}, journal = {American journal of Alzheimer's disease and other dementias}, volume = {35}, number = {}, pages = {1533317520922380}, doi = {10.1177/1533317520922380}, pmid = {32383387}, issn = {1938-2731}, support = {K01 HL142847/HL/NHLBI NIH HHS/United States ; }, abstract = {OBJECTIVE: To identify characteristics associated with an increased risk of cardiovascular events in patients diagnosed with Alzheimer disease (AD) and treated with antidementia medications.

METHODS: Demographics, diagnoses, and medication usage of 30 433 Medicare patients were analyzed using 2006 to 2013 claims data and a combined model of screening, ranking and stepwise logistic regressions to evaluate factors associated with composite outcomes of 6 cardiovascular events.

RESULTS: Incidence rate of at least 1 cardiovascular event was 25.1%. Fifty-five factors were identified from the 10 381 candidate variables by the combined model with a c-statistic of 67% and an accuracy of 75%. Factors associated with increased risk of cardiovascular events include history of heart rhythm disorders, alteration of consciousness (odds ratio [OR]: 1.25; 95% confidence interval [CI]: 1.14-1.36), and usage of β-blockers (OR: 1.19; 95% CI: 1.13-1.27).

CONCLUSIONS: Clinicians should consider the increased risk of cardiovascular events in patients with AD with heart rhythm disorders and on β-blockers.}, } @article {pmid32381283, year = {2020}, author = {Isaia, G and Marinello, R and Tibaldi, V and Tamone, C and Bo, M}, title = {Atypical Presentation of Covid-19 in an Older Adult With Severe Alzheimer Disease.}, journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry}, volume = {}, number = {}, pages = {}, pmid = {32381283}, issn = {1545-7214}, } @article {pmid32380752, year = {2020}, author = {Maron, R and Armony, G and Tsoory, M and Wilchek, M and Frenkel, D and Arnon, R}, title = {Peptide Interference with APP and Tau Association: Relevance to Alzheimer's Disease Amelioration.}, journal = {International journal of molecular sciences}, volume = {21}, number = {9}, pages = {}, pmid = {32380752}, issn = {1422-0067}, support = {7221100//estastr ethel lena levy alzheimer's disease research/ ; }, abstract = {The two major proteins involved in Alzheimer's disease (AD) are the amyloid precursor protein (APP) and Tau. Here, we demonstrate that these two proteins can bind to each other. Four possible peptides APP1 (390-412), APP2 (713-730), Tau1 (19-34) and Tau2 (331-348), were predicted to be involved in this interaction, with actual binding confirmed for APP1 and Tau1. In vivo studies were performed in an Alzheimer Disease animal model-APP double transgenic (Tg) 5xFAD-as well as in 5xFAD crossed with Tau transgenic 5xFADXTau (FT), which exhibit declined cognitive reduction at four months of age. Nasal administration of APP1 and Tau1 mixture, three times a week for four or five months, reduced amyloid plaque burden as well as the level of soluble Aβ 1-42 in the brain. The treatment prevented the deterioration of cognitive functions when initiated at the age of three months, before cognitive deficiency was evident, and also at the age of six months, when such deficiencies are already observed, leading to a full regain of cognitive function.}, } @article {pmid32380223, year = {2020}, author = {Pérez-González, M and Mendioroz, M and Badesso, S and Sucunza, D and Roldan, M and Espelosín, M and Ursua, S and Luján, R and Cuadrado-Tejedor, M and Garcia-Osta, A}, title = {PLA2G4E, a candidate gene for resilience in Alzheimer´s disease and a new target for dementia treatment.}, journal = {Progress in neurobiology}, volume = {191}, number = {}, pages = {101818}, doi = {10.1016/j.pneurobio.2020.101818}, pmid = {32380223}, issn = {1873-5118}, abstract = {Clinical studies revealed that some aged-individuals accumulate a significant number of histopathological Alzheimer´s disease (AD) lesions in their brain, yet without developing any signs of dementia. Animal models of AD represent suitable tools to identify genes that might promote cognitive resilience and hence, this study first set out to identify cognitively resilient individuals in the aged-Tg2576 mouse model. A transcriptomic analysis of these mice identified PLA2G4E as a gene that might confer resistance to dementia. Indeed, a significant decrease in PLA2G4E is evident in the brain of late-stage AD patients, whereas no such changes are observed in early stage patients with AD neuropathological lesions but no signs of dementia. We demonstrated that adeno-associated viral vector-mediated overexpression of PLA2G4E in hippocampal neurons completely restored cognitive deficits in elderly APP/PS1 mice, without affecting the amyloid or tau pathology. These PLA2G4E overexpressing APP/PS1 mice developed significantly more dendritic spines than sham-injected mice, coinciding with the cognitive improvement observed. Hence, these results support the idea that a loss of PLA2G4E might play a key role in the onset of dementia in AD, highlighting the potential of PLA2G4E overexpression as a novel therapeutic strategy to manage AD and other disorders that course with memory deficits.}, } @article {pmid32379048, year = {2020}, author = {Tsolaki, AC and Tsolaki, M and Pandria, N and Lazarou, E and Gkatzima, O and Zilidou, V and Karagianni, M and Iakovidou-Kritsi, Z and Kimiskidis, VK and Bamidis, PD}, title = {Web-Based Intervention Effects on Mild Cognitive Impairment Based on Apolipoprotein E Genotype: Quasi-Experimental Study.}, journal = {Journal of medical Internet research}, volume = {22}, number = {5}, pages = {e14617}, pmid = {32379048}, issn = {1438-8871}, abstract = {BACKGROUND: Apolipoprotein E (APOE) ε4 allele is a major genetic risk factor for Alzheimer disease and mild cognitive impairment (MCI). Computer-based training programs can improve cognitive performance in elderly populations. However, the effects of computer-based interventions on MCI APOE ε4 carriers have never been studied before.

OBJECTIVE: The effects of different web-based interventions and the APOE isoform-specific differences in training outcomes are investigated.

METHODS: Using a quasi-experimental study design, 202 participants with MCI aged 60 years and older took part in three different intervention programs (physical and cognitive [Long-Lasting Memories, or LLM], cognitive [Active Control, or AC], or physical intervention [Physical Training Control, or PTC]) via an innovative information and communication technologies exergaming platform. Participants in each interventional group were subdivided into APOE ε4 carriers and non-APOE ε4 carriers. All participants underwent an extensive neuropsychological evaluation before and after the training, blood tests, and brain imaging.

RESULTS: All interventions resulted in multiple statistically significant cognitive benefits after the intervention. Verbal learning (California Verbal Learning Test: immediate recall test score-LLM: P=.04; AC: P<.001), working memory (digit span forward and backward test scores-AC: P=.03; PTC: P=.02 and P=.006, respectively), and long-term memory (California Verbal Learning Test: delayed recall test score-LLM: P=.02; AC: P=.002; and PTC: P=.02) were improved. There was no statistically significant difference among the intervention effects. APOE ε4 presence moderates intervention effects as the LLM intervention improved only their task-switching processing speed (Trail Making Test, Part B: P=.03) and the PTC intervention improved only the working memory (digit span backward: P=.03). No significant performance alteration was noted for the APOE ε4+ cognitive AC training group.

CONCLUSIONS: None of the applied interventions could be identified as the optimal one; it is suggested, however, that combined cognitive and physical training and physical training via exergaming may be more effective for the high-risk MCI ΑPOE ε4+ subgroup.}, } @article {pmid32378825, year = {2020}, author = {Kadah, A and Khoury, T and Sbeit, W}, title = {Early Buried Bumper Syndrome Treated by Bedside Replacement.}, journal = {The Israel Medical Association journal : IMAJ}, volume = {22}, number = {5}, pages = {315-319}, pmid = {32378825}, issn = {1565-1088}, mesh = {Aged ; Aged, 80 and over ; Device Removal/methods ; Enteral Nutrition/*instrumentation ; Female ; Gastrostomy/*instrumentation ; Humans ; Male ; Point-of-Care Systems ; Postoperative Complications/*surgery ; Retreatment ; Time Factors ; }, abstract = {BACKGROUND: Buried bumper syndrome (BBS) mostly occurs as a late complication after percutaneous endoscopic gastrostomy (PEG) insertion; however, early BBS has been rarely reported, and the treatment of this condition is still unclear.

OBJECTIVES: To evaluate the Seldinger technique for treatment of early BBS after PEG insertion.

METHODS: We report two cases of early BBS in two consecutive patients who underwent PEG insertion to maintain oral intake. The first patient was an 83-year-old woman showing Alzheimer type dementia, while the other one was a 76-year-old man who presented with maxillary cancer and treated with radiotherapy followed by left maxillectomy. Post-surgery, he developed progressive difficulty of swallowing due to mouth deformation and treatment related nerve toxicity. The first patient presented with fever and purulent discharge from the gastrostomy insertion site, without ability to rotate or slide the tube through the stoma 10 days after the PEG insertion. The man was admitted to the hospital 5 days following PEG insertion due to a fever of 38°C and peritubal swelling with purulent discharge. In addition, the tube could not rotate or slide through the stoma.

RESULTS: Buried bumper syndrome was demonstrated by computed tomography scan. Gastroscopy and gastrostomy tube replacement was performed successfully according to the Seldinger technique (replacement over guidewire) in both cases. Correct intragastric tube positioning was demonstrated radiographically before resuming tube feeding. The two patients were discharged in good physical condition several days later.

CONCLUSIONS: External replacement over guide wire should be considered in such cases.}, } @article {pmid32378448, year = {2020}, author = {El Haj, M and Boudoukha, AH and Moustafa, AA}, title = {Future-Oriented Repetitive Thought: Pessimistic View of Future in Patients With Alzheimer Disease.}, journal = {Journal of geriatric psychiatry and neurology}, volume = {}, number = {}, pages = {891988720924723}, doi = {10.1177/0891988720924723}, pmid = {32378448}, issn = {0891-9887}, abstract = {OBJECTIVE: In this study, we, for the first time, evaluated future-oriented repetitive thought in patients with Alzheimer disease (AD), that is, how they think and worry about the future.

METHODS: We administered the Future-Oriented Repetitive Thought scale to 34 patients with AD and 37 control participants. This scale assessed 3 categories of future-oriented repetitive thought: (1) pessimistic repetitive future thinking (eg, "I think about the possibility of losing people or things that are important to me"), (2) repetitive thinking about future goals (eg, "I make specific plans for how to get things that I want in life"), and (3) positive indulging about the future (eg, "When I picture good things happening in my future, it is as if they were actually happening to me now").

RESULTS: Analysis demonstrated more pessimistic repetitive future thinking, but less repetitive thinking about future goals and positive indulging about the future, in patients with AD than in control participants.

CONCLUSION: Our findings demonstrate a pessimistic view of future in patients with AD, which is possibly attributed to hopelessness and depression.}, } @article {pmid32376688, year = {2020}, author = {Crooks, EJ and Irizarry, BA and Ziliox, M and Kawakami, T and Victor, TW and Xu, F and Hojo, H and Chiu, K and Simmerling, C and Van Nostrand, WE and Smith, SO and Miller, LM}, title = {Copper stabilizes antiparallel β-sheet fibrils of the amyloid β40 (Aβ40)-Iowa variant.}, journal = {The Journal of biological chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1074/jbc.RA119.011955}, pmid = {32376688}, issn = {1083-351X}, support = {R01 NS094201/NS/NINDS NIH HHS/United States ; }, abstract = {Cerebral amyloid angiopathy (CAA) is a vascular disorder that primarily involves deposition of the 40-residue-long amyloid β peptide (Aβ40) in and along small blood vessels of the brain. CAA is often associated with Alzheimer's disease (AD), which is characterized by amyloid plaques in the brain parenchyma enriched in the Aβ42 peptide. Several recent studies have suggested a structural origin that underlies the differences between the vascular amyloid deposits in CAA and the parenchymal plaques in AD. We previously have found that amyloid fibrils in vascular amyloid contain antiparallel β-sheet, whereas previous studies by other researchers have reported parallel β-sheet in fibrils from parenchymal amyloid. Using X-ray fluorescence microscopy, here we found that copper strongly co-localizes with vascular amyloid in human sporadic CAA and familial Iowa-type CAA brains compared with control brain blood vessels lacking amyloid deposits. We show that binding of Cu(II) ions to antiparallel fibrils can block the conversion of these fibrils to the more stable parallel, in-register conformation and enhances their ability to serve as templates for seeded growth. These results provide an explanation for how thermodynamically less stable antiparallel fibrils may form amyloid in or on cerebral vessels by using Cu(II) as a structural cofactor.}, } @article {pmid32376150, year = {2020}, author = {Ulamec, SM and Radford, SE}, title = {Spot the Difference: Function versus Toxicity in Amyloid Fibrils.}, journal = {Trends in biochemical sciences}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.tibs.2020.04.007}, pmid = {32376150}, issn = {0968-0004}, abstract = {In a recent study, Hervas et al. extracted Orb2 fibrils, that are involved in long-term memory formation, from Drosophila brains, characterised their function, and determined their structure using cryo-electron microscopy (cryo-EM). The fibrils show a remarkable resemblance to amyloid β (Aβ) fibrils associated with Alzheimer's disease, highlighting the subtle difference between functional and dysfunctional amyloid.}, } @article {pmid32375819, year = {2020}, author = {Solár, P and Zamani, A and Kubíčková, L and Dubový, P and Joukal, M}, title = {Choroid plexus and the blood-cerebrospinal fluid barrier in disease.}, journal = {Fluids and barriers of the CNS}, volume = {17}, number = {1}, pages = {35}, pmid = {32375819}, issn = {2045-8118}, support = {CZ.02.2.69/0.0/0.0/16_027/0008360//Ministerstvo Školství, Mládeže a Tělovýchovy (CZ)/ ; ROZV/23/LF14/2019//Ministerstvo Školství, Mládeže a Tělovýchovy (CZ)/ ; MUNI/A/1086/2018//Masarykova Univerzita (CZ)/ ; MUNI/A/0975/2019//Masarykova Univerzita (CZ)/ ; }, abstract = {The choroid plexus (CP) forming the blood-cerebrospinal fluid (B-CSF) barrier is among the least studied structures of the central nervous system (CNS) despite its clinical importance. The CP is an epithelio-endothelial convolute comprising a highly vascularized stroma with fenestrated capillaries and a continuous lining of epithelial cells joined by apical tight junctions (TJs) that are crucial in forming the B-CSF barrier. Integrity of the CP is critical for maintaining brain homeostasis and B-CSF barrier permeability. Recent experimental and clinical research has uncovered the significance of the CP in the pathophysiology of various diseases affecting the CNS. The CP is involved in penetration of various pathogens into the CNS, as well as the development of neurodegenerative (e.g., Alzheimer´s disease) and autoimmune diseases (e.g., multiple sclerosis). Moreover, the CP was shown to be important for restoring brain homeostasis following stroke and trauma. In addition, new diagnostic methods and treatment of CP papilloma and carcinoma have recently been developed. This review describes and summarizes the current state of knowledge with regard to the roles of the CP and B-CSF barrier in the pathophysiology of various types of CNS diseases and sets up the foundation for further avenues of research.}, } @article {pmid32375809, year = {2020}, author = {Ismail, R and Parbo, P and Madsen, LS and Hansen, AK and Hansen, KV and Schaldemose, JL and Kjeldsen, PL and Stokholm, MG and Gottrup, H and Eskildsen, SF and Brooks, DJ}, title = {The relationships between neuroinflammation, beta-amyloid and tau deposition in Alzheimer's disease: a longitudinal PET study.}, journal = {Journal of neuroinflammation}, volume = {17}, number = {1}, pages = {151}, pmid = {32375809}, issn = {1742-2094}, abstract = {BACKGROUND: The aim of this longitudinal study was to assess with positron emission tomography (PET) the relationship between levels of inflammation and the loads of aggregated β-amyloid and tau at baseline and again after 2 years in prodromal Alzheimer's disease.

METHODS: Forty-three subjects with mild cognitive impairment (MCI) had serial 11C-PK11195 PET over 2 years to measure inflammation changes, and 11C-PiB PET to determine β-amyloid fibril load; 22 also had serial 18F-Flortaucipir PET to determine tau tangle load. Cortical surface statistical mapping was used to localise areas showing significant changes in tracer binding over time and to interrogate correlations between tracer binding of the tracers at baseline and after 2 years.

RESULTS: Those MCI subjects with high 11C-PiB uptake at baseline (classified as prodromal Alzheimer's disease) had raised inflammation levels which significantly declined across cortical regions over 2 years although their β-amyloid levels continued to rise. Those MCI cases who had low/normal 11C-PiB uptake at baseline but their levels then rose over 2 years were classified as prodromal AD with low Thal phase 1-2 amyloid deposition at baseline. They showed levels of cortical inflammation which correlated with their rising β-amyloid load. Those MCI cases with baseline low 11C-PiB uptake that remained stable were classified as non-AD, and they showed no correlated inflammation levels. Finally, MCI cases which showed both high 11C-PiB and 18F-Flortaucipir uptake at baseline (MCI due to AD) showed a further rise in their tau tangle load over 2 years with a correlated rise in levels of inflammation.

CONCLUSIONS: Our baseline and 2-year imaging findings are compatible with a biphasic trajectory of inflammation in Alzheimer's disease: MCI cases with low baseline but subsequently rising β-amyloid load show correlated levels of microglial activation which then later decline when the β-amyloid load approaches AD levels. Later, as tau tangles form in β-amyloid positive MCI cases with prodromal AD, the rising tau load is associated with higher levels of inflammation.}, } @article {pmid32374412, year = {2020}, author = {Munter, LM}, title = {The lipid component of Alzheimer's disease research: An Editorial Highlight for "Brain region-specific amyloid plaque-associated myelin lipid loss, APOE deposition and disruption of the myelin sheath in familial Alzheimer's disease mice" on https://doi.org/10.1111/jnc.14999.}, journal = {Journal of neurochemistry}, volume = {}, number = {}, pages = {}, doi = {10.1111/jnc.15025}, pmid = {32374412}, issn = {1471-4159}, support = {RR172187//Weston Brain Institute/ ; PTJ 162302/CAPMC/CIHR/Canada ; RGPIN-2015-04645//Natural Sciences and Engineering Research Council of Canada/ ; 20-02//Alzheimer Society/ ; PTJ 162302/CAPMC/CIHR/Canada ; }, abstract = {It may not be surprising that the brain as a lipid-rich organ shows perturbed lipid profiles in neurodegenerative conditions such as Alzheimer's disease. It is, however, more challenging to detect these changes as they may only occur in a spatially small area. This Editorial highlights the work by Kaya et al. using a raising technology called MALDI IMS to identify up- or downregulation of specific lipids in and around the amyloid plaque, one of the pathological hallmarks of Alzheimer's disease. Interestingly, such lipid changes were paralleled with disrupted myelin structure only at the border between white and gray matter. The sequestration of apolipoprotein E towards the amyloid plaque may provide a clue towards the underlying mechanisms leading to disrupted lipid profiles. This study highlights the necessity to increase research activities related to lipid metabolism in Alzheimer's disease and demonstrates that the technological progress now facilitates the advancement of this area.}, } @article {pmid32371375, year = {2020}, author = {Ducat, A and Couderc, B and Bouter, A and Biquard, L and Aouache, R and Passet, B and Doridot, L and Cohen, MB and Ribaux, P and Apicella, C and Gaillard, I and Palfray, S and Chen, Y and Vargas, A and Julé, A and Frelin, L and Cocquet, J and San Martin, CR and Jacques, S and Busato, F and Tost, J and Méhats, C and Laissue, P and Vilotte, JL and Miralles, F and Vaiman, D}, title = {Molecular Mechanisms of Trophoblast Dysfunction Mediated by Imbalance between STOX1 Isoforms.}, journal = {iScience}, volume = {23}, number = {5}, pages = {101086}, doi = {10.1016/j.isci.2020.101086}, pmid = {32371375}, issn = {2589-0042}, abstract = {STOX1 is a transcription factor involved in preeclampsia and Alzheimer disease. We show that the knock-down of the gene induces rather mild effect on gene expression in trophoblast cell lines (BeWo). We identified binding sites of STOX1 shared by the two major isoforms, STOX1A and STOX1B. Profiling gene expression of cells overexpressing either STOX1A or STOX1B, we identified genes downregulated by both isoforms, with a STOX1 binding site in their promoters. Among those, STOX1-induced Annexin A1 downregulation led to abolished membrane repair in BeWo cells. By contrast, overexpression of STOX1A or B has opposite effects on trophoblast fusion (acceleration and inhibition, respectively) accompanied by syncytin genes deregulation. Also, STOX1A overexpression led to abnormal regulation of oxidative and nitrosative stress. In sum, our work shows that STOX1 isoform imbalance is a cause of gene expression deregulation in the trophoblast, possibly leading to placental dysfunction and preeclampsia.}, } @article {pmid32370954, year = {2020}, author = {, and Moonis, G and Subramaniam, RM and Trofimova, A and Burns, J and Bykowski, J and Chakraborty, S and Holloway, K and Ledbetter, LN and Lee, RK and Pannell, JS and Pollock, JM and Powers, WJ and Roca, RP and Rosenow, JM and Shih, RY and Utukuri, PS and Corey, AS}, title = {ACR Appropriateness Criteria® Dementia.}, journal = {Journal of the American College of Radiology : JACR}, volume = {17}, number = {5S}, pages = {S100-S112}, doi = {10.1016/j.jacr.2020.01.040}, pmid = {32370954}, issn = {1558-349X}, abstract = {Degenerative disease of the central nervous system is a growing public health concern. The primary role of neuroimaging in the workup of patients with probable or possible Alzheimer disease has typically been to exclude other significant intracranial abnormalities. In general, the imaging findings in structural studies, such as MRI, are nonspecific and have limited potential in differentiating different types of dementia. Advanced imaging methods are not routinely used in community or general practices for the diagnosis or differentiation of forms of dementia. Nonetheless, in patients who have been evaluated by a dementia expert, FDG-PET helps to distinguish Alzheimer disease from frontotemporal dementia. In patients with suspected dementia with Lewy bodies, functional imaging of the dopamine transporter (ioflupane) using SPECT may be helpful. In patients with suspected normal-pressure hydrocephalus, DTPA cisternography and HMPAO SPECT/CT brain may provide assessment. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.}, } @article {pmid32368960, year = {2020}, author = {Rauchmann, BS and Ghaseminejad, F and Mekala, S and Perneczky, R and , }, title = {Cerebral Microhemorrhage at MRI in Mild Cognitive Impairment and Early Alzheimer Disease: Association with Tau and Amyloid β at PET Imaging.}, journal = {Radiology}, volume = {296}, number = {1}, pages = {134-142}, doi = {10.1148/radiol.2020191904}, pmid = {32368960}, issn = {1527-1315}, abstract = {Background Growing evidence indicates an association between cerebral microhemorrhages (MHs) and amyloid β accumulation in Alzheimer disease (AD), but to the knowledge of the authors the association with tau burden is unknown. Purpose To investigate the association between cerebral MH load and tau pathologic structure measured in healthy older individuals and individuals along the AD spectrum, stratified by using the A (amyloid β)/T (tau)/N (neurodegeneration) biomarker classification system. Materials and methods In this prospective cohort study, participants from the AD Neuroimaging Initiative were included (healthy control participants, participants with mild cognitive impairment, and participants with AD dementia; data from October 2005 to January 2019). T2*-weighted gradient-echo MRI was performed to quantify MH, fluorine 18 (18F) flortaucipir (AV-1451) PET was performed to quantify tau, and 18F-florbetaben/18F- florbetapir (AV45) PET was performed to quantify amyloid β to study associations of MH with regional and global tau and amyloid β load. Associations with cerebrospinal fluid (CSF) biomarkers (amyloid β1-42, total tau, phosphorylated tau 181) were also assessed. Analysis of covariance and Spearman rank correlation test for cross-sectional analysis and Wilcoxon signed rank test for longitudinal analyses were used, controlling for multiple comparisons (Bonferroni significance threshold, P < .008). Results Evaluated were 343 participants (mean age, 75 years ± 7; 186 women), including 205 participants who were A-TN- (mean age, 73 years ± 7; 115 women), 80 participants who were A+TN- (mean age, 76 years ± 7; 38 women), and 58 participants who were A+TN+ (mean age, 77 ± 8; 34 women). MH count was associated with global (Spearman ρ = 0.27; P = .004) and frontal (ρ = 0.27; P = .005) amyloid β load and global tau load (ρ = 0.31; P = .001). In a longitudinal analysis, MH count increased significantly over approximately 5 years in the entire cohort (T-1, 81 [range, 0-6 participants]; T0, 214 [range, 0-58 participants]; P < .001), in A+TN+ (T-1, 20 [range, 0-5 participants]; T0, 119 [range, 1-58 participants]; P < .001), A+TN- (T-1, 31 [range, 0-6 participants]; T0, 43 [range, 0-8 participants]; P = .03), and A-TN- (T-1, 30 [range, 0-4 participants]; T0, 52 [range, 0-6 participants]; P = .007). A higher MH count was associated with higher future global (ρ = 0.29; P = .008) and parietal (ρ = 0.31; P = .005) amyloid β and parietal tau load (ρ = 0.31; P = .005). Conclusion Cerebral microhemorrhage load is associated spatially with tau accumulation, both cross-sectionally and longitudinally. © RSNA, 2020 Online supplemental material is available for this article.}, } @article {pmid32367740, year = {2020}, author = {Weng, X and George, DR and Jiang, B and Wang, L}, title = {Association Between Subjective Cognitive Decline and Social and Emotional Support in US Adults.}, journal = {American journal of Alzheimer's disease and other dementias}, volume = {35}, number = {}, pages = {1533317520922392}, doi = {10.1177/1533317520922392}, pmid = {32367740}, issn = {1938-2731}, abstract = {Subjective cognitive decline (SCD) has been linked to Alzheimer's Disease in the literature. However, little is known about whether SCD is associated with social/emotional support (SES). To investigate this association, this study utilized the 2015 and 2016 Behavioral Risk Factor Surveillance System data. A study population of 17206 participants aged 45 years and older who responded to both the Emotional Support and Life Satisfaction survey module and the Cognition Decline survey module were included. Of this study population, 11.22% had SCD, and 21.83% reported insufficient SES. A much higher percentage of those with insufficient SES experienced SCD compared to those with sufficient SES (21.15% vs 8.45%, P < .0001). Insufficient SES was significantly associated with SCD (odds ratio = 1.68, 95% confidence interval: 1.37-2.06), after controlling for other factors. Furthermore, this study found certain demographic groups such as female, white, or married groups were more likely to receive sufficient SES.}, } @article {pmid32367182, year = {2020}, author = {Jellinger, KA}, title = {Neuropathological findings in multiple system atrophy with cognitive impairment.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {127}, number = {7}, pages = {1031-1039}, doi = {10.1007/s00702-020-02201-2}, pmid = {32367182}, issn = {1435-1463}, abstract = {Cognitive impairment (CI), previously considered an exclusion criterium for the diagnosis of multiple system atrophy (MSA) according to the second consensus criteria, is not uncommon in MSA. Mild cognitive impairment (MCI) has been reported in up to 47% of MSA patients, while severe dementia is rare. We related clinical CI with neuropathological findings in 48 autopsy-proven cases of MSA. This retrospective study included 33 parkinsonism predominant MSA (MSA-P), and 15 cerebellar ataxia-predominant MSA (MSA-C) cases (mean age at death 60.5 ± 7.8; range 46-82 years). Cognitive state was assessed from hospital charts, however, without comprehensive neuropsychological testing. Neuropathological examination, in addition to grading of the MSA pathologies, included semiquantitative assessment of Lewy and Alzheimer-related co-pathologies. Their incidence was compared with 143 age-matched controls (mean age 60.5 ± 7.6 years). MCI reported in ten cases (20.8%) was associated with moderate cortical tau pathology in only three; moderate CI in seven patients (14.5%) was associated with cortical amyloid plaques and moderate cortical tau pathology in six each, and one with probable primary age-related tauopathy (PART); a female aged 82 years with severe dementia showed fully developed Alzheimer disease. Cortical amyloid plaques, observed in eight cases, three of them without tau pathology, were associated with clinical MCI, as was cortical Lewy pathology in five. Two cases with cortical Lewy pathology and neuritic Braak stages II and III, and three with Braak stage IV, without cortical Lewy bodies, had shown moderate CI. Cortical Lewy pathology observed in four cases was not associated with clinical CI. 77.1% of the MSA cases were free of Alzheimer-type lesions, compared to 42% of controls; while Lewy pathology in the MSA cohort (22.9%) was significantly higher than in the control group (8.4%) both p < 0.001. Mild-to-moderate CI, reported in 35.3% of MSA patients, being significantly older than those without CI, were frequently associated with cortical Alzheimer (Braak stages III and IV) and Lewy pathologies, while only one with severe dementia had fully developed Alzheimer disease. In view of these findings in a limited series of MSA patients, further studies to elucidate the pathological basis of cognitive impairment in MSA are warranted.}, } @article {pmid32366785, year = {2020}, author = {Zukotynski, K and Gaudet, V and Kuo, PH and Adamo, S and Goubran, M and Scott, CJM and Bocti, C and Borrie, M and Chertkow, H and Frayne, R and Hsiung, R and Laforce, R and Noseworthy, MD and Prato, FS and Sahlas, DJ and Smith, EE and Sossi, V and Thiel, A and Soucy, JP and Tardif, JC and Black, SE}, title = {The Use of Random Forests to Identify Brain Regions on Amyloid and FDG PET Associated With MoCA Score.}, journal = {Clinical nuclear medicine}, volume = {45}, number = {6}, pages = {427-433}, doi = {10.1097/RLU.0000000000003043}, pmid = {32366785}, issn = {1536-0229}, abstract = {PURPOSE: The aim of this study was to evaluate random forests (RFs) to identify ROIs on F-florbetapir and F-FDG PET associated with Montreal Cognitive Assessment (MoCA) score.

MATERIALS AND METHODS: Fifty-seven subjects with significant white matter disease presenting with either transient ischemic attack/lacunar stroke or mild cognitive impairment from early Alzheimer disease, enrolled in a multicenter prospective observational trial, had MoCA and F-florbetapir PET; 55 had F-FDG PET. Scans were processed using the MINC toolkit to generate SUV ratios, normalized to cerebellar gray matter (F-florbetapir PET), or pons (F-FDG PET). SUV ratio data and MoCA score were used for supervised training of RFs programmed in MATLAB.

RESULTS: F-Florbetapir PETs were randomly divided into 40 training and 17 testing scans; 100 RFs of 1000 trees, constructed from a random subset of 16 training scans and 20 ROIs, identified ROIs associated with MoCA score: right posterior cingulate gyrus, right anterior cingulate gyrus, left precuneus, left posterior cingulate gyrus, and right precuneus. Amyloid increased with decreasing MoCA score. F-FDG PETs were randomly divided into 40 training and 15 testing scans; 100 RFs of 1000 trees, each tree constructed from a random subset of 16 training scans and 20 ROIs, identified ROIs associated with MoCA score: left fusiform gyrus, left precuneus, left posterior cingulate gyrus, right precuneus, and left middle orbitofrontal gyrus. F-FDG decreased with decreasing MoCA score.

CONCLUSIONS: Random forests help pinpoint clinically relevant ROIs associated with MoCA score; amyloid increased and F-FDG decreased with decreasing MoCA score, most significantly in the posterior cingulate gyrus.}, } @article {pmid32366352, year = {2020}, author = {Arsenault-Lapierre, G and Sourial, N and Pakzad, S and Hardouin, M and Couturier, Y and Bergman, H and Vedel, I}, title = {Validation of a Questionnaire for Family Physicians: Knowledge, Attitude, Practice on Dementia Care.}, journal = {Canadian journal on aging = La revue canadienne du vieillissement}, volume = {}, number = {}, pages = {1-10}, doi = {10.1017/S0714980820000069}, pmid = {32366352}, issn = {1710-1107}, abstract = {Our study objective was to develop and validate a questionnaire assessing the knowledge, attitude, and practice (KAP) of family physicians regarding dementia care and dementia strategies in Canada. Using a multistage process with a panel of experts, we developed and distributed an 83-item questionnaire to 542 eligible family physicians in 42 interdisciplinary primary care teams participating in the Quebec Alzheimer Plan implementation. Altogether, 369 physicians (68%) returned questionnaires. Median item-specific non-response rate was 0.8 per cent (0.3%-8.1%). Exploratory factor analyses and scale correlation supported the questionnaire validity. The final questionnaire contained five factors and 31 items. The KAP questionnaire has proved to be a reliable instrument for assessing the KAP of family physicians regarding dementia care and dementia strategies. This questionnaire provides researchers, clinicians, managers, and decision-makers with a tool to assess an intervention, a program, or a policy change implemented in primary health care for patients with dementia.}, } @article {pmid32365315, year = {2020}, author = {Barco, PP and Wallendorf, M and Rutkoski, K and Dolan, K and Rakus, D and Johnson, A and Carr, DB}, title = {Validity and Reliability of the Traffic Sign Naming Test (TSNT) and Written Exam for Driving Decisions (WEDD) as Measures of Fitness to Drive Among Older Adults.}, journal = {The American journal of occupational therapy : official publication of the American Occupational Therapy Association}, volume = {74}, number = {3}, pages = {7403205090p1-7403205090p10}, doi = {10.5014/ajot.2020.034389}, pmid = {32365315}, issn = {0272-9490}, abstract = {IMPORTANCE: Occupational therapists need valid and reliable tools to help determine fitness to drive of older drivers with medical conditions such as dementia.

OBJECTIVE: To establish the validity and reliability of the Traffic Sign Naming Test (TSNT) and Written Exam for Driving Decisions (WEDD) as measures of fitness to drive of adults with and without dementia.

DESIGN: Cross-sectional.

SETTING: Washington University Medical School in St. Louis in collaboration with the Rehabilitation Institute of St. Louis.

PARTICIPANTS: Older drivers diagnosed with dementia (n = 130) and without dementia (n = 34). Drivers with dementia required a physician referral indicating a medical need for a driving evaluation, a diagnosis of dementia, and an Alzheimer Detection 8 score of 2. Drivers without dementia were required to be age 55 yr or older and not meet criteria for dementia.

OUTCOMES AND MEASURES: Participants completed a comprehensive driving evaluation (CDE) that included clinical measures of vision, motor, and cognition; TSNT; and WEDD. The outcome measure was performance on a standardized on-road assessment.

RESULTS: The TSNT's interrater reliability was determined to be strong (κ = .80). The TSNT and WEDD demonstrated convergent validity with cognitive measures (p < .001) and discriminant validity with visual and motor measures in the CDE. The TSNT (area under the curve [AUC] = .74) and WEDD (AUC = .71) had fair ability to predict failure on a standardized on-road assessment.

CONCLUSION AND RELEVANCE: TSNT and WEDD are recommended for use by occupational therapists in combination with other performance measures when determining fitness to drive or need for a CDE.

WHAT THIS ARTICLE ADDS: The TSNT and WEDD can be included as screening tools (in addition to other performance measures) to assist clinicians in determining which clients need to be referred for a CDE. The TSNT and WEDD can also be included as part of a CDE to assist driving rehabilitation specialists in making final recommendations regarding fitness to drive. The scores generated from the TSNT and WEDD address driving knowledge in a way that may be more understandable to clients and more relatable to skills needed to actually drive.}, } @article {pmid32364046, year = {2020}, author = {Ebadi, A and Olyaie, SS and Dastan, D}, title = {To be ionized or not to be ionized: the vital role of physicochemical properties of galbanic acid derivatives in AChE assay.}, journal = {Journal of biomolecular structure & dynamics}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/07391102.2020.1764391}, pmid = {32364046}, issn = {1538-0254}, abstract = {Alzheimer's disease is a progressive neurodegenerative disorder and patients suffer from memory loss, a decline in language skill and impairment in other cognitive functions. In the cholinergic hypothesis, dysfunction of cholinergic neurons especially in the hippocampus and cerebral cortex contributes to cognitive decline in patients. So agents that enhance acetylcholine concentration could improve cognitive function. AChEIs are among the most studied anti-Alzheimer agents. Galbanic acid as a natural compound with a sesquiterpene coumarin scaffold is a weak inhibitor of AChE. In the present contribution, we discussed the impact of carboxylic group ionization on inhibitory effects. We performed in vitro and in silico studies on galbanic acid, methyl and ethyl galbanates as AChE inhibitors. The order of inhibitory effect on AChE was obtained as ethyl galbanate ∼ methyl galbanate > galbanic acid. Our study highlights the important role of the physicochemical properties of natural lead compounds in each specific assay.Communicated by Ramaswamy H. Sarma.}, } @article {pmid32363488, year = {2020}, author = {Pardini, M and Nobili, F and Arnaldi, D and Morbelli, S and Bauckneht, M and Rissotto, R and Serrati, C and Serafini, G and Lapucci, C and Ghio, L and Amore, M and Massucco, D and Sassos, D and Bonzano, L and Mancardi, GL and Roccatagliata, L and , }, title = {123I-FP-CIT SPECT validation of nigro-putaminal MRI tractography in dementia with Lewy bodies.}, journal = {European radiology experimental}, volume = {4}, number = {1}, pages = {27}, pmid = {32363488}, issn = {2509-9280}, abstract = {BACKGROUND: Assessment of nigrostriatal degeneration is a key element to discriminate between dementia with Lewy bodies (DLB) and Alzheimer disease (AD), and it is often evaluated using ioflupane (123I-FP-CIT) single-photon emission computed tomography (SPECT). Given the limited availability of 123I-FP-CIT SPECT, we evaluated if a mask-based approach to nigroputaminal magnetic resonance imaging (MRI) diffusion-weighted tractography could be able to capture microstructural changes reflecting nigroputaminal degeneration in DLB.

METHODS: A nigroputaminal bundle mask was delineated on 12 healthy volunteers (HV) and applied to MRI diffusion-weighted data of 18 subjects with DLB, 21 subjects with AD and another group of 12 HV. The correlation between nigroputaminal fractional anisotropy (FA) values and 123I-FP-CIT SPECT findings was investigated. Shapiro-Wilk, ANOVA, ANCOVA, and parametric correlation statistics as well as receiver operating characteristic (ROC) analysis were used.

RESULTS: DLB patients showed a higher nigroputaminal FA values compared with both AD and HV-controls groups (p = 0.001 for both comparisons), while no difference was observed between HV-controls and AD groups (p = 0.450); at ROC analysis, the area under the curve for the discriminating DLB and AD subjects was 0.820; FA values correlated with 123I-FP-CIT values (on the left, r = -0.670; on the right, r = -720). No significant differences were observed for the FA of the corticospinal tract across the three groups (p = 0.740).

CONCLUSIONS: In DLB, nigroputaminal degeneration could be reliably assessed on MRI diffusion scans using a mask of nigroputaminal bundle trajectory. Nigroputaminal FA in DLB patients correlated with 123I-FP-CIT values data may allow to differentiate these patients from AD patients and HV-controls.}, } @article {pmid32363431, year = {2020}, author = {Boccardi, V and Bubba, V and Murasecco, I and Pigliautile, M and Monastero, R and Cecchetti, R and Scamosci, M and Bastiani, P and Mecocci, P and , }, title = {Serum alkaline phosphatase is elevated and inversely correlated with cognitive functions in subjective cognitive decline: results from the ReGAl 2.0 project.}, journal = {Aging clinical and experimental research}, volume = {}, number = {}, pages = {}, doi = {10.1007/s40520-020-01572-6}, pmid = {32363431}, issn = {1720-8319}, abstract = {BACKGROUND: Alkaline phosphatase has been found on neuronal membranes and plasma alkaline phosphatase (ALP) activity increases during brain injury and cerebrovascular diseases, suggesting that its levels may reflect the neuronal loss. It is known that ALP is higher in subjects affected by Alzheimer's dementia and inversely correlated with cognitive functions. No study has investigated the relationship between ALP and cognitive functions in old-age subject with pre-clinical cognitive impairment.

METHODS: This is a cross-sectional study with data gathered from the ReGAl 2.0 project (Rete Geriatrica Alzheimer-Geriatric Network on Alzheimer's disease), a large Italian multicentric clinical-based study. A cohort of 209 old-age subjects healthy controls (HC), Subjective cognitive decline (SCD), and Mild Cognitive Impairment (MCI) was included in the study. Cognitive performances were assessed with a large neuropsychological battery. The same day, serum alkaline phosphatase activity was measured in all subjects.

RESULTS: We found that the SCD group had significantly higher ALP levels as compared with HC (p = 0.001). Among all neuropsychological tests, in all population ALP levels negatively correlated with scores at attentional matrices (r = - 0.243, p = 0.002), Digit Span Forward (r = - 0.241, p = 0.003) and Letter Fluency Test (r = - 0.196, p = 0.044). Attentional Matrices (r = - 0.208, p = 0.014) and Letter Fluency Test (r = - 0.229, p = 0.019) remained significantly correlated with ALP even after controlling for gender. In the SCD group, only the Attentional Matrices significantly and negatively correlated with ALP (r = - 0.344 p = 0.035), while no significant correlations were found in HC or MCI.

CONCLUSIONS: Results indicate that serum alkaline phosphatase activity is increased in SCD and inversely correlates with cognitive functions. Further studies are needed to investigate the role of ALP in the progression to AD.}, } @article {pmid32363346, year = {2019}, author = {Hershenhouse, KS and Shauly, O and Gould, DJ and Patel, KM}, title = {Meningeal Lymphatics: A Review and Future Directions From a Clinical Perspective.}, journal = {Neuroscience insights}, volume = {14}, number = {}, pages = {1179069519889027}, pmid = {32363346}, issn = {2633-1055}, abstract = {The recent discovery of lymphatic vessels in the meningeal layers calls into question the known mechanisms of fluid and macromolecule homeostasis and immunoregulation within the central nervous system. These meningeal lymphatic vessels and their potential role in the pathophysiology of neurological disease have become a rapidly expanding area of research, with the hopes that they may provide a novel therapeutic target in the treatment of many devastating conditions. This article reviews the current state of knowledge surrounding the anatomical structure of the vessels, their functions in fluid and solute transport and immune surveillance, as well as their studied developmental biology, relationship with the novel hypothesized "glymphatic" system, and implications in neurodegenerative disease in animal models. Furthermore, this review summarizes findings from the human studies conducted thus far regarding the presence, anatomy, and drainage patterns of meningeal lymphatic vessels and discusses, from a clinical perspective, advancements in both imaging technologies and interventional methodologies used to access ultrafine peripheral lymphatic vessels.}, } @article {pmid32362228, year = {2020}, author = {Royea, J and Lacalle-Aurioles, M and Trigiani, LJ and Fermigier, A and Hamel, E}, title = {AT2R's (Angiotensin II Type 2 Receptor's) Role in Cognitive and Cerebrovascular Deficits in a Mouse Model of Alzheimer Disease.}, journal = {Hypertension (Dallas, Tex. : 1979)}, volume = {75}, number = {6}, pages = {1464-1474}, doi = {10.1161/HYPERTENSIONAHA.119.14431}, pmid = {32362228}, issn = {1524-4563}, abstract = {Antihypertensive medications targeting the renin-angiotensin system have lowered the incidence and progression of Alzheimer disease. Understanding how these medications function could lead to novel therapeutic strategies. AT4Rs (angiotensin IV receptors) have been associated with angiotensin receptor blockers' cognitive, cerebrovascular, and neuroinflammatory rescue in Alzheimer disease models. Yet, whether AT4Rs act alone or with AT2Rs remains unknown. Here, we investigated whether AT2Rs contribute to losartan's benefits and whether chronic AT2R activation could mimic angiotensin receptor blocker benefits in transgenic mice overexpressing familial Alzheimer disease mutations of the human APP (amyloid precursor protein). Losartan-treated mice (10 mg/kg per day, drinking water, 7 months) received intracerebroventricular (1 month) administration of vehicle or AT2R antagonist PD123319 (1.6 nmol/day). PD123319 countered losartan's benefits on spatial learning and memory, neurovascular coupling, and hampered those on oxidative stress and nitric oxide bioavailability. PD123319 did not oppose losartan's benefits on short-term memory and vasodilatory function and had no benefit on neuroinflammation or Aβ (amyloid β) pathology. Mice receiving either vehicle or selective AT2R agonist compound 21 (intracerebroventricular: 1 nmol/day, 1 month or drinking water: 10 mg/kg per day, 7 months), showed no improvement in memory, vasodilatory function, or nitric oxide bioavailability. Compound 21 treatment normalized neurovascular coupling, reduced astrogliosis independent of persisting microgliosis, and exacerbated oxidative stress in APP mice. Compound 21 reduced dense core Aβ plaques, but not diffuse plaques or Aβ species. Our findings suggest that targeting AT2Rs is not an ideal strategy for restoring Aβ-related cognitive and cerebrovascular deficits.}, } @article {pmid32362075, year = {2020}, author = {Frydrýšková, K and Mašek, T and Pospíšek, M}, title = {Changing faces of stress: Impact of heat and arsenite treatment on the composition of stress granules.}, journal = {Wiley interdisciplinary reviews. RNA}, volume = {}, number = {}, pages = {e1596}, doi = {10.1002/wrna.1596}, pmid = {32362075}, issn = {1757-7012}, support = {SVV-260426//Charles University/ ; GA19-13491S//Grantová Agentura České Republiky/ ; //Martina Roeselová Memorial Fellowship/ ; }, abstract = {Stress granules (SGs), hallmarks of the cellular adaptation to stress, promote survival, conserve cellular energy, and are fully dissolved upon the cessation of stress treatment. Different stresses can initiate the assembly of SGs, but arsenite and heat are the best studied of these stresses. The composition of SGs and posttranslational modifications of SG proteins differ depending on the type and severity of the stress insult, methodology used, cell line, and presence of overexpressed and tagged proteins. A group of 18 proteins showing differential localization to SGs in heat- and arsenite-stressed mammalian cell lines is described. Upon severe and prolonged stress, physiological SGs transform into more solid protein aggregates that are no longer reversible and do not contain mRNA. Similar pathological inclusions are hallmarks of neurodegenerative diseases. SGs induced by heat stress are less dynamic than SGs induced by arsenite and contain a set of unique proteins and linkage-specific polyubiquitinated proteins. The same types of ubiquitin linkages have been found to contribute to the development of neurodegenerative disorders such as Parkinson disease, Alzheimer disease, and amyotrophic lateral sclerosis (ALS). We propose heat stress-induced SGs as a possible model of an intermediate stage along the transition from dynamic, fully reversible arsenite stress-induced SGs toward aberrant SGs, the hallmark of neurodegenerative diseases. Stress- and methodology-specific differences in the compositions of SGs and the transition of SGs to aberrant protein aggregates are discussed. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes RNA Export and Localization > RNA Localization.}, } @article {pmid32360240, year = {2020}, author = {Kang, J and Shin, DW and Han, K and Park, SH and Lee, WG and Yoo, JE and Woo, SH and Park, J}, title = {Risk of dementia in prostate cancer survivors: A nationwide cohort study in Korea.}, journal = {Current problems in cancer}, volume = {}, number = {}, pages = {100578}, doi = {10.1016/j.currproblcancer.2020.100578}, pmid = {32360240}, issn = {1535-6345}, abstract = {OBJECTIVES: To investigate the effects of prostate cancer (PC) and various treatment modalities for PC, specifically androgen deprivation therapy (ADT), on the risk of dementia and dementia subtypes in PC survivors.

MATERIAL AND METHODS: A total of 51,252 patients newly diagnosed with PC from 2007 to 2013, who had no prior diagnosis of cancer or dementia, were included and matched with 209,659 non-cancer control. The screening subset was comprised of subjects who participated in a health screening program. We used Cox proportional hazards model to estimate the relative risk of dementia and dementia subtypes according to the primary treatment for the PC.

RESULTS: Compared to non-PC matched controls, PC survivors showed slightly higher risk for dementia and Alzheimer disease (AD) only in the screening cohort. While PC survivors who underwent ADT were higher risk for dementia and AD, patients who underwent surgery were lower risk for dementia and AD, compared to the non-cancer population. Compared to surgery, ADT, surgery + ADT, and active surveillance/watchful waiting showed a significantly elevated risk for dementia.

CONCLUSION: PC survivors had slightly higher risk for dementia compared to non-PC controls, which might be related to the screening effects of PC. The risk for dementia was most prominent among PC patients who underwent ADT, followed by patients who underwent AS/WW, and those who underwent surgery + ADT. This finding suggests that individualized ADT strategies that consider the survival benefit and underlying dementia risk in PC survivors are necessary.}, } @article {pmid32360163, year = {2020}, author = {Karaca, O and Buyukmert, A and Tepe, N and Ozcan, E and Kus, I}, title = {Volume estimation of brain ventricles using Cavalieri's principle and Atlas-based methods in Alzheimer disease: Consistency between methods.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jocn.2020.04.092}, pmid = {32360163}, issn = {1532-2653}, abstract = {Automatic estimations of brain ventricles are needed to assess disease progression in neurodegenerative disorders such as Alzheimer Disease (AD). The objectives of this study are to evaluate the diagnostic performances of an automated volumetric assessment tool in estimating lateral ventricle volumes in AD and to compare this with Cavalieri's principle, which is accepted as the gold standard method. This is across-sectional volumetric study including 25 Alzheimer patients and 25 healthy subjects undergoing magnetic resonance images (MRI) with a 3D turbo spin echo sequence at 1.5 Tesla. The Atlas-based method incorporated MRIStudio software to automatically measure he volumes of brain ventricles. To compare the corresponding measurements, we used manual point-counting and semi-automatic planimetry methods based on Cavalieri's principle. Bland-Altman test results indicated an excellent agreement between Cavalieri's principle and the Atlas-based method in all volumetric measurements (p < 0.05). We obtained a 64% sensitivity and 92% specificity for lateral ventricular volumes according to the Atlas-based method. AD subjects had significantly larger left and right lateral ventricle volume (LVV) when compared to control subjects in respect to three volumetric methods (p < 0.01). Lateral ventricle-to-brain ratio (VBR) statistically increased 49.23% in measurements done with the point-counting method, 45.12% with the planimetry method, and 45.49% with the Atlas-based method in AD patients (p < 0.01). As a result, the Atlas-based method may be used instead of manual volumetry to estimate brain volumes. Additionally, this method provides rapid and accurate estimations of brain ventricular volumes in-vivo examination of MRI.}, } @article {pmid32359337, year = {2020}, author = {Hrabinova, M and Pejchal, J and Kucera, T and Jun, D and Schmidt, M and Soukup, O}, title = {Is It the Twilight of BACE1 Inhibitors?.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/1570159X18666200503023323}, pmid = {32359337}, issn = {1875-6190}, abstract = {β-secretase (BACE1) has been regarded as a prime target for the development of amyloid beta (Aβ) lowering drugs in the therapy of Alzheimer´s disease (AD). Although the enzyme was discovered in 1991 and helped to formulate the Aβ hypothesis as one of the very important features of AD etiopathogenesis, progress in AD treatment utilizing BACE1 inhibitors has remained limited. Moreover, in the last years, major pharmaceutical companies have discontinued clinical trials of five BACE1 inhibitors that had been strongly perceived as prospective. In our review, the Aβ hypothesis, the enzyme, its functions, and selected substrates are described. BACE1 inhibitors are classified into four generations. Those that underwent clinical trials displayed adverse effects, including weight loss, skin rashes, worsening of neuropsychiatric symptoms, etc. Some inhibitors could not establish a statistically significant risk-benefit ratio, or even scored worse than placebo. We still believe that drugs targeting BACE1 may still hide some potential, but a different approach to BACE1 inhibition or a shift of focus to modulation of its trafficking and/or post-translational modification should now be followed.}, } @article {pmid32358220, year = {2020}, author = {Bernath, MM and Bhattacharyya, S and Nho, K and Barupal, DK and Fiehn, O and Baillie, R and Risacher, SL and Arnold, M and Jacobson, T and Trojanowski, JQ and Shaw, LM and Weiner, MW and Doraiswamy, PM and Kaddurah-Daouk, R and Saykin, AJ and , }, title = {Serum triglycerides in Alzheimer disease: Relation to neuroimaging and CSF biomarkers.}, journal = {Neurology}, volume = {94}, number = {20}, pages = {e2088-e2098}, doi = {10.1212/WNL.0000000000009436}, pmid = {32358220}, issn = {1526-632X}, abstract = {OBJECTIVE: To investigate the association of triglyceride (TG) principal component scores with Alzheimer disease (AD) and the amyloid, tau, neurodegeneration, and cerebrovascular disease (A/T/N/V) biomarkers for AD.

METHODS: Serum levels of 84 TG species were measured with untargeted lipid profiling of 689 participants from the Alzheimer's Disease Neuroimaging Initiative cohort, including 190 cognitively normal older adults (CN), 339 with mild cognitive impairment (MCI), and 160 with AD. Principal component analysis with factor rotation was used for dimension reduction of TG species. Differences in principal components between diagnostic groups and associations between principal components and AD biomarkers (including CSF, MRI and [18F]fluorodeoxyglucose-PET) were assessed with a generalized linear model approach. In both cases, the Bonferroni method of adjustment was used to correct for multiple comparisons.

RESULTS: The 84 TGs yielded 9 principal components, 2 of which, consisting of long-chain, polyunsaturated fatty acid-containing TGs (PUTGs), were significantly associated with MCI and AD. Lower levels of PUTGs were observed in MCI and AD compared to CN. PUTG principal component scores were also significantly associated with hippocampal volume and entorhinal cortical thickness. In participants carrying the APOE ε4 allele, these principal components were significantly associated with CSF β-amyloid1-42 values and entorhinal cortical thickness.

CONCLUSION: This study shows that PUTG component scores were significantly associated with diagnostic group and AD biomarkers, a finding that was more pronounced in APOE ε4 carriers. Replication in independent larger studies and longitudinal follow-up are warranted.}, } @article {pmid32356456, year = {2020}, author = {Isella, V and Rosazza, C and Gazzotti, M and Sala, J and Morzenti, S and Crivellaro, C and Appollonio, IM and Ferrarese, C and Luzzatti, C}, title = {A Metabolic Imaging Study of Lexical and Phonological Naming Errors in Alzheimer Disease.}, journal = {American journal of Alzheimer's disease and other dementias}, volume = {35}, number = {}, pages = {1533317520922390}, doi = {10.1177/1533317520922390}, pmid = {32356456}, issn = {1938-2731}, abstract = {Patients with Alzheimer disease (AD) produce a variety of errors on confrontation naming that indicate multiple loci of impairment along the naming process in this disease. We correlated brain hypometabolism, measured with 18fluoro-deoxy-glucose positron emission tomography, with semantic and formal errors, as well as nonwords deriving from phonological errors produced in a picture-naming test by 63 patients with AD. Findings suggest that neurodegeneration leads to: (1) phonemic errors, by interfering with phonological short-term memory, or with control over retrieval of phonological or prearticulatory representations, within the left supramarginal gyrus; (2) semantic errors, by disrupting general semantic or visual-semantic representations at the level of the left posterior middle and inferior occipitotemporal cortex, respectively; (3) formal errors, by damaging the lexical-phonological output interface in the left mid-anterior segment of middle and superior temporal gyri. This topography of semantic-lexical-phonological steps of naming is in substantial agreement with dual-stream neurocognitive models of word generation.}, } @article {pmid32355772, year = {2020}, author = {Yang, C and Bao, X and Zhang, L and Li, Y and Li, L and Zhang, L}, title = {Cornel iridoid glycoside ameliorates cognitive deficits in APP/PS1/tau triple transgenic mice by attenuating amyloid-beta, tau hyperphosphorylation and neurotrophic dysfunction.}, journal = {Annals of translational medicine}, volume = {8}, number = {6}, pages = {328}, pmid = {32355772}, issn = {2305-5839}, abstract = {Background: Targeted proteinopathy is involved in creating pharmacological agents that protect against Alzheimer disease (AD). Cornel iridoid glycoside (CIG) is an effective component derived from Cornus officinalis. The present study aimed to determine the effects of CIG on β-amyloid (Aβ) and tau pathology and the underlying mechanisms in APP/PS1/tau triple transgenic (3×Tg) model mice.

Methods: We intragastrically administered 16-month-old 3×Tg mice with CIG (100 and 200 mg/kg) daily for two months. Learning and memory abilities were determined using the Morris water maze (MWM) and object recognition tests (ORT). Amyloid plaques and Aβ40/42 and the expression of related proteins in the cerebral cortex and hippocampus of mice was determined by western blotting.

Results: CIG improved learning and memory impairment in 3×Tg model mice, decreased amyloid plaque deposition, Aβ40/42 and the expression of full-length amyloid precursor protein, and increased levels of ADAM-10 (α-secretase), neprilysin (NEP), and insulin degrading enzyme (IDE) in the brains of the model mice. CIG also reduced tau hyperphosphorylation, and elevated phosphorylation level of GSK-3β at Ser9 and methylation of PP2A catalytic subunit C in the model mice. Moreover, CIG increased the expression of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and phosphorylated cAMP-responsive element binding protein (p-CREB) in the brain of 3×Tg mice.

Conclusions: CIG ameliorated learning and memory deficit via reducing Aβ content and, tau hyperphosphorylation and increasing neurotrophic factors in the brain of 3×Tg mice. These results suggest that CIG may be beneficial for AD therapy.}, } @article {pmid32355332, year = {2020}, author = {Mentis, AA and Dardiotis, E and Chrousos, GP}, title = {Apolipoprotein E4 and meningeal lymphatics in Alzheimer disease: a conceptual framework.}, journal = {Molecular psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41380-020-0731-7}, pmid = {32355332}, issn = {1476-5578}, support = {GZL044-1/2015-2016//Alexander S. Onassis Public Benefit Foundation (Onassis Foundation)/ ; }, abstract = {The potential existence and roles of the meningeal lymphatic system in normal and pathological brain function have been a long-standing enigma. Recent evidence suggests that meningeal lymphatic vessels are present in both the mouse and human brain; in mice, they seem to play a role in clearing toxic amyloid-beta peptides, which have been connected with Alzheimer disease (AD). Here, we review the evidence linking the meningeal lymphatic system with human AD. Novel findings suggest that the recently described meningeal lymphatic vessels could be linked to, and possibly drain, the efferent paravascular glial lymphatic (glymphatic) system carrying cerebrospinal fluid, after solute and immune cell exchange with brain interstitial fluid. In so doing, the glymphatic system could contribute to the export of toxic solutes and immune cells from the brain (an exported fluid we wish to describe as glymph, similarly to lymph) to the meningeal lymphatic system; the latter, by being connected with downstream anatomic regions, carries the glymph to the conventional cervical lymphatic vessels and nodes. Thus, abnormal function in the meningeal lymphatic system could, in theory, lead to the accumulation, in the brain, of amyloid-beta, cellular debris, and inflammatory mediators, as well as immune cells, resulting in damage of the brain parenchyma and, in turn, cognitive and other neurologic dysfunctions. In addition, we provide novel insights into APOE4-the leading genetic risk factor for AD-and its relation to the meningeal lymphatic system. In this regard, we have reanalyzed previously published RNA-Seq data to show that induced pluripotent stem cells (iPSCs) carrying the APOE4 allele (either as APOE4 knock-in or stemming from APOE4 patients) express lower levels of (a) genes associated with lymphatic markers, and (b) genes for which well-characterized missense mutations have been linked to peripheral lymphedema. Taking into account this evidence, we propose a new conceptual framework, according to which APOE4 could play a novel role in the premature shrinkage of meningeal lymphatic vessels (meningeal lymphosclerosis), leading to abnormal meningeal lymphatic functions (meningeal lymphedema), and, in turn, reduction in the clearance of amyloid-beta and other macromolecules and inflammatory mediators, as well as immune cells, from the brain, exacerbation of AD manifestations, and progression of the disease. Altogether, these findings and their potential interpretations may herald novel diagnostic tools and therapeutic approaches in patients with AD.}, } @article {pmid32354700, year = {2020}, author = {Gutierrez, E and Lütjohann, D and Kerksiek, A and Fabiano, M and Oikawa, N and Kuerschner, L and Thiele, C and Walter, J}, title = {Importance of γ-secretase in the regulation of liver X receptor and cellular lipid metabolism.}, journal = {Life science alliance}, volume = {3}, number = {6}, pages = {}, pmid = {32354700}, issn = {2575-1077}, abstract = {Presenilins (PS) are the catalytic components of γ-secretase complexes that mediate intramembrane proteolysis. Mutations in the PS genes are a major cause of familial early-onset Alzheimer disease and affect the cleavage of the amyloid precursor protein, thereby altering the production of the amyloid β-peptide. However, multiple additional protein substrates have been identified, suggesting pleiotropic functions of γ-secretase. Here, we demonstrate that inhibition of γ-secretase causes dysregulation of cellular lipid homeostasis, including up-regulation of liver X receptors, and complex changes in the cellular lipid composition. Genetic and pharmacological inhibition of γsecretase leads to strong accumulation of cytoplasmic lipid droplets, associated with increased levels of acylglycerols, but lowered cholesteryl esters. Furthermore, accumulation of lipid droplets was augmented by increasing levels of amyloid precursor protein C-terminal fragments, indicating a critical involvement of this γ-secretase substrate. Together, these data provide a mechanism that functionally connects γ-secretase activity to cellular lipid metabolism. These effects were also observed in human astrocytic cells, indicating an important function of γ-secretase in cells critical for lipid homeostasis in the brain.}, } @article {pmid32353091, year = {2020}, author = {Scheide, MR and Schneider, AR and Jardim, GAM and Martins, GM and Durigon, DC and Saba, S and Rafique, J and Braga, AL}, title = {Electrochemical synthesis of selenyl-dihydrofurans via anodic selenofunctionalization of allyl-naphthol/phenol derivatives and their anti-Alzheimer activity.}, journal = {Organic & biomolecular chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1039/d0ob00629g}, pmid = {32353091}, issn = {1477-0539}, abstract = {Herein, we report an eco-friendly, electrosynthetic approach for the intramolecular oxyselenylation of allyl-naphthol/phenol derivatives. This reaction proceeds with 0.2 equiv. of nBu4NClO4 as an electrolyte and Pt working electrodes in an undivided cell, resulting in the selenyl-dihydrofurans in good to excellent yields. Furthermore, several of the synthesized products presented a high percentage of acetylcholinesterase (AChE) inhibition, highlighting their potential anti-Alzheimer activity.}, } @article {pmid32352149, year = {2020}, author = {Moretti, E and Baggi Menozzi, F and Elzi, L and Lepori, M}, title = {Chromobacterium violaceum bacteraemia: a new entity in Switzerland.}, journal = {Swiss medical weekly}, volume = {150}, number = {}, pages = {w20220}, doi = {10.4414/smw.2020.20220}, pmid = {32352149}, issn = {1424-3997}, abstract = {We report the uncommon clinical case of our patient, an 83-year-old woman with Alzheimer disease, who acquired a potentially fatal tropical infection in an open-air swimming pool in the Alps. Chromobacterium violaceum is a rare gram-negative anaerobe bacillus, generally associated with serious waterborne infections in tropical and subtropical regions. The patient presented to our emergency department with a 2-day history of fever and a small non-necrotic wound on the right leg after a minor injury 9 days before. It turned out to be the first infection in Switzerland due to C. violaceum, a deadly bacterium typical of tropical regions. C. violaceum appeared for the first time in Europe in the 2011. This is now the third documented case in less than a year and the second autochthonous infection ever in our continent. A delay in adequate treatment of this emerging pathogen may be associated with high fatality rates.}, } @article {pmid32351618, year = {2020}, author = {You, JS and Li, CY and Chen, W and Wu, XL and Huang, LJ and Li, RK and Gao, F and Zhang, MY and Liu, HL and Qu, WL}, title = {A network pharmacology-based study on Alzheimer disease prevention and treatment of Qiong Yu Gao.}, journal = {BioData mining}, volume = {13}, number = {}, pages = {2}, doi = {10.1186/s13040-020-00212-z}, pmid = {32351618}, issn = {1756-0381}, abstract = {Background and objective: As the pathological mechanisms of AD are complex, increasing evidence have demonstrated Chinese Medicine with multi-ingredients and multi-targets may be more suitable for the treatment of diseases with complex pathogenesis. Therefore, the study was to preliminarily decipher the bioactive compounds and potential mechanisms of Qiong Yu Gao (QYG) for AD prevention and treatment by an integrated network pharmacology approach.

Methods: Putative ingredients of QYG and significant genes of AD were retrieved from public database after screening. Then QYG ingredients target proteins/genes were obtained by target fishing. Compound-target-disease network was constructed using Cytoscape to decipher the mechanism of QYG for AD. KEGG pathway and GO enrichment analysis were performed to investigate the molecular mechanisms and pathways related to QYG for AD treatments.

Results: Finally, 70 compounds and 511 relative drug targets were collected. In which, 17 representative direct targets were found. Gene ontology enrichment analysis revealed that the adenylate cyclase-inhibiting G-protein coupled acetylcholine receptor signaling pathway was the key biological processes and were regulated simultaneously by the 17 direct targets. The KEGG pathway enrichment analysis found that three signaling pathways were closely related to AD prevention and treatment by QYG, including PI3K-Akt signaling pathway, regulation of actin cytoskeleton pathway and insulin resistance pathway.

Conclusion: This study demonstrated that QYG exerted the effect of preventing and treating AD by regulating multi-targets with multi-components. Furthermore, the study demonstrated that a network pharmacology-based approach was useful for elucidation of the interrelationship between complex diseases and interventions of Chinese herbal medicines.}, } @article {pmid32351378, year = {2020}, author = {Levit, A and Cheng, S and Hough, O and Liu, Q and Agca, Y and Agca, C and Hachinski, V and Whitehead, SN}, title = {Hypertension and Pathogenic hAPP Independently Induce White Matter Astrocytosis and Cognitive Impairment in the Rat.}, journal = {Frontiers in aging neuroscience}, volume = {12}, number = {}, pages = {82}, doi = {10.3389/fnagi.2020.00082}, pmid = {32351378}, issn = {1663-4365}, abstract = {Hypertension is recognized as a risk factor for Alzheimer disease, but the causal link remains undetermined. Although astrocytes and microglia play an important role in maintaining the neurovascular unit, astrocytes and microglia have been understudied in comorbid models of hypertension and Alzheimer disease. In this study, male transgenic Fischer 344 rats (TgAPP21) overexpressing a pathogenic human amyloid precursor protein received 8 weeks of Angiotensin II infusion to increase blood pressure, and the rats were evaluated for astrocytosis, microgliosis, and cognitive function. A linear relationship between astrocytosis and blood pressure was observed in the corpus callosum and cingulum of wildtype rats, with hypertensive wildtype rats matching the elevated baseline astrocytosis seen in normotensive transgenic rats. In contrast, hypertensive transgenic rats did not demonstrate a further increase of astrocytosis, suggesting a deficient response. Angiotensin II infusion did not affect activation of microglia, which were elevated in the white matter and hippocampus of transgenic rats. Angiotensin II infusion did impair both wildtype and transgenic rats' executive functions in the Morris Water Maze. These results present important implications for the interaction between hypertension and pathogenic human amyloid precursor protein expression, as Angiotensin II infusion produced cognitive impairments in both genotypes, but transgenic rats were additionally impaired in developing a normal astrocytic response to elevated blood pressure.}, } @article {pmid32351363, year = {2020}, author = {Wang, L and Zhang, L}, title = {Circulating Exosomal miRNA as Diagnostic Biomarkers of Neurodegenerative Diseases.}, journal = {Frontiers in molecular neuroscience}, volume = {13}, number = {}, pages = {53}, pmid = {32351363}, issn = {1662-5099}, abstract = {Neurodegenerative diseases (NDDs) are a group of diseases caused by chronic and progressive degeneration of neural tissue. The main pathological manifestations are neuronal degeneration and loss in the brain and/or spinal cord. Common NDDs include Alzheimer disease (AD), Parkinson disease (PD), Huntington disease (HD), and amyotrophic lateral sclerosis (ALS). The complicated pathological characteristics and different clinical manifestations of NDDs result in a lack of sensitive and efficient diagnostic methods. In addition, no sensitive biomarkers are available to monitor the course of NDDs, predict their prognosis, and monitor the therapeutic response. Despite extensive research in recent years, analysis of amyloid β (Aβ) and α-synuclein has failed to effectively improve NDD diagnosis. Although recent studies have indicated circulating miRNAs as promising diagnostic biomarkers of NDDs, the miRNA in the peripheral circulation is susceptible to interference by other components, making circulating miRNA results less consistent. Exosomes are small membrane vesicles with a diameter of approximately 30-100 nm that transport proteins, lipids, mRNA, and miRNA. Because recent studies have shown that exosomes have a double-membrane structure that can resist ribonuclease in the blood, giving exosomal miRNA high stability and making them resistant to degradation, they may become an ideal biomarker of circulating fluids. In this review, we discuss the applicability of circulating exosomal miRNAs as biomarkers, highlight the technical aspects of exosomal miRNA analysis, and review studies that have used circulating exosomal miRNAs as candidate diagnostic biomarkers of NDDs.}, } @article {pmid32350798, year = {2020}, author = {Zhu, L and Wang, Z and Du, Z and Qi, X and Shu, H and Liu, D and Su, F and Ye, Q and Liu, X and Zhou, Z and Tang, Y and Song, R and Wang, X and Lin, L and Li, S and Han, Y and Wang, L and Zhang, Z}, title = {Impaired Parahippocampal Gyrus-Orbitofrontal Cortex Circuit Associated with Visuospatial Memory Deficit as a Potential Biomarker and Interventional Approach for Alzheimer Disease.}, journal = {Neuroscience bulletin}, volume = {}, number = {}, pages = {}, doi = {10.1007/s12264-020-00498-3}, pmid = {32350798}, issn = {1995-8218}, abstract = {The parahippocampal gyrus-orbitofrontal cortex (PHG-OFC) circuit in humans is homologous to the postrhinal cortex (POR)-ventral lateral orbitofrontal cortex (vlOFC) circuit in rodents. Both are associated with visuospatial malfunctions in Alzheimer's disease (AD). However, the underlying mechanisms remain to be elucidated. In this study, we explored the relationship between an impaired POR-vlOFC circuit and visuospatial memory deficits through retrograde tracing and in vivo local field potential recordings in 5XFAD mice, and investigated alterations of the PHG-OFC circuit by multi-domain magnetic resonance imaging (MRI) in patients on the AD spectrum. We demonstrated that an impaired glutamatergic POR-vlOFC circuit resulted in deficient visuospatial memory in 5XFAD mice. Moreover, MRI measurements of the PHG-OFC circuit had an accuracy of 77.33% for the classification of amnestic mild cognitive impairment converters versus non-converters. Thus, the PHG-OFC circuit explains the neuroanatomical basis of visuospatial memory deficits in AD, thereby providing a potential predictor for AD progression and a promising interventional approach for AD.}, } @article {pmid32350108, year = {2020}, author = {Österlund, N and Lundqvist, M and Ilag, LL and Gräslund, A and Emanuelsson, C}, title = {Amyloid-β oligomers are captured by the DNAJB6 chaperone: Direct detection of interactions that can prevent primary nucleation.}, journal = {The Journal of biological chemistry}, volume = {295}, number = {24}, pages = {8135-8144}, pmid = {32350108}, issn = {1083-351X}, abstract = {A human molecular chaperone protein, DnaJ heat shock protein family (Hsp40) member B6 (DNAJB6), efficiently inhibits amyloid aggregation. This inhibition depends on a unique motif with conserved serine and threonine (S/T) residues that have a high capacity for hydrogen bonding. Global analysis of kinetics data has previously shown that DNAJB6 especially inhibits the primary nucleation pathways. These observations indicated that DNAJB6 achieves this remarkably effective and sub-stoichiometric inhibition by interacting not with the monomeric unfolded conformations of the amyloid-β symbol (Aβ) peptide but with aggregated species. However, these pre-nucleation oligomeric aggregates are transient and difficult to study experimentally. Here, we employed a native MS-based approach to directly detect oligomeric forms of Aβ formed in solution. We found that WT DNAJB6 considerably reduces the signals from the various forms of Aβ (1-40) oligomers, whereas a mutational DNAJB6 variant in which the S/T residues have been substituted with alanines does not. We also detected signals that appeared to represent DNAJB6 dimers and trimers to which varying amounts of Aβ are bound. These data provide direct experimental evidence that it is the oligomeric forms of Aβ that are captured by DNAJB6 in a manner which depends on the S/T residues. We conclude that, in agreement with the previously observed decrease in primary nucleation rate, strong binding of Aβ oligomers to DNAJB6 inhibits the formation of amyloid nuclei.}, } @article {pmid32349283, year = {2020}, author = {Patnaik, A and Spiombi, E and Frasca, A and Landsberger, N and Zagrebelsky, M and Korte, M}, title = {Fingolimod Modulates Dendritic Architecture in a BDNF-Dependent Manner.}, journal = {International journal of molecular sciences}, volume = {21}, number = {9}, pages = {}, pmid = {32349283}, issn = {1422-0067}, support = {KO 1674/5-1//Deutsche Forschungsgemeinschaft/ ; }, abstract = {The brain-derived neurotrophic factor (BDNF) plays crucial roles in both the developing and mature brain. Moreover, alterations in BDNF levels are correlated with the cognitive impairment observed in several neurological diseases. Among the different therapeutic strategies developed to improve endogenous BDNF levels is the administration of the BDNF-inducing drug Fingolimod, an agonist of the sphingosine-1-phosphate receptor. Fingolimod treatment was shown to rescue diverse symptoms associated with several neurological conditions (i.e., Alzheimer disease, Rett syndrome). However, the cellular mechanisms through which Fingolimod mediates its BDNF-dependent therapeutic effects remain unclear. We show that Fingolimod regulates the dendritic architecture, dendritic spine density and morphology of healthy mature primary hippocampal neurons. Moreover, the application of Fingolimod upregulates the expression of activity-related proteins c-Fos and pERK1/2 in these cells. Importantly, we show that BDNF release is required for these actions of Fingolimod. As alterations in neuronal structure underlie cognitive impairment, we tested whether Fingolimod application might prevent the abnormalities in neuronal structure typical of two neurodevelopmental disorders, namely Rett syndrome and Cdk5 deficiency disorder. We found a significant rescue in the neurite architecture of developing cortical neurons from Mecp2 and Cdkl5 mutant mice. Our study provides insights into understanding the BDNF-dependent therapeutic actions of Fingolimod.}, } @article {pmid32348895, year = {2020}, author = {Mantovani, P and Albini-Riccioli, L and Giannini, G and Milletti, D and Sorenson, TJ and Stanzani-Maserati, M and Oppi, F and Elder, BD and Cevoli, S and Cortelli, P and Palandri, G and , }, title = {Anterior Callosal Angle: A New Marker of Idiopathic Normal Pressure Hydrocephalus?.}, journal = {World neurosurgery}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.wneu.2020.04.085}, pmid = {32348895}, issn = {1878-8769}, abstract = {OBJECTIVE: Diagnosing idiopathic normal pressure hydrocephalus (iNPH) still remains a clinical challenge. The callosal angle (CA) is a widely used neuroradiologic marker for iNPH. However, the relationship of the CA to clinical features has not been well investigated. We hypothesize that iNPH symptoms might better correlate with a variant of the CA (anterior callosal angle [ACA]). We aim to establish the validity of the ACA measurement for the diagnosis of iNPH and compare it with current radiologic parameters.

METHODS: The multidisciplinary BOLOGNA PRO-HYDRO Study Group performed a retrospective review of consecutive iNPH patients. Magnetic resonance imaging studies for these patients were collected, as well as magnetic resonance imaging studies from Alzheimer disease and healthy control patients. The CA, ACA, and Evans Index were measured by 2 blinded members of the study team based on magnetic resonance images for each of these populations.

RESULTS: The ACA shows high accuracy, sensitivity, and specificity in distinguishing iNPH patients from healthy control and Alzheimer disease patients. The optimal pathologic diagnostic cut-off value for the ACA is 119 degrees. The diagnostic accuracy of the ACA is not significantly different from the CA.

CONCLUSIONS: The ACA could be a valid radiologic parameter in the diagnostic armamentarium for iNPH.}, } @article {pmid32348221, year = {2020}, author = {Sethiya, A and Agarwal, DK and Agarwal, S}, title = {Current Trends in Drug Delivery System of Curcumin and its Therapeutic Applications.}, journal = {Mini reviews in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/1389557520666200429103647}, pmid = {32348221}, issn = {1875-5607}, abstract = {Curcumin is a polyphenolic compound extracted from turmeric. Over the past years, it has acquired significant interest among researchers due to its numerous pharmacological activities like anti-cancer, anti-Alzheimer, anti-diabetic, anti-bacterial, anti-inflammatory and so on. However, the clinical use of curcumin is still obstructed due to tremendously poor bioavailability, rapid metabolism, lower gastrointestinal absorption, and low permeability through cell that makes its pharmacology thrilling. These issues have led to an enormous surge of investigation to develop curcumin nanoformulations which can overcome these restrictive causes. The scientists all across the universe are working on designing several drug delivery systems viz. liposomes, micelles, magnetic nanocarriers, etc. for curcumin and its composites which not only improve its physicochemical properties but also enhanced its therapeutic applications. The review aims to systematically examine the treasure of information about the medicinal use of curcumin. This article delivers a general idea of the current study piloted to overwhelm the complications with the bioavailability of curcumin which have exhibited an enhanced biological activity than curcumin. This article explains the latest and detailed study of curcumin and its conjugates, its phytochemistry, and biological perspectives and also proved curcumin as an efficient drug candidate for the treatment of numerous diseases. Recent advancements and futuristic viewpoints are also deliberated which shall help researchers and foster commercial translations of improved nano-sized curcumin combination for the treatment of various diseases.}, } @article {pmid32347327, year = {2020}, author = {Bronner, K and Bodner, L and Jox, RJ and Marckmann, G and Diehl-Schmid, J and Hamann, J}, title = {[Development of a decision aid for participative advance planning for people with dementia and their relatives].}, journal = {Der Nervenarzt}, volume = {}, number = {}, pages = {}, doi = {10.1007/s00115-020-00911-2}, pmid = {32347327}, issn = {1433-0407}, abstract = {BACKGROUND: Patients with a diagnosis of dementia face various important social and health-related decisions. Due to the progression of the disease it seems crucial that patients try to deal with these decisions early in the course of the disease to have the opportunity to make decisions autonomously. Professional support can help to plan in advance according to the wishes and possibilities in an effective and individualized manner.

MATERIAL AND METHODS: The instrument was developed in a multiphase process based on advance care planning and shared decision-making. The prototype was pretested on 8 patient-relative dyads from a special outpatient department for early recognition and adapted as best as possible to their needs. Subsequently, in a pilot study the applicability of the decision aid was tested as an intervention in a further 19 patient-relative dyads with trained conversion attendants (diagnosis of Alzheimer's dementia or mixed form; mini mental state examination, MMSE (Mini-Mental-State-Test-Summenwert) >20 and <27).

RESULTS: The result was a written decision-making aid for people with early stage dementia and their relatives, which supports the decision-making process (health care proxy, advance directive, living and care, driving ability). The first results showed good acceptance and handling. Patients and relatives dealt with the individual topics to a high degree and found them to be highly relevant.

CONCLUSION: Despite positive feedback from the participants with respect to acceptance and applicability, there were major difficulties in recruiting. In the future, the systematic use of decision support as part of routine care could help to support the decision-making process in this patient group.}, } @article {pmid32345767, year = {2020}, author = {Bashford, J}, title = {'Fasciculations': linguistic slip or judicious advance?.}, journal = {Practical neurology}, volume = {20}, number = {3}, pages = {262}, doi = {10.1136/practneurol-2020-002564}, pmid = {32345767}, issn = {1474-7766}, } @article {pmid32345751, year = {2020}, author = {Jinawong, K and Apaijai, N and Wongsuchai, S and Pratchayasakul, W and Chattipakorn, N and Chattipakorn, SC}, title = {Necrostatin-1 Mitigates Cognitive Dysfunction in Prediabetic Rats With No Alteration in Insulin Sensitivity.}, journal = {Diabetes}, volume = {69}, number = {7}, pages = {1411-1423}, doi = {10.2337/db19-1128}, pmid = {32345751}, issn = {1939-327X}, abstract = {Previous studies showed that 12 weeks of high-fat diet (HFD) consumption caused not only prediabetes but also cognitive decline and brain pathologies. Recently, necrostatin-1 (nec-1), a necroptosis inhibitor, showed beneficial effects in brain against stroke. However, the comparative effects of nec-1 and metformin on cognition and brain pathologies in prediabetes have not been investigated. We hypothesized that nec-1 and metformin equally attenuated cognitive decline and brain pathologies in prediabetic rats. Rats (n = 32) were fed with either normal diet (ND) or HFD for 20 weeks. At week 13, ND-fed rats were given a vehicle (n = 8) and HFD-fed rats were randomly assigned into three subgroups (n = 8/subgroup) with vehicle, nec-1, or metformin for 8 weeks. Metabolic parameters, cognitive function, brain insulin receptor function, synaptic plasticity, dendritic spine density, microglial morphology, brain mitochondrial function, Alzheimer protein, and cell death were determined. HFD-fed rats exhibited prediabetes, cognitive decline, and brain pathologies. Nec-1 and metformin equally improved cognitive function, synaptic plasticity, dendritic spine density, microglial morphology, and brain mitochondrial function and reduced hyperphosphorylated Tau and necroptosis in HFD-fed rats. Interestingly, metformin, but not nec-1, improved brain insulin sensitivity in those rats. In conclusion, necroptosis inhibition directly improved cognition in prediabetic rats without alteration in insulin sensitivity.}, } @article {pmid32342466, year = {2020}, author = {Gholamnezhad, Z and Boskabady, MH and Jahangiri, Z}, title = {Exercise and Dementia.}, journal = {Advances in experimental medicine and biology}, volume = {1228}, number = {}, pages = {303-315}, doi = {10.1007/978-981-15-1792-1_20}, pmid = {32342466}, issn = {0065-2598}, abstract = {Several experimental and human studies documented the preventive and therapeutic effects of exercise on various diseases as well as the normal physiological function of different systems during aging. The findings of several basic animal studies and clinical investigations identified the advantageous effects of exercise as non-pharmaceutical intervention on dementia and Alzheimer's disease (AD). The main positive effects suggested for exercise are less cognitive and behavioral impairment or decline, development of health-associated conditions (stress, sleep), reduction of dementia risk factors including chronic non-communicable disease (diabetes, cardiovascular disease), increase in neurotrophins, enhancement of brain blood flow, angiogenesis, neurogenesis, synaptogenesis and synaptic plasticity in the brain memory-related region (e.g., hippocampus), and reduction of neuroinflammation and apoptosis. However, regarding the controversial evidence in literature, designing standard clinical and experimental studies to reveal the correlation between physical activity and dementia sign and symptom including biomarker alternation, brain supramolecular and molecular changes, and neuropsychological manifestation is necessary for preparation of effective guidelines and recommendations.}, } @article {pmid32341240, year = {2020}, author = {Mavroudis, I and Petridis, F and Chatzikonstantinou, S and Kazis, D}, title = {Alpha-synuclein Levels in the Differential Diagnosis of Lewy Bodies Dementia and Other Neurodegenerative Disorders: A Meta-analysis.}, journal = {Alzheimer disease and associated disorders}, volume = {}, number = {}, pages = {}, doi = {10.1097/WAD.0000000000000381}, pmid = {32341240}, issn = {1546-4156}, abstract = {SUBJECTIVES: Lewy body dementia (LBD) is the second most common type of neurodegenerative dementia after Alzheimer disease (AD). It is characterized by the accumulation of Lewy bodies and Lewy neurites which are composed of aggregated phosphorylated alpha-synuclein, which is a presynaptic neuronal protein genetically and neuropathologically linked to Parkinson disease and to LBD. Alpha-synuclein is thought to contribute to LBD pathogenesis and to linked to disruption of cellular homeostasis and neuronal death, through effects on various intracellular targets, including synaptic function.

METHODS: In the present study, we did a meta-analysis on the reliability of alpha-synuclein levels in the cerebrospinal fluid (CSF) for the discrimination between LBD and other neurodegenerative disorders including AD, Parkinson disease (PD) dementia, progressive supranuclear palsy (PSP), multiple system atrophy (MSA) and frontotemporal dementia (FTD).

RESULTS: CSF alpha-synuclein levels were significantly different in LBD compared with AD, but no statistical difference was found between LBD, and dementia in PD, MSA, PSP, and FTD.

CONCLUSION: Alpha-synuclein levels in the CSF can be used for the discrimination between LBD and AD, but not LBD and other neurodegenerative disorders such as dementia in PD, MSA, FTD, and PSP.}, } @article {pmid32340040, year = {2020}, author = {Hemmy, LS and Linskens, EJ and Silverman, PC and Miller, MA and Talley, KMC and Taylor, BC and Ouellette, JM and Greer, NL and Wilt, TJ and Butler, M and Fink, HA}, title = {Brief Cognitive Tests for Distinguishing Clinical Alzheimer-Type Dementia From Mild Cognitive Impairment or Normal Cognition in Older Adults With Suspected Cognitive Impairment.}, journal = {Annals of internal medicine}, volume = {172}, number = {10}, pages = {678-687}, doi = {10.7326/M19-3889}, pmid = {32340040}, issn = {1539-3704}, abstract = {BACKGROUND: The accuracy and harms of brief cognitive tests for identifying clinical Alzheimer-type dementia (CATD) are uncertain.

PURPOSE: To summarize evidence on accuracy and harms of brief cognitive tests for CATD in older adults with suspected cognitive impairment.

DATA SOURCES: Electronic bibliographic databases (from inception to November 2019) and systematic review bibliographies.

STUDY SELECTION: English-language, controlled observational studies in older adults that evaluated the accuracy of brief cognitive tests (standalone tests; memory, executive function, and language tests; and brief multidomain batteries) for distinguishing CATD from mild cognitive impairment (MCI) or normal cognition as defined by established diagnostic criteria. Studies with low or medium risk of bias (ROB) were analyzed.

DATA EXTRACTION: Two reviewers rated ROB. One reviewer extracted data; the other verified extraction accuracy.

DATA SYNTHESIS: Fifty-seven studies met analysis criteria. Many brief, single cognitive tests were highly sensitive and specific for distinguishing CATD from normal cognition. These included standalone tests (clock-drawing test, median sensitivity 0.79 and specificity 0.88 [8 studies]; Mini-Mental State Examination, 0.88 and 0.94 [7 studies]; Montreal Cognitive Assessment, 0.94 and 0.94 [2 studies]; and Brief Alzheimer Screen, 0.92 and 0.97 [1 study]), memory tests (list delayed recall, 0.89 and 0.94 [5 studies]), and language tests (category fluency, 0.92 and 0.89 [9 studies]). Accuracy was lower in distinguishing mild CATD from normal cognition and distinguishing CATD from MCI. No studies reported on testing harms.

LIMITATIONS: Studies were small. Few test metrics were evaluated by multiple studies. Few studies directly compared different tests, scores, cut points, or test combinations.

CONCLUSION: Many brief, single cognitive tests accurately distinguish CATD from normal cognition in older adults but are less accurate in distinguishing mild CATD from normal cognition or CATD from MCI. No studies reported on testing harms.

PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. (PROSPERO: CRD42018117897).}, } @article {pmid32340038, year = {2020}, author = {Fink, HA and Linskens, EJ and Silverman, PC and McCarten, JR and Hemmy, LS and Ouellette, JM and Greer, NL and Wilt, TJ and Butler, M}, title = {Accuracy of Biomarker Testing for Neuropathologically Defined Alzheimer Disease in Older Adults With Dementia.}, journal = {Annals of internal medicine}, volume = {172}, number = {10}, pages = {669-677}, doi = {10.7326/M19-3888}, pmid = {32340038}, issn = {1539-3704}, abstract = {BACKGROUND: Biomarker accuracy for Alzheimer disease (AD) is uncertain.

PURPOSE: To summarize evidence on biomarker accuracy for classifying AD in older adults with dementia.

DATA SOURCES: Electronic bibliographic databases (searched from January 2012 to November 2019 for brain imaging and cerebrospinal fluid [CSF] tests and from inception to November 2019 for blood tests), ClinicalTrials.gov (to November 2019), and systematic review bibliographies.

STUDY SELECTION: English-language studies evaluating the accuracy of brain imaging, CSF testing, or blood tests for distinguishing neuropathologically defined AD from non-AD among older adults with dementia. Studies with low or medium risk of bias were analyzed.

DATA EXTRACTION: Two reviewers rated risk of bias. One extracted data; the other verified accuracy.

DATA SYNTHESIS: Fifteen brain imaging studies and 9 CSF studies met analysis criteria. Median sensitivity and specificity, respectively, were 0.91 and 0.92 for amyloid positron emission tomography (PET), 0.89 and 0.74 for 18F-labeled fluorodeoxyglucose (18F-FDG) PET, 0.64 and 0.83 for single-photon emission computed tomography, and 0.91 and 0.89 for medial temporal lobe atrophy on magnetic resonance imaging (MRI). Individual CSF biomarkers and ratios had moderate sensitivity (range, 0.62 to 0.83) and specificity (range, 0.53 to 0.69); in the few direct comparisons, β-amyloid 42 (Aβ42)/phosphorylated tau (p-tau) ratio, total tau (t-tau)/Aβ42 ratio, and p-tau appeared more accurate than Aβ42 and t-tau alone. Single studies suggested that amyloid PET, 18F-FDG PET, and CSF test combinations may add accuracy to clinical evaluation.

LIMITATIONS: Studies were small, biomarker cut points and neuropathologic AD were inconsistently defined, and methods with uncertain applicability to typical clinical settings were used. Few studies directly compared biomarkers, assessed test combinations, evaluated whether biomarkers improved classification accuracy when added to clinical evaluation, or reported harms.

CONCLUSION: In methodologically heterogeneous studies of uncertain applicability to typical clinical settings, amyloid PET, 18F-FDG PET, and MRI were highly sensitive for neuropathologic AD. Amyloid PET, 18F-FDG PET, and CSF test combinations may add accuracy to clinical evaluation.

PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. (PROSPERO: CRD42018117897).}, } @article {pmid32340037, year = {2020}, author = {Fink, HA and Linskens, EJ and MacDonald, R and Silverman, PC and McCarten, JR and Talley, KMC and Forte, ML and Desai, PJ and Nelson, VA and Miller, MA and Hemmy, LS and Brasure, M and Taylor, BC and Ng, W and Ouellette, JM and Sheets, KM and Wilt, TJ and Butler, M}, title = {Benefits and Harms of Prescription Drugs and Supplements for Treatment of Clinical Alzheimer-Type Dementia.}, journal = {Annals of internal medicine}, volume = {172}, number = {10}, pages = {656-668}, doi = {10.7326/M19-3887}, pmid = {32340037}, issn = {1539-3704}, abstract = {BACKGROUND: Effects of drug treatment of clinical Alzheimer-type dementia (CATD) are uncertain.

PURPOSE: To summarize evidence on the effects of prescription drugs and supplements for CATD treatment.

DATA SOURCES: Electronic bibliographic databases (inception to November 2019), ClinicalTrials.gov (to November 2019), and systematic review bibliographies.

STUDY SELECTION: English-language trials of prescription drug and supplement treatment in older adults with CATD that report cognition, function, global measures, behavioral and psychological symptoms of dementia (BPSD), or harms. Minimum treatment was 24 weeks (≥2 weeks for selected BPSD).

DATA EXTRACTION: Studies with low or medium risk of bias (ROB) were analyzed. Two reviewers rated ROB. One reviewer extracted data; another verified extraction accuracy.

DATA SYNTHESIS: Fifty-five studies reporting non-BPSD outcomes (most ≤26 weeks) and 12 reporting BPSD (most ≤12 weeks) were analyzed. Across CATD severity, mostly low-strength evidence suggested that, compared with placebo, cholinesterase inhibitors produced small average improvements in cognition (median standardized mean difference [SMD], 0.30 [range, 0.24 to 0.52]), no difference to small improvement in function (median SMD, 0.19 [range, -0.10 to 0.22]), no difference in the likelihood of at least moderate improvement in global clinical impression (median absolute risk difference, 4% [range, 2% to 4%]), and increased withdrawals due to adverse events. In adults with moderate to severe CATD receiving cholinesterase inhibitors, low- to insufficient-strength evidence suggested that, compared with placebo, add-on memantine inconsistently improved cognition and improved global clinical impression but not function. Evidence was mostly insufficient about prescription drugs for BPSD and about supplements for all outcomes.

LIMITATION: Most drugs had few trials without high ROB, especially for supplements, active drug comparisons, BPSD, and longer trials.

CONCLUSION: Cholinesterase inhibitors and memantine slightly reduced short-term cognitive decline, and cholinesterase inhibitors slightly reduced reported functional decline, but differences versus placebo were of uncertain clinical importance. Evidence was mostly insufficient on drug treatment of BPSD and on supplements for all outcomes.

PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. (PROSPERO: CRD42018117897).}, } @article {pmid32340036, year = {2020}, author = {Shah, RC and Bennett, DA}, title = {Physicians and Alzheimer Dementia: Past, Present, and Future.}, journal = {Annals of internal medicine}, volume = {172}, number = {10}, pages = {695-696}, doi = {10.7326/M20-1500}, pmid = {32340036}, issn = {1539-3704}, } @article {pmid32338734, year = {2020}, author = {Fleisher, AS and Pontecorvo, MJ and Devous, MD and Lu, M and Arora, AK and Truocchio, SP and Aldea, P and Flitter, M and Locascio, T and Devine, M and Siderowf, A and Beach, TG and Montine, TJ and Serrano, GE and Curtis, C and Perrin, A and Salloway, S and Daniel, M and Wellman, C and Joshi, AD and Irwin, DJ and Lowe, VJ and Seeley, WW and Ikonomovic, MD and Masdeu, JC and Kennedy, I and Harris, T and Navitsky, M and Southekal, S and Mintun, MA and , }, title = {Positron Emission Tomography Imaging With [18F]flortaucipir and Postmortem Assessment of Alzheimer Disease Neuropathologic Changes.}, journal = {JAMA neurology}, volume = {}, number = {}, pages = {}, pmid = {32338734}, issn = {2168-6157}, support = {P30 AG019610/AG/NIA NIH HHS/United States ; }, abstract = {Importance: Positron emission tomography (PET) may increase the diagnostic accuracy and confirm the underlying neuropathologic changes of Alzheimer disease (AD).

Objective: To determine the accuracy of antemortem [18F]flortaucipir PET images for predicting the presence of AD-type tau pathology at autopsy.

This diagnostic study (A16 primary cohort) was conducted from October 2015 to June 2018 at 28 study sites (27 in US sites and 1 in Australia). Individuals with a terminal illness who were older than 50 years and had a projected life expectancy of less than 6 months were enrolled. All participants underwent [18F]flortaucipir PET imaging, and scans were interpreted by 5 independent nuclear medicine physicians or radiologists. Supplemental autopsy [18F]flortaucipir images and pathological samples were also collected from 16 historically collected cases. A second study (FR01 validation study) was conducted from March 26 to April 26, 2019, in which 5 new readers assessed the original PET images for comparison to autopsy.

Main Outcomes and Measures: [18F]flortaucipir PET images were visually assessed and compared with immunohistochemical tau pathology. An AD tau pattern of flortaucipir retention was assessed for correspondence with a postmortem B3-level (Braak stage V or VI) pathological pattern of tau accumulation and to the presence of amyloid-β plaques sufficient to meet the criteria for high levels of AD neuropathological change. Success was defined as having at least 3 of the 5 readers above the lower bounds of the 95% CI for both sensitivity and specificity of 50% or greater.

Results: A total of 156 patients were enrolled in the A16 study and underwent [18F]flortaucipir PET imaging. Of these, 73 died during the study, and valid autopsies were performed for 67 of these patients. Three autopsies were evaluated as test cases and removed from the primary cohort (n = 64). Of the 64 primary cohort patients, 34 (53%) were women and 62 (97%) were white; mean (SD) age was 82.5 (9.6) years; and 49 (77%) had dementia, 1 (2%) had mild cognitive impairment, and 14 (22%) had normal cognition. Prespecified success criteria were met for the A16 primary cohort. The flortaucipir PET scans predicted a B3 level of tau pathology, with sensitivity ranging from 92.3% (95% CI, 79.7%-97.3%) to 100.0% (95% CI, 91.0%-100.0%) and specificity ranging from 52.0% (95% CI, 33.5%-70.0%) to 92.0% (95% CI, 75.0%-97.8%). A high level of AD neuropathological change was predicted with sensitivity of 94.7% (95% CI, 82.7%-98.5%) to 100.0% (95% CI, 90.8%-100.0%) and specificity of 50.0% (95% CI, 32.1%-67.9%) to 92.3% (95% CI, 75.9%-97.9%). The FR01 validation study also met prespecified success criteria. Addition of the supplemental autopsy data set and 3 test cases, which comprised a total of 82 patients and autopsies for both the A16 and FR01 studies, resulted in improved specificity and comparable overall accuracy. Among the 156 enrolled participants, 14 (9%) experienced at least 1 treatment-emergent adverse event.

Conclusions and Relevance: This study's findings suggest that PET imaging with [18F]flortaucipir could be used to identify the density and distribution of AD-type tau pathology and the presence of high levels of AD neuropathological change, supporting a neuropathological diagnosis of AD.}, } @article {pmid32337333, year = {2020}, author = {Bussies, PL and Rajabli, F and Griswold, A and Dorfsman, DA and Whitehead, P and Adams, LD and Mena, PR and Cuccaro, M and Haines, JL and Byrd, GS and Beecham, GW and Pericak-Vance, MA and Young, JI and Vance, JM}, title = {Use of local genetic ancestry to assess TOMM40-523' and risk for Alzheimer disease.}, journal = {Neurology. Genetics}, volume = {6}, number = {2}, pages = {e404}, pmid = {32337333}, issn = {2376-7839}, abstract = {Objective: Here, we re-examine TOMM40-523' as a race/ethnicity-specific risk modifier for late-onset Alzheimer disease (LOAD) with adjustment for local genomic ancestry (LGA) in Apolipoprotein E (APOE) ε4 haplotypes.

Methods: The TOMM40-523' size was determined by fragment analysis and whole genome sequencing in homozygous APOE ε3 and APOE ε4 haplotypes of African (AF) or European (EUR) ancestry. The risk for LOAD was assessed within groups by allele size.

Results: The TOMM40-523' length did not modify risk for LOAD in APOE ε4 haplotypes with EUR or AF LGA. Increasing length of TOMM40-523' was associated with a significantly reduced risk for LOAD in EUR APOE ε3 haplotypes.

Conclusions: Adjustment for LGA confirms that TOMM40-523' cannot explain the strong differential risk for LOAD between APOE ε4 with EUR and AF LGA. Our study does confirm previous reports that increasing allele length of the TOMM40-523' repeat is associated with decreased risk for LOAD in carriers of homozygous APOE ε3 alleles and demonstrates that this effect is occurring in those individuals with the EUR LGA APOE ε3 allele haplotype.}, } @article {pmid32337326, year = {2020}, author = {Raj, S and Vishnoi, A and Srivastava, A}, title = {GOLD standard dataset for Alzheimer genes.}, journal = {Data in brief}, volume = {30}, number = {}, pages = {105439}, pmid = {32337326}, issn = {2352-3409}, abstract = {Alzheimer disease is a genetically complex multigenic neurodegenerative disorder, resulting from the interaction between multiple genes. Most of the earlier studies reported only few specific genes that have involvement in Alzheimer. However more than hundreds of susceptible genes have been observed, that have significant role in the development and progression of Alzheimer. Among all the existing data resources, Genetic association database is the most popular data source that contains information about genes, their association classes into positive, negative and neutral class and supporting reference. However, it contains lot of false positives and negatives associations. We have taken this data as reference and performed the double fold cross validation to compile the comprehensive list of Alzheimer genes, their association class viz, positive, negative or ambiguous with the disease and reference sentence confirming the association. The data generated will be used as a GOLD standard reference data set for the training of machine learning classifier to predict the classification of published literature not only in Alzheimer but in other diseases as well. In addition, positive associated genes data can also be used for the system level modelling or meta analysis of Alzheimer.}, } @article {pmid32336408, year = {2020}, author = {Maestú, F and Fernández, A}, title = {Role of Magnetoencephalography in the Early Stages of Alzheimer Disease.}, journal = {Neuroimaging clinics of North America}, volume = {30}, number = {2}, pages = {217-227}, doi = {10.1016/j.nic.2020.01.003}, pmid = {32336408}, issn = {1557-9867}, abstract = {As synaptic dysfunction is an early manifestation of Alzheimer disease (AD) pathology, magnetoencephalography (MEG) is capable of detecting disruptions by assessing the synchronized oscillatory activity of thousands of neurons that rely on the integrity of neural connections. MEG findings include slowness of the oscillatory activity, accompanied by a reduction of the alpha band power, and dysfunction of the functional networks. These findings are associated with the neuropathology of the disease and cognitive impairment. These neurophysiological biomarkers predict which patients with mild cognitive impairment will develop dementia. MEG has demonstrated its utility as a noninvasive biomarker for early detection of AD.}, } @article {pmid32336252, year = {2020}, author = {Chorlton, SD}, title = {Reanalysis of Alzheimer's brain sequencing data reveals absence of purported HHV6A and HHV7.}, journal = {Journal of bioinformatics and computational biology}, volume = {18}, number = {1}, pages = {2050012}, doi = {10.1142/S0219720020500122}, pmid = {32336252}, issn = {1757-6334}, abstract = {Readhead et al. recently reported in Neuron the detection and association of human herpesviruses 6A (HHV6A) and 7 (HHV7) with Alzheimer's disease by shotgun sequencing. I was skeptical of the specificity of their modified Viromescan bioinformatics method and subsequent analysis for numerous reasons. Using their supplementary data, the prevalence of variola virus, the etiological agent of the eradicated disease smallpox, can be calculated at 97.5% of their Mount Sinai Brain Bank dataset. Reanalysis of Readhead et al.'s data using highly sensitive and specific alternative methods finds no HHV7 reads in their samples; HHV6A reads were found in only 2 out of their top 15 samples sorted by reported HHV6A abundance. Finally, recreation of Readhead et al.'s modified Viromescan method identifies reasons for its low specificity.}, } @article {pmid32334404, year = {2020}, author = {Koenig, LN and Day, GS and Salter, A and Keefe, S and Marple, LM and Long, J and LaMontagne, P and Massoumazada, P and Snider, BJ and Kanthamneni, M and Raji, CA and Ghoshal, N and Gordon, BA and Miller-Thomas, M and Morris, JC and Shimony, JS and Benzinger, TLS and , }, title = {Select Atrophied Regions in Alzheimer disease (SARA): An improved volumetric model for identifying Alzheimer disease dementia.}, journal = {NeuroImage. Clinical}, volume = {26}, number = {}, pages = {102248}, doi = {10.1016/j.nicl.2020.102248}, pmid = {32334404}, issn = {2213-1582}, support = {R01 AG043434/AG/NIA NIH HHS/United States ; U01 AG024904/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; UL1 TR000448/TR/NCATS NIH HHS/United States ; U19 AG032438/AG/NIA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; P50 AG005681/AG/NIA NIH HHS/United States ; R01 EB009352/EB/NIBIB NIH HHS/United States ; P30 NS098577/NS/NINDS NIH HHS/United States ; }, abstract = {INTRODUCTION: Volumetric biomarkers for Alzheimer disease (AD) are attractive due to their wide availability and ease of administration, but have traditionally shown lower diagnostic accuracy than measures of neuropathological contributors to AD. Our purpose was to optimize the diagnostic specificity of structural MRIs for AD using quantitative, data-driven techniques.

METHODS: This retrospective study assembled several non-overlapping cohorts (total n = 1287) with publicly available data and clinical patients from Barnes-Jewish Hospital (data gathered 1990-2018). The Normal Aging Cohort (n = 383) contained amyloid biomarker negative, cognitively normal (CN) participants, and provided a basis for determining age-related atrophy in other cohorts. The Training (n = 216) and Test (n = 109) Cohorts contained participants with symptomatic AD and CN controls. Classification models were developed in the Training Cohort and compared in the Test Cohort using the receiver operating characteristics areas under curve (AUCs). Additional model comparisons were done in the Clinical Cohort (n = 579), which contained patients who were diagnosed with dementia due to various etiologies in a tertiary care outpatient memory clinic.

RESULTS: While the Normal Aging Cohort showed regional age-related atrophy, classification models were not improved by including age as a predictor or by using volumetrics adjusted for age-related atrophy. The optimal model used multiple regions (hippocampal volume, inferior lateral ventricle volume, amygdala volume, entorhinal thickness, and inferior parietal thickness) and was able to separate AD and CN controls in the Test Cohort with an AUC of 0.961. In the Clinical Cohort, this model separated AD from non-AD diagnoses with an AUC 0.820, an incrementally greater separation of the cohort than by hippocampal volume alone (AUC of 0.801, p = 0.06). Greatest separation was seen for AD vs. frontotemporal dementia and for AD vs. non-neurodegenerative diagnoses.

CONCLUSIONS: Volumetric biomarkers distinguished individuals with symptomatic AD from CN controls and other dementia types but were not improved by controlling for normal aging.}, } @article {pmid32333900, year = {2020}, author = {Karikari, TK and Pascoal, TA and Ashton, NJ and Janelidze, S and Benedet, AL and Rodriguez, JL and Chamoun, M and Savard, M and Kang, MS and Therriault, J and Schöll, M and Massarweh, G and Soucy, JP and Höglund, K and Brinkmalm, G and Mattsson, N and Palmqvist, S and Gauthier, S and Stomrud, E and Zetterberg, H and Hansson, O and Rosa-Neto, P and Blennow, K}, title = {Blood phosphorylated tau 181 as a biomarker for Alzheimer's disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts.}, journal = {The Lancet. Neurology}, volume = {19}, number = {5}, pages = {422-433}, doi = {10.1016/S1474-4422(20)30071-5}, pmid = {32333900}, issn = {1474-4465}, abstract = {BACKGROUND: CSF and PET biomarkers of amyloid β and tau accurately detect Alzheimer's disease pathology, but the invasiveness, high cost, and poor availability of these detection methods restrict their widespread use as clinical diagnostic tools. CSF tau phosphorylated at threonine 181 (p-tau181) is a highly specific biomarker for Alzheimer's disease pathology. We aimed to assess whether blood p-tau181 could be used as a biomarker for Alzheimer's disease and for prediction of cognitive decline and hippocampal atrophy.

METHODS: We developed and validated an ultrasensitive blood immunoassay for p-tau181. Assay performance was evaluated in four clinic-based prospective cohorts. The discovery cohort comprised patients with Alzheimer's disease and age-matched controls. Two validation cohorts (TRIAD and BioFINDER-2) included cognitively unimpaired older adults (mean age 63-69 years), participants with mild cognitive impairment (MCI), Alzheimer's disease, and frontotemporal dementia. In addition, TRIAD included healthy young adults (mean age 23 years) and BioFINDER-2 included patients with other neurodegenerative disorders. The primary care cohort, which recruited participants in Montreal, Canada, comprised control participants from the community without a diagnosis of a neurological condition and patients referred from primary care physicians of the Canadian National Health Service for specialist care. Concentrations of plasma p-tau181 were compared with established CSF and PET biomarkers and longitudinal measurements using Spearman correlation, area under the curve (AUC), and linear regression analyses.

FINDINGS: We studied 37 individuals in the discovery cohort, 226 in the first validation cohort (TRIAD), 763 in the second validation cohort (BioFINDER-2), and 105 in the primary care cohort (n=1131 individuals). In all cohorts, plasma p-tau181 showed gradual increases along the Alzheimer's disease continuum, from the lowest concentrations in amyloid β-negative young adults and cognitively unimpaired older adults, through higher concentrations in the amyloid β-positive cognitively unimpaired older adults and MCI groups, to the highest concentrations in the amyloid β-positive MCI and Alzheimer's disease groups (p<0·001, Alzheimer's disease vs all other groups). Plasma p-tau181 distinguished Alzheimer's disease dementia from amyloid β-negative young adults (AUC=99·40%) and cognitively unimpaired older adults (AUC=90·21-98·24% across cohorts), as well as other neurodegenerative disorders, including frontotemporal dementia (AUC=82·76-100% across cohorts), vascular dementia (AUC=92·13%), progressive supranuclear palsy or corticobasal syndrome (AUC=88·47%), and Parkinson's disease or multiple systems atrophy (AUC=81·90%). Plasma p-tau181 was associated with PET-measured cerebral tau (AUC=83·08-93·11% across cohorts) and amyloid β (AUC=76·14-88·09% across cohorts) pathologies, and 1-year cognitive decline (p=0·0015) and hippocampal atrophy (p=0·015). In the primary care cohort, plasma p-tau181 discriminated Alzheimer's disease from young adults (AUC=100%) and cognitively unimpaired older adults (AUC=84·44%), but not from MCI (AUC=55·00%).

INTERPRETATION: Blood p-tau181 can predict tau and amyloid β pathologies, differentiate Alzheimer's disease from other neurodegenerative disorders, and identify Alzheimer's disease across the clinical continuum. Blood p-tau181 could be used as a simple, accessible, and scalable test for screening and diagnosis of Alzheimer's disease.

FUNDING: Alzheimer Drug Discovery Foundation, European Research Council, Swedish Research Council, Swedish Alzheimer Foundation, Swedish Dementia Foundation, Alzheimer Society Research Program.}, } @article {pmid32332458, year = {2020}, author = {Chan Kwong, A and Cassé-Perrot, C and Costes-Salon, MC and Jouve, E and Lanteaume, L and Audebert, C and Rouby, F and Lefebvre, MN and Ranjeva, JP and Beck, A and Deplanque, D and Ponchel, A and Vervueren, C and Truillet, R and Babilon, C and Auffret, A and Richardson, JC and Payoux, P and Bartrés-Faz, D and Blin, O and Bordet, R and Micallef, J and , }, title = {An Alzheimer Disease Challenge Model: 24-Hour Sleep Deprivation in Healthy Volunteers, Impact on Working Memory, and Reversal Effect of Pharmacological Intervention: A Randomized, Double-Blind, Placebo-Controlled, Crossover Study.}, journal = {Journal of clinical psychopharmacology}, volume = {40}, number = {3}, pages = {222-230}, doi = {10.1097/JCP.0000000000001199}, pmid = {32332458}, issn = {1533-712X}, abstract = {PURPOSE/BACKGROUND: Alzheimer disease (AD) is a public health issue because of the low number of symptomatic drugs and the difficulty to diagnose it at the prodromal stage. The need to develop new treatments and to validate sensitive tests for early diagnosis could be met by developing a challenge model reproducing cognitive impairments of AD. Therefore, we implemented a 24-hour sleep deprivation (SD) design on healthy volunteers in a randomized, double-blind, placebo-controlled, crossover study on 36 healthy volunteers.

METHODS/PROCEDURE: To validate the SD model, cognitive tests were chosen to assess a transient worsening of cognitive functions after SD and a restoration under modafinil as positive control (one dose of 200 mg). Then, the same evaluations were replicated after 15 days of donepezil (5 mg/d) or memantine (10 mg/d). The working memory (WM) function was assessed by the N-back task and the rapid visual processing (RVP) task.

FINDINGS/RESULTS: The accuracy of the N-back task and the reaction time of the RVP revealed the alteration of the WM with SD and its restoration with modafinil (changes in score after SD compared with baseline before SD), respectively, in the placebo group and in the modafinil group (-0.2% and +1.0% of satisfactory answers, P = 0.022; +21.3 and +1.9 milliseconds of reaction time, P = 0.025). Alzheimer disease drugs also tended to reverse this deterioration: the accuracy of the N-back task was more stable through SD (compared with -3.0% in the placebo group, respectively, in the memantine group and in the donepezil group: -1.4% and -1.6%, P = 0.027 and P = 0.092) and RVP reaction time was less impacted (compared with +41.3 milliseconds in the placebo group, respectively, in the memantine group and in the donepezil group: +16.1 and +29.3 milliseconds, P = 0.034 and P = 0.459).

IMPLICATIONS/CONCLUSIONS: Our SD challenge model actually led to a worsening of WM that was moderated by both modafinil and AD drugs. To use this approach, the cognitive battery, the vulnerability of the subjects to SD, and the expected drug effect should be carefully considered.}, } @article {pmid32332125, year = {2020}, author = {Smirnov, DS and Galasko, D and Edland, SD and Filoteo, JV and Hansen, LA and Salmon, DP}, title = {Cognitive decline profiles differ in Parkinson disease dementia and dementia with Lewy bodies.}, journal = {Neurology}, volume = {94}, number = {20}, pages = {e2076-e2087}, doi = {10.1212/WNL.0000000000009434}, pmid = {32332125}, issn = {1526-632X}, abstract = {OBJECTIVE: To examine whether domain-specific patterns of cognitive impairment and trajectories of decline differed in patients with clinically diagnosed Parkinson disease dementia (PDD) (N = 29) and autopsy-confirmed dementia with Lewy bodies (DLB) (N = 58) or Alzheimer disease (AD) (N = 174) and to determine the impact of pooling patients with PDD and DLB in clinical trials targeting cognition.

METHODS: Patients were matched on demographics and level of global cognitive impairment. Patterns of cross-sectional performance and longitudinal decline were examined in 4 cognitive domains: Visuospatial, Memory, Executive, and Language. Power analyses were performed to determine the numbers of participants needed to adequately power a hypothetical clinical trial to slow cognitive decline in pure PDD, pure DLB, or a mixed PDD/DLB group.

RESULTS: Both DLB and PDD were more impaired and declined more rapidly than AD in the Visuospatial domain. Patients with PDD exhibited the most impairment and fastest decline in Executive, although patients with DLB also declined faster than AD. Memory was more impaired in AD than DLB and in both compared with PDD; however, all 3 groups declined at comparable rates. In contrast, PDD declined at a slower rate on Language measures than DLB or AD. Power analyses suggest that Visuospatial and Executive outcome measures would be most sensitive in PDD, but Memory and Language in DLB.

CONCLUSION: DLB and PDD differ from each other, and from AD, in a cognitive domain-specific manner. As such, different outcome measures may be most sensitive to detecting changes in DLB vs PDD, suggesting that the 2 should be analyzed separately in clinical trials.}, } @article {pmid32331609, year = {2020}, author = {Hamm, S and Sudres, JL}, title = {[Art therapy, Alzheimer's disease and identity? Mrs Lila and the return to herself].}, journal = {Soins. Gerontologie}, volume = {25}, number = {142}, pages = {40-44}, doi = {10.1016/j.sger.2020.01.010}, pmid = {32331609}, issn = {1268-6034}, mesh = {Aged ; Alzheimer Disease/psychology/*therapy ; *Art Therapy ; Humans ; Self Concept ; Treatment Outcome ; }, abstract = {Alzheimer's disease and related syndromes require non-medicated support in which art therapy can play a vital role. The practice of therapy in people with these diseases must be based on targeted, flexible and capable of being assessed. Presentation of a clinical case.}, } @article {pmid32331524, year = {2020}, author = {Schröder, N and Schaffrath, A and Welter, JA and Putzka, T and Griep, A and Ziegler, P and Brandt, E and Samer, S and Heneka, MT and Kaddatz, H and Zhan, J and Kipp, E and Pufe, T and Tauber, SC and Kipp, M and Brandenburg, LO}, title = {Inhibition of formyl peptide receptors improves the outcome in a mouse model of Alzheimer disease.}, journal = {Journal of neuroinflammation}, volume = {17}, number = {1}, pages = {131}, pmid = {32331524}, issn = {1742-2094}, support = {BR 3666/6-1//Deutsche Forschungsgemeinschaft/ ; #13809//Alzheimer Forschungsinitiative/ ; }, abstract = {BACKGROUND: An important hallmark of Alzheimer's disease (AD) is the increase of Aβ1-42 burden and its accumulation to senile plaques, leading the reactive gliosis and neurodegeneration. The modulation of glia cell function represents an attractive therapeutic strategy, but is currently limited by an incomplete understanding of its relevance for AD. The chemotactic G-protein coupled formyl peptide receptor (FPR), which is known to modulate Aβ1-42 uptake and signal transduction, might be one candidate molecule regulating glia function in AD. Here, we investigate whether the modulation of FPR exerts beneficial effects in an AD preclinical model.

METHODS: To address this question, APP/PS1 double-transgenic AD mice were treated for 20 weeks with either the pro-inflammatory FPR agonist fMLF, the FPR1/2 antagonist Boc2 or the anti-inflammatory FPR2 agonist Ac2-26. Spatial learning and memory were evaluated using a Morris water maze test. Immunohistological staining, gene expression studies, and flow cytometry analyses were performed to study neuronal loss, gliosis, and Aß-load in the hippocampus and cortex, respectively.

RESULTS: FPR antagonism by Boc2-treatment significantly improved spatial memory performance, reduced neuronal pathology, induced the expression of homeostatic growth factors, and ameliorated microglia, but not astrocyte, reactivity. Furthermore, the elevated levels of amyloid plaques in the hippocampus were reduced by Boc2-treatment, presumably by an induction of amyloid degradation.

CONCLUSIONS: We suggest that the modulation of FPR signaling cascades might be considered as a promising therapeutic approach for alleviating the cognitive deficits associated with early AD. Additional studies are now needed to address the downstream effectors as well as the safety profile of Boc2.}, } @article {pmid32331051, year = {2020}, author = {Garland, JS and Tsui, M and Jaskot, EM and Knoll, M and Taylor, J and Buccellato, K and Swanberg, M and Pasquina, PF}, title = {136 Repetitive Transcranial Magnetic Stimulation as a Protective Measure Against Early-Onset Alzheimer's Disease: A Case Report.}, journal = {CNS spectrums}, volume = {25}, number = {2}, pages = {286-287}, doi = {10.1017/S1092852920000528}, pmid = {32331051}, issn = {1092-8529}, abstract = {DISCLAIMER: The views expressed in this abstract are those of the authors and do not reflect the official policy of the Department of Army/Navy/Air Force, Department of Defense, or U.S. Government.

BACKGROUND: Alzheimer s disease (AD) is a progressive neurodegenerative disease leading to cognitive decline and eventually death. Degradation of cortical neuroplasticity is thought to be a major catalyst of AD-related cognitive decline. Repetitive transcranial magnetic stimulation (rTMS), which uses pulsed magnetism to stimulate neurons, increases cortical plasticity and induces long-lasting neuroplastic changes. Patients have benefited from rTMS to treat AD, especially when done in conjunction with cognitive training exercises. This case report presents a 31-year-old male who tested positive for an autosomal dominant mutation implicated in early-onset AD. rTMS and cognitive training were employed to assist in the delay of early-onset AD manifestation in two cycles.

METHODS: Prior to each treatment cycle, the patient completed questionnaires and interviews designed to test his cognitive functioning; his spouse was interviewed to provide a third-party assessment of his functioning. Following pre-treatment data collection, 30 daily rTMS/cognitive training sessions were completed in the first cycle and 35 daily rTMS/cognitive training sessions were completed in the second cycle. The bilateral dorsolateral prefrontal cortices each received 1,000 pulses (10 Hz, 110% SMT). Tolerability and side effect data were collected after each treatment. Immediately following rTMS, the patient played cognitive training games at our Brain Fitness Center. All pre-treatment assessments were repeated after completion of the 30 sessions in the first cycle and the 35 sessions in the second cycle for comparison of pre- to post-treatment cognitive functionality.

RESULTS: Pre-treatment testing indicated the patient was asymptomatic before each cycle. The patient completed 30 daily rTMS sessions in the first cycle and 35 daily rTMS sessions in the second cycle. Tolerability/side effect data showed he tolerated treatment well and experienced only minor pain. The patient also completed 30 cognitive training sessions in the first cycle and 35 cognitive training sessions in the second cycle and showed moderate improvement across all cognitive domains. Post-treatment assessments indicated no change in functioning except to note the patient s improved sleep. A third treatment cycle is scheduled to begin in February 2020.

CONCLUSIONS: This case report supports rTMS paired with cognitive training to be a safe and tolerable treatment for early-onset AD. However, more treatment cycles must be completed before conclusions about its efficacy can be determined.}, } @article {pmid32330468, year = {2020}, author = {Schiavi, A and Strappazzon, F and Ventura, N}, title = {Mitophagy and iron: two actors sharing the stage in age-associated neuronal pathologies.}, journal = {Mechanisms of ageing and development}, volume = {188}, number = {}, pages = {111252}, doi = {10.1016/j.mad.2020.111252}, pmid = {32330468}, issn = {1872-6216}, abstract = {Aging is characterized by the deterioration of different cellular and organismal structures and functions. A typical hallmark of the aging process is the accumulation of dysfunctional mitochondria and excess iron, leading to a vicious cycle that promotes cell and tissue damage, which ultimately contribute to organismal aging. Accordingly, altered mitochondrial quality control pathways such as mitochondrial autophagy (mitophagy) as well as altered iron homeostasis, with consequent iron overload, can accelerate the aging process and the development and progression of different age-associated disorders. In this review we first briefly introduce the aging process and summarize molecular mechanisms regulating mitophagy and iron homeostasis. We then provide an overview on how dysfunction of these two processes impact on aging and age-associated neurodegenerative disorders with a focus on Alzheimer's disease, Parkinson's disease and Amyotrophic Lateral Sclerosis. Finally, we summarize some recent evidence showing mechanistic links between iron metabolism and mitophagy and speculate on how regulating the crosstalk between the two processes may provide protective effects against aging and age-associated neuronal pathologies.}, } @article {pmid32330418, year = {2020}, author = {Cochran, JN and Geier, EG and Bonham, LW and Newberry, JS and Amaral, MD and Thompson, ML and Lasseigne, BN and Karydas, AM and Roberson, ED and Cooper, GM and Rabinovici, GD and Miller, BL and Myers, RM and Yokoyama, JS and , }, title = {Non-coding and Loss-of-Function Coding Variants in TET2 are Associated with Multiple Neurodegenerative Diseases.}, journal = {American journal of human genetics}, volume = {106}, number = {5}, pages = {632-645}, pmid = {32330418}, issn = {1537-6605}, abstract = {We conducted genome sequencing to search for rare variation contributing to early-onset Alzheimer's disease (EOAD) and frontotemporal dementia (FTD). Discovery analysis was conducted on 435 cases and 671 controls of European ancestry. Burden testing for rare variation associated with disease was conducted using filters based on variant rarity (less than one in 10,000 or private), computational prediction of deleteriousness (CADD) (10 or 15 thresholds), and molecular function (protein loss-of-function [LoF] only, coding alteration only, or coding plus non-coding variants in experimentally predicted regulatory regions). Replication analysis was conducted on 16,434 independent cases and 15,587 independent controls. Rare variants in TET2 were enriched in the discovery combined EOAD and FTD cohort (p = 4.6 × 10-8, genome-wide corrected p = 0.0026). Most of these variants were canonical LoF or non-coding in predicted regulatory regions. This enrichment replicated across several cohorts of Alzheimer's disease (AD) and FTD (replication only p = 0.0029). The combined analysis odds ratio was 2.3 (95% confidence interval [CI] 1.6-3.4) for AD and FTD. The odds ratio for qualifying non-coding variants considered independently from coding variants was 3.7 (95% CI 1.7-9.4). For LoF variants, the combined odds ratio (for AD, FTD, and amyotrophic lateral sclerosis, which shares clinicopathological overlap with FTD) was 3.1 (95% CI 1.9-5.2). TET2 catalyzes DNA demethylation. Given well-defined changes in DNA methylation that occur during aging, rare variation in TET2 may confer risk for neurodegeneration by altering the homeostasis of key aging-related processes. Additionally, our study emphasizes the relevance of non-coding variation in genetic studies of complex disease.}, } @article {pmid32330284, year = {2020}, author = {Manni, G and Lewis, V and Senesi, M and Spagnolli, G and Fallarino, F and Collins, SJ and Mouillet-Richard, S and Biasini, E}, title = {The cellular prion protein beyond prion diseases.}, journal = {Swiss medical weekly}, volume = {150}, number = {}, pages = {w20222}, doi = {10.4414/smw.2020.20222}, pmid = {32330284}, issn = {1424-3997}, abstract = {The cellular prion protein (PrPC), a cell surface glycoprotein originally identified for its central role in prion diseases (also called transmissible spongiform encephalopathies), has recently been implicated in the pathogenesis of other neurodegenerative disorders, such as Alzheimer&rsquo;s and Parkinson&rsquo;s diseases, by acting as a toxicity-transducing receptor for different misfolded protein isoforms, or in some case by exerting neuroprotective effects. Interestingly, PrPC has also been reported to play unexpected functions outside the nervous system, for example by contributing to myelin homeostasis, regulating specific processes of the immune system and participating in various aspects of cancer progression. Collectively, these observations point to a much broader role for PrPC in physiological and disease processes than originally assumed. In this manuscript, we provide an overview of what is known about the role of PrPC beyond prion disorders and discuss the potential implications of targeting this protein in different diseases.}, } @article {pmid32329369, year = {2020}, author = {Bartos, A and Hohinova, M and Holla, M}, title = {High electronic name agreement of 70 pictures in normative study of 5,290 Czechs for easy multicultural replication.}, journal = {Applied neuropsychology. Adult}, volume = {}, number = {}, pages = {1-12}, doi = {10.1080/23279095.2020.1753744}, pmid = {32329369}, issn = {2327-9109}, abstract = {The aim of this normative study was to verify recognition and name agreement of 70 black and white line pictures on a large Czech population sample using an electronic form. The set of pictures was selected based on previous research showing preliminary evidence of high name agreement with one word only. The pictures were arrayed into an electronic form that was distributed via the internet and filled in by 6,055 participants across the whole country. The group for final evaluation comprised of 5,290 respondents (age range 11-90 years, average ± SD: 53 ± 15 years, 77% of women, years of completed education: range 8-28 years, 15 ± 3 years) from all regions. The average name agreement for all pictures was 98%. Name agreement in the majority of pictures was not influenced by gender, age, and education. The most useful 14 pictures are entirely independent of all sociodemographic factors and include table, scissors, bell, ski, crown, chimney, glasses, steering wheel, heart, chain, ladder, horseshoe, bone, and alarm clock. The presented set of pictures named by one word only can be used for diagnostic or therapeutic purposes. The pictures and the electronic form are freely available for replication in other languages at our website www.abadeco.cz.}, } @article {pmid32329360, year = {2020}, author = {Ogunlade, B and Adelakun, SA and Agie, JA}, title = {Nutritional supplementation of gallic acid ameliorates Alzheimer-type hippocampal neurodegeneration and cognitive impairment induced by aluminum chloride exposure in adult Wistar rats.}, journal = {Drug and chemical toxicology}, volume = {}, number = {}, pages = {1-12}, doi = {10.1080/01480545.2020.1754849}, pmid = {32329360}, issn = {1525-6014}, abstract = {Prolonged exposure to aluminum through occupational hazards or food/water intake has been linked to the occurrence of Alzheimer's disease (AD). This study aimed at investigating the neuroprotective effects of Gallic Acid (GA) against aluminum-chloride induced AD in adult Wistar rats. Twenty eight (28) adult Wistar rats were divided into four groups (n = 7). Group A received normal saline as placebo; Group B received 200 mg/kg bw of AlCl3 only; Group C received 100 mg/kg bw of GA only and group D received 100 mg/kg bw of GA and 200 mg/kg bw of AlCl3. At the end of the 60 days experiment, blood samples were collected to obtain serum for analysis and the brain was harvested. Neurobehavioural tests (Morris Water maze, Y-Maze), neurotransmitter levels, oxidative stress markers, serum electrolytes, antioxidant enzymes and histological assessment were carried out. There was a significant decrease in antioxidant enzymes (CAT, GSH and SOD), serum electrolyte (except K+) and neurotransmitter levels (except norepinephrine) with corresponding increase in stress markers (MDA, H2O2 and NO) among group B compared to control but was restored nearly to normal after GA administration. Neurobehavioral tests showed decreased spatial memory impairment and learning deficit in group B compared to control but was ameliorated with GA administration. Histological observation showed neurofibrillary tangles and amyloid plaques in the external granular layer of group B but protected by GA administration. Nutritional supplementation of GA preserve the morphological and physiological integrity of the hippocampus against environmental neurotoxins (AlCl3) by mopping up free radicals associated with oxidative stress induced AD.}, } @article {pmid32329299, year = {2020}, author = {Ayka, A and Şehirli, AÖ}, title = {The Role of the SLC Transporters Protein in the Neurodegenerative Disorders.}, journal = {Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology}, volume = {18}, number = {2}, pages = {174-187}, pmid = {32329299}, issn = {1738-1088}, abstract = {The solute carrier (SLC) superfamily is one of the major sub-groups of membrane proteins in mammalian cells. The solute carrier proteins include more than 400 different membrane-spanning solute carriers organized with 65 families in the human. In solute carrier family neurons, neurotransmitter is considered to be a pharmacological target of neuropsychiatric drugs because of their important role in the recovery of neurotransmitters such as GABA, glutamate, serotonin, dopamine and noradrenaline and regulation of their concentration in synaptic regions. Therefore, solute carrier transporters play vital and different roles in neurodegenerative disorders. In this article, the role of solute carrier transporters in neurodegenerative disorders such as Alzheimer disease, amyotrophic lateral sclerosis, Huntington disease, Parkinson's diseases, depression, post-traumatic stress disorder, dementia, schizophrenia, and Epilepsy reviewed and discussed to see how defects or absences in SLC transporter cause neurodegenerative disorders. In this review, we try to summarize what is known about solute carriers with respect to brain distribution and expression. The review summarizes current knowledge on the roles of solute carrier transporters in neurodegenerative disorders.}, } @article {pmid32327491, year = {2020}, author = {Sarycheva, T and Lavikainen, P and Taipale, H and Tiihonen, J and Tanskanen, A and Hartikainen, S and Tolppanen, AM}, title = {Antiepileptic drug use and mortality among community-dwelling persons with Alzheimer disease.}, journal = {Neurology}, volume = {94}, number = {20}, pages = {e2099-e2108}, doi = {10.1212/WNL.0000000000009435}, pmid = {32327491}, issn = {1526-632X}, abstract = {OBJECTIVE: To evaluate the risk of death in relation to incident antiepileptic drug (AED) use compared with nonuse in people with Alzheimer disease (AD) through the assessment in terms of duration of use, specific drugs, and main causes of death.

METHODS: The MEDALZ (Medication Use and Alzheimer Disease) cohort study includes all Finnish persons who received a clinically verified AD diagnosis (n = 70,718) in 2005-2011. Incident AED users were identified with 1-year washout period. For each incident AED user (n = 5,638), 1 nonuser was matched according to sex, age, and time since AD diagnosis. Analyses were conducted with Cox proportional regression models and inverse probability of treatment weighting (IPTW).

RESULTS: Nearly 50% discontinued AEDs within 6 months. Compared with nonusers, AED users had an increased relative risk of death (IPTW hazard ratio [HR], 1.23; 95% confidence interval [CI], 1.12-1.36). This was mainly due to deaths from dementia (IPTW HR, 1.62; 95% CI, 1.42-1.86). There was no difference in cardiovascular and cerebrovascular deaths (IPTW HR, 0.98; 95% CI, 0.67-1.44). The overall mortality was highest during the first 90 days of AED use (IPTW HR, 2.40; 95% CI, 1.91-3.03). Among users of older AEDs, relative risk of death was greater compared to users of newer AEDs (IPTW HR, 1.79; 95% CI, 1.52-2.16).

CONCLUSION: In older vulnerable patients with a cognitive disorder, careful consideration of AED initiation and close adverse events monitoring are needed.}, } @article {pmid32324139, year = {2020}, author = {Ding, H and An, N and Au, R and Devine, S and Auerbach, SH and Massaro, J and Joshi, P and Liu, X and Liu, Y and Mahon, E and Ang, TF and Lin, H}, title = {Exploring the Hierarchical Influence of Cognitive Functions for Alzheimer Disease: The Framingham Heart Study.}, journal = {Journal of medical Internet research}, volume = {22}, number = {4}, pages = {e15376}, pmid = {32324139}, issn = {1438-8871}, support = {R01 NS017950/NS/NINDS NIH HHS/United States ; R01 AG016495/AG/NIA NIH HHS/United States ; R01 AG049810/AG/NIA NIH HHS/United States ; R01 AG008122/AG/NIA NIH HHS/United States ; R56 AG062109/AG/NIA NIH HHS/United States ; N01HC25195/HL/NHLBI NIH HHS/United States ; R01 AG062109/AG/NIA NIH HHS/United States ; UL1 TR001430/TR/NCATS NIH HHS/United States ; RF1 AG054156/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: Although some neuropsychological (NP) tests are considered more central for the diagnosis of Alzheimer disease (AD), there is a lack of understanding about the interaction between different cognitive tests.

OBJECTIVE: This study aimed to demonstrate a global view of hierarchical probabilistic dependencies between NP tests and the likelihood of cognitive impairment to assist physicians in recognizing AD precursors.

METHODS: Our study included 2091 participants from the Framingham Heart Study. These participants had undergone a variety of NP tests, including Wechsler Memory Scale, Wechsler Adult Intelligence Scale, and Boston Naming Test. Heterogeneous cognitive Bayesian networks were developed to understand the relationship between NP tests and the cognitive status. The performance of probabilistic inference was evaluated by the 10-fold cross validation.

RESULTS: A total of 4512 NP tests were used to build the Bayesian network for the dementia diagnosis. The network demonstrated conditional dependency between different cognitive functions that precede the development of dementia. The prediction model reached an accuracy of 82.24%, with sensitivity of 63.98% and specificity of 92.74%. This probabilistic diagnostic system can also be applied to participants that exhibit more heterogeneous profiles or with missing responses for some NP tests.

CONCLUSIONS: We developed a probabilistic dependency network for AD diagnosis from 11 NP tests. Our study revealed important psychological functional segregations and precursor evidence of AD development and heterogeneity.}, } @article {pmid32322100, year = {2020}, author = {Ashton, NJ and Hye, A and Rajkumar, AP and Leuzy, A and Snowden, S and Suárez-Calvet, M and Karikari, TK and Schöll, M and La Joie, R and Rabinovici, GD and Höglund, K and Ballard, C and Hortobágyi, T and Svenningsson, P and Blennow, K and Zetterberg, H and Aarsland, D}, title = {An update on blood-based biomarkers for non-Alzheimer neurodegenerative disorders.}, journal = {Nature reviews. Neurology}, volume = {16}, number = {5}, pages = {265-284}, doi = {10.1038/s41582-020-0348-0}, pmid = {32322100}, issn = {1759-4766}, abstract = {Cerebrospinal fluid analyses and neuroimaging can identify the underlying pathophysiology at the earliest stage of some neurodegenerative disorders, but do not have the scalability needed for population screening. Therefore, a blood-based marker for such pathophysiology would have greater utility in a primary care setting and in eligibility screening for clinical trials. Rapid advances in ultra-sensitive assays have enabled the levels of pathological proteins to be measured in blood samples, but research has been predominantly focused on Alzheimer disease (AD). Nonetheless, proteins that were identified as potential blood-based biomarkers for AD, for example, amyloid-β, tau, phosphorylated tau and neurofilament light chain, are likely to be relevant to other neurodegenerative disorders that involve similar pathological processes and could also be useful for the differential diagnosis of clinical symptoms. This Review outlines the neuropathological, clinical, molecular imaging and cerebrospinal fluid features of the most common neurodegenerative disorders outside the AD continuum and gives an overview of the current status of blood-based biomarkers for these disorders.}, } @article {pmid32321203, year = {2020}, author = {Huh, TH and Yoon, JL and Cho, JJ and Kim, MY and Ju, YS}, title = {Survival Analysis of Patients with Alzheimer's Disease: A Study Based on Data from the Korean National Health Insurance Services' Senior Cohort Database.}, journal = {Korean journal of family medicine}, volume = {}, number = {}, pages = {}, doi = {10.4082/kjfm.18.0114}, pmid = {32321203}, issn = {2005-6443}, abstract = {Background: Korea's rapidly aging population has experienced a sharp rise in the prevalence of dementia. Patients with Alzheimer's disease (AD), which is estimated to be about three-quarters of all patients with dementia, tend to have higher mortality rates compared with patients without Alzheimer's disease. In this study, a survival analysis of patients with AD was conducted in order to provide knowledge to those who provide medical care to these patients.

Methods: Data on individuals over 65 years old in 2004 were extracted from the Korean National Health Insurance Services' Senior Cohort database (2002-2013). The subjects were 209,254 patients, including 2,695 who were first diagnosed with AD (the AD group) and 206,559 that had not been diagnosed with the disease (non-AD group). To investigate the independent effect of AD on survival, the Cox proportional-hazards model, hazard ratios (confidence interval of 95%), and the Kaplan-Meier method were used.

Results: Mean survival time in the AD group was 5.3±3.3 years, which was about 2.5 years shorter than that in the non-AD group (7.8±2.4 years). The mortality rate in the AD group (66.3%) was higher than that in the non-AD group (26.3%). The adjusted hazard ratio in the AD group was 2.5 and, therefore, it was found that the AD group had a 2.5-fold higher risk of death than the non-AD group.

Conclusion: Overall, AD has a large, independent impact on survival. Survival time was shorter, and the mortality rate and risk were generally higher in the AD group, compared with the non-AD group.}, } @article {pmid32320019, year = {2020}, author = {Shishtar, E and Rogers, GT and Blumberg, JB and Au, R and Jacques, PF}, title = {Long-term dietary flavonoid intake and risk of Alzheimer disease and related dementias in the Framingham Offspring Cohort.}, journal = {The American journal of clinical nutrition}, volume = {}, number = {}, pages = {}, doi = {10.1093/ajcn/nqaa079}, pmid = {32320019}, issn = {1938-3207}, abstract = {BACKGROUND: Findings from existing prospective observational studies on the protective associations of flavonoid intake and the risk of Alzheimer disease and related dementias (ADRD) are inconsistent largely due to limitations of these studies.

OBJECTIVES: To examine the prospective relation between total and 6 classes of dietary flavonoid intake and risk of ADRD and Alzheimer disease (AD) while addressing limitations of earlier observational studies.

METHODS: We used data from the Framingham Heart Study Offspring Cohort exams 5 through 9. Participants were ADRD-free with a valid FFQ at baseline. Flavonoid intakes were updated at each exam to represent the cumulative average intake across the 5 exams, and were expressed as percentile categories of intake (≤15th, >15th to 30th, >30th to 60th, >60th) to handle their nonlinear relation with ADRD and AD. Cox proportional hazards regression was used to estimate the HRs for the association between the flavonoid intakes and incidence of ADRD and AD.

RESULTS: Over an average follow-up of 19.7 y in 2801 participants (mean baseline age = 59.1 y; 52% females), there were 193 ADRD events of which 158 were AD. After multivariate and dietary adjustments, individuals with the highest (>60th percentile) intakes of flavonols, anthocyanins, and flavonoid polymers had a lower risk of ADRD relative to individuals with the lowest intakes (≤15th percentile), with HRs (95% CI; P-trend) of 0.54 (0.32, 0.90; P = 0.003) for flavonols, 0.24 (0.15, 0.39; P < 0.001) for anthocyanins, and 0.58 (0.35, 0.94; P = 0.03) for flavonoid polymers. The same pattern of associations was seen with AD for flavonols and anthocyanins but not for flavonoid polymers.

CONCLUSIONS: Our findings imply that higher long-term dietary intakes of flavonoids are associated with lower risks of ADRD and AD in US adults.}, } @article {pmid32319955, year = {2020}, author = {Zahid, M and Gallant, NL and Hadjistavropoulos, T and Stroulia, E}, title = {Behavioral Pain Assessment Implementation in Long-Term Care Using a Tablet App: Case Series and Quasi-Experimental Design.}, journal = {JMIR mHealth and uHealth}, volume = {8}, number = {4}, pages = {e17108}, pmid = {32319955}, issn = {2291-5222}, abstract = {BACKGROUND: Pain is often underassessed and undertreated among long-term care (LTC) residents living with dementia. When used regularly, the Pain Assessment Checklist for Seniors With Limited Ability to Communicate (PACSLAC) scales have been shown to have beneficial effects on pain assessment and management practices and stress and burnout levels in frontline staff in LTC facilities. Such scales, however, are not utilized as often as recommended, which is likely to be related to additional record-keeping and tracking over time involved with their paper-and-pencil administration.

OBJECTIVE: Using implementation science principles, we assessed the introduction of the PACSLAC-II scale by comparing two methods of administration-a newly developed tablet app version and the original paper-and-pencil version-with respect to the frequency of pain assessment and facility staff feedback.

METHODS: Using a case series approach, we tracked pain-related quality indicators at baseline, implementation, and follow-up periods. A quasi-experimental design was used to evaluate the effect of the method of administration (ie, paper-and-pencil only [n=18], tablet only [n=12], paper-and-pencil followed by tablet app [n=31], and tablet app followed by paper-and-pencil [n=31]) on pain assessment frequency and frontline staff stress and burnout levels. Finally, semistructured interviews were conducted with frontline staff to obtain perspectives on each method of administration.

RESULTS: The implementation effort resulted in a great increase in pain assessment frequency across 7 independent LTC units, although these increases were not maintained during the follow-up period. Frontline staff reported lower levels of workload in the paper-and-pencil followed by tablet app condition than those in the paper-and-pencil only (P<.001) and tablet app followed by paper-and-pencil (P<.001) conditions. Frontline staff also reported lower levels of workload in the tablet-only condition than those in the paper-and-pencil only condition (P=.05). Similarly, lower levels of emotional exhaustion were reported by frontline staff in the paper-and-pencil followed by tablet app condition than those in the paper-and-pencil only (P=.002) and tablet app followed by paper-and-pencil (P=.002) conditions. Finally, frontline staff reported higher levels of depersonalization in the paper-and-pencil only condition than those in the tablet app only (P=.008), paper-and-pencil followed by tablet app (P<.001), and tablet app followed by paper-and-pencil (P<.001) conditions. Furthermore, narrative data from individual interviews with frontline staff revealed a preference for the tablet app over the paper-and-pencil method of administration.

CONCLUSIONS: This study provides support for the use of either the tablet app or the paper-and-pencil version of the PACSLAC-II to improve pain-related quality indicators, but a reported preference for and lower levels of stress and burnout with the use of the tablet app method of administration suggests that the use of the tablet app may have more advantages compared with the paper-and-pencil method of administration.}, } @article {pmid32317127, year = {2020}, author = {Ramos-Campoy, O and Antonell, A and Falgàs, N and Balasa, M and Borrego-Écija, S and Rodríguez-Santiago, B and Datta, D and Armengol, L and Fernández-Villullas, G and Bosch, B and Olives, J and Muñoz-García, C and Castellví, M and Tort-Merino, A and Sánchez-Valle, R and Lladó, A}, title = {Screening of dementia genes by whole-exome sequencing in Spanish patients with early-onset dementia: likely pathogenic, uncertain significance and risk variants.}, journal = {Neurobiology of aging}, volume = {93}, number = {}, pages = {e1-e9}, doi = {10.1016/j.neurobiolaging.2020.02.008}, pmid = {32317127}, issn = {1558-1497}, abstract = {Early-onset Alzheimer's disease (EOAD) and frontotemporal dementia (FTD) have a high proportion of genetically determined cases. Next-generation sequencing technologies have triggered the discovery of new mutations and genetic variants in dementia-causal genes. We performed whole-exome sequencing and selective analysis of known genes causative of EOAD and FTD in a well-characterized Spanish cohort of 103 patients (60 EOAD, 43 FTD) to find genetic variants associated to patients' phenotype. In EOAD patients, a new likely pathogenic variant in PSEN1 gene (p.G378R) was found. In FTD patients, 2 likely pathogenic variants were found, one in MAPT gene (p.P397S) and one in VCP gene (p.R159H). In our series, 2% of early-onset dementia without criteria for clinical genetic testing according to current guidelines presented a likely pathogenic mutation. We have also detected 13 additional variants of uncertain significance in causal genes, as well as rare variants in risk genes for dementia (ABCA7, SORL1, SQSTM1, and TREM2). Next-generation technologies in neurodegenerative diseases constitute a powerful tool that significantly contributes to patients' diagnosis.}, } @article {pmid32315185, year = {2020}, author = {Rodrigues, BDS and Kanekiyo, T and Singh, J}, title = {Nerve Growth Factor Gene Delivery across the Blood-Brain Barrier to Reduce Beta Amyloid Accumulation in AD Mice.}, journal = {Molecular pharmaceutics}, volume = {17}, number = {6}, pages = {2054-2063}, doi = {10.1021/acs.molpharmaceut.0c00218}, pmid = {32315185}, issn = {1543-8392}, abstract = {The therapeutic potential of the nerve growth factor (NGF) gene using brain-targeted liposomal nanoparticles was investigated for the treatment of Alzheimer's disease (AD). We designed brain-targeted gene delivery systems with prolonged systemic circulation and enhanced cellular penetration by conjugating the transferrin (Tf) ligand and the penetratin (Pen) peptide to liposomes via a 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol) phospholipid. In vitro characterization studies showed that the nanoparticles had homogeneous particle size and positive zeta potential and were able to protect the plasmid DNA against enzymatic degradation. In vivo brain targeting efficiency of designed liposomes was mimicked using an in vitro triple coculture blood-brain barrier (BBB) model. Liposomal nanoparticles dual-modified with Tf and Pen encasing plasmid NGF efficiently crossed the in vitro BBB model and, subsequently, transfected the primary neuronal cells. Increasing NGF expression in primary neuronal cells following treatment with liposomes increased the levels of the presynaptic marker synaptophysin in vitro. A dose-response study in vivo was performed in order to select the appropriate dose of plasmid NGF to induce significant NGF expression and, consequently, a therapeutic effect. Administration of PenTf-liposomes containing pNGF to amyloid precursor protein (APP)/PS1 mice (aged 3 months) for 4 weeks (one injection per week) significantly decreased (p < 0.05) the levels of toxic soluble and insoluble Aβ peptides as compared to those levels in untreated APP/PS1 mice. Additionally, the treatment stimulated cell proliferation and increased the levels of synaptic markers, synaptophysin and PSD-95. These data suggest the therapeutic potential of PenTf-liposome-mediated NGF gene therapy, and this system can be considered a candidate for the treatment of AD.}, } @article {pmid32314929, year = {2020}, author = {Wang, X and Zhang, R and Lin, Y and Shi, P}, title = {Inhibition of NF-κB might enhance the protective role of roflupram on SH-SY5Y cells under amyloid β stimulation via PI3K/AKT/mTOR signaling pathway.}, journal = {The International journal of neuroscience}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/00207454.2020.1759588}, pmid = {32314929}, issn = {1563-5279}, abstract = {Alzheimer disease (AD) is a progressive neurodegenerative disease and mostly endanger the health of people older than 65 years. Accumulation of beta amyloid protein (Aβ) is the main characteristic of AD. Roflupram (ROF) could improve the behavior of AD in a mouse model. In this study, we first detected the increased concentration of molecules related to inflammatory response in serum sample of patients with AD. Next, a cell model of nuclear factor kappa B (NF-κB) inhibition and NF-κB overexpression was established in SH-SY5Y cells, Aβ was used to simulate the toxicity to cells. ROF treatment decreased expression of apoptosis-related molecules via inhibition of PI3K/AKT/mTOR signaling pathway, decreased expression of pro-inflammatory factors, and increased expression of key enzymes in the tricarboxylic acid (TCA) cycle was observed in SH-SY5Y cells after ROF treatment. Inhibition of NF-κB could enlarge these trends whereas overexpression of NF-κB could reduce these trends.}, } @article {pmid32314661, year = {2020}, author = {Burke, SL and Grudzien, A and Burgess, A and Rodriguez, MJ and Rivera, Y and Loewenstein, D}, title = {The Utility of Cognitive Screeners in the Detection of Dementia Spectrum Disorders in Spanish-Speaking Populations.}, journal = {Journal of geriatric psychiatry and neurology}, volume = {}, number = {}, pages = {891988720915513}, doi = {10.1177/0891988720915513}, pmid = {32314661}, issn = {0891-9887}, abstract = {Increasing rates of dementia spectrum disorders among Spanish-speaking geriatric populations necessitate the development of culturally appropriate cognitive screening tests that can identify neurodegenerative disorders in their earliest stages when emerging disease-modifying treatments are most likely to be effective. This scoping review identified 26 brief Spanish language cognitive screening tools (<20 minutes) by searching academic databases using a combination of search terms. Results suggest that the Mini-Mental Status Examination and Montreal Cognitive Assessment appear to be less valid than other screeners. Instruments such as the 7-Minute Screen and Mini-Cog evidence higher classification rates of dementia, while Phototest detected mild cognitive impairment at higher rates more consistently than other screeners. Different sensitivity and specificity outcomes and cutoffs were observed when the same cognitive screener was evaluated in different countries. Results indicate that it is imperative to increase nation-specific validation and normative data for these instruments to best serve diverse populations.}, } @article {pmid32311931, year = {2020}, author = {Park, SY and Byun, BH and Kim, BI and Lim, SM and Ko, IO and Lee, KC and Kim, KM and Kim, YK and Lee, JY and Bu, SH and Kim, JH and Chi, DY and Ha, JH}, title = {The correlation of neuropsychological evaluation with 11C-PiB and 18F-FC119S amyloid PET in mild cognitive impairment and Alzheimer disease.}, journal = {Medicine}, volume = {99}, number = {16}, pages = {e19620}, pmid = {32311931}, issn = {1536-5964}, mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/*diagnostic imaging/metabolism/psychology ; Amyloid/*metabolism ; Aniline Compounds ; Carbon Radioisotopes ; Cognitive Dysfunction/*diagnostic imaging/metabolism/psychology ; Female ; Fluorine Radioisotopes ; Humans ; Male ; Middle Aged ; Neuroimaging/methods ; Neuropsychological Tests ; Positron Emission Tomography Computed Tomography/*methods ; Radioactive Tracers ; Thiazoles ; }, abstract = {For the diagnosis of mild cognitive impairment (MCI) and Alzheimer disease (AD), variable neuroimaging and neuropsychological tests have been used. We aimed to evaluate the correlation of neuropsychological domain with new amyloid positron emission tomography (PET) study and to validate the availability of new PET tracer.We enrolled 20 patients who underwent C-PiB-PET/CT, new PET tracer F-FC119S PET/CT from November, 2014 to July, 2015. Among them, 10 patients were diagnosed with AD and 10 patients with MCI. The current version of Seoul Neuropsychological Screening Battery (SNSB) II was performed for cognitive evaluation. Each parameter of SNSB was compared between 2 patient groups. Spearman correlation analysis between value of SNSB domain and standardized uptake value ratio (SUVR) of PET was also performed.The AD group presented significant poor z-score in Korean-Boston Naming Test(K-BNT) (P = .01),copy score of Rey Complex Figure Test (RCFT) (P = .049), immediate (P = .028)and delayed memory of Seoul Verbal Learning Test (SVLT) (P = .028), recognition of RCFT (P = .004), "animal" of Controlled Oral Word Association Test (COWAT) (P = .041), color reading of Korean-Color Word Stroop test (K-CWST) (P = .014), and Digit Symbol Coding (DSC) (P = .007) compared with MCI group. That means, except attention domain, all other cognitive domains were relatively impaired in AD compared with MCI. In correlation analysis, we found that poor performances on copy score of RCFT in MCI groups were associated with great beta amyloid burden in frontal area in both C-PiB-PET/CT and F-FC119S PET/CT. In AD group, F-FC119S PET presented more extensive correlation in each cognitive domain with multiple cortical areas compared with C-PiB-PET.The degree of amyloid burden assessed on F-FC119S PET was significantly correlated with neuropsychological test in AD, and also MCI patients. The combination of neuropsychological evaluation with novel F-FC119S PET/CT can be used for valid biomarker for MCI and AD.}, } @article {pmid32310138, year = {2020}, author = {Seelye, A and Leese, MI and Dorociak, K and Bouranis, N and Mattek, N and Sharma, N and Beattie, Z and Riley, T and Lee, J and Cosgrove, K and Fleming, N and Klinger, J and Ferguson, J and Lamberty, GJ and Kaye, J}, title = {Feasibility of In-Home Sensor Monitoring to Detect Mild Cognitive Impairment in Aging Military Veterans: Prospective Observational Study.}, journal = {JMIR formative research}, volume = {4}, number = {6}, pages = {e16371}, doi = {10.2196/16371}, pmid = {32310138}, issn = {2561-326X}, abstract = {BACKGROUND: Aging military veterans are an important and growing population who are at an elevated risk for developing mild cognitive impairment (MCI) and Alzheimer dementia, which emerge insidiously and progress gradually. Traditional clinic-based assessments are administered infrequently, making these visits less ideal to capture the earliest signals of cognitive and daily functioning decline in older adults.

OBJECTIVE: This study aimed to evaluate the feasibility of a novel ecologically valid assessment approach that integrates passive in-home and mobile technologies to assess instrumental activities of daily living (IADLs) that are not well captured by clinic-based assessment methods in an aging military veteran sample.

METHODS: Participants included 30 community-dwelling military veterans, classified as healthy controls (mean age 72.8, SD 4.9 years; n=15) or MCI (mean age 74.3, SD 6.0 years; n=15) using the Clinical Dementia Rating Scale. Participants were in relatively good health (mean modified Cumulative Illness Rating Scale score 23.1, SD 2.9) without evidence of depression (mean Geriatrics Depression Scale score 1.3, SD 1.6) or anxiety (mean generalized anxiety disorder questionnaire 1.3, SD 1.3) on self-report measures. Participants were clinically assessed at baseline and 12 months later with health and daily function questionnaires and neuropsychological testing. Daily computer use, medication taking, and physical activity and sleep data were collected via passive computer monitoring software, an instrumented pillbox, and a fitness tracker watch in participants' environments for 12 months between clinical study visits.

RESULTS: Enrollment began in October 2018 and continued until the study groups were filled in January 2019. A total of 201 people called to participate following public posting and focused mailings. Most common exclusionary criteria included nonveteran status 11.4% (23/201), living too far from the study site 9.4% (19/201), and having exclusionary health concerns 17.9% (36/201). Five people have withdrawn from the study: 2 with unanticipated health conditions, 2 living in a vacation home for more than half of the year, and 1 who saw no direct benefit from the research study. At baseline, MCI participants had lower Montreal Cognitive Assessment (P<.001) and higher Functional Activities Questionnaire (P=.04) scores than healthy controls. Over seven months, research personnel visited participants' homes a total of 73 times for technology maintenance. Technology maintenance visits were more prevalent for MCI participants (P=.04) than healthy controls.

CONCLUSIONS: Installation and longitudinal deployment of a passive in-home IADL monitoring platform with an older adult military veteran sample was feasible. Knowledge gained from this pilot study will be used to help develop acceptable and effective home-based assessment tools that can be used to passively monitor cognition and daily functioning in older adult samples.}, } @article {pmid32308094, year = {2020}, author = {Arslan, ME and Türkez, H and Mardinoğlu, A}, title = {In vitro neuroprotective effects of farnesene sesquiterpene on alzheimer's disease model of differentiated neuroblastoma cell line.}, journal = {The International journal of neuroscience}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/00207454.2020.1754211}, pmid = {32308094}, issn = {1563-5279}, abstract = {Objective: To investigate neuroprotective properties of the farnesene sesquiterpene on the experimental Alzheimer's disease model in vitro.Methods: Human neuroblastoma cell line (SHSY-5Y) was differentiated into neuron-like cells by using retinoic acid to constitute the in vitro Alzheimer's Disease model. β-amyloid 1-42 protein was applied to the transformed cells for 24 and 48 hours in a wide dose ranges (3.125-200 μM) to establish AD cytotoxicity. Then, farnesene was applied to cell cultures in a wide spectrum dose interval (1.625-100 μg/ml) to investigate neuroprotective effect against β-amyloid for 24 and 48 hours. 3-(4,5-dimethyl-thiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) release tests were executed to determine cytotoxicity in the Alzheimer model. Nuclear DNA integrity of cells was examined under the fluorescent microscope using the Hoechst 33258 staining method. Furthermore, acetylcholinesterase (AChE) activity, total antioxidant capacity (TAC) and total oxidative status (TOS) levels were analyzed to understand the protection mechanism of the farnesene application on the cell culture model. Finally, flow cytometry analysis was used to find out the cell death mechanism after beta-amyloid and farnesene application to the cell culture.Results: Cell viability tests revealed significant neuroprotection against β-amyloid toxicity in both 24 and 48 hours and the Hoechst 33258 fluorescence staining method showed a significant decrease in necrotic deaths after farnesene application in the cell cultures. Finally, flow cytometry analysis put forth that farnesene could decrease necrotic cell death up to 3-fold resulted from beta-amyloid exposure.Conclusion: According to the investigations, farnesene can potentially be a safe, anti-necrotic and neuroprotective agents against Alzheimer's disease.}, } @article {pmid32308012, year = {2020}, author = {Bonner, GJ and Freels, S and Ferrans, C and Steffen, A and Suarez, ML and Dancy, BL and Watkins, YJ and Collinge, W and Hart, AS and Aggarwal, NT and Wilkie, DJ}, title = {Advance Care Planning for African American Caregivers of Relatives With Dementias: Cluster Randomized Controlled Trial.}, journal = {The American journal of hospice & palliative care}, volume = {}, number = {}, pages = {1049909120916127}, doi = {10.1177/1049909120916127}, pmid = {32308012}, issn = {1938-2715}, support = {R01 AG043485/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND AND OBJECTIVES: African-American family caregivers may have insufficient knowledge to make informed end-of-life (EOL) decisions for relatives with dementias. Advance Care Treatment Plan (ACT-Plan) is a community-based education intervention to enhance knowledge of dementia and associated EOL medical treatments, self-efficacy, intentions, and behavior (written EOL care plan). This study evaluated efficacy of the intervention compared to attention control.

RESEARCH DESIGN AND METHODS: In a theoretically based, 2-group, cluster randomized controlled trial, 4 similar Midwestern urban megachurches were randomized to experimental or control conditions. Each church recruited African-American caregivers, enrolling concurrent waves of 5 to 9 participants in 4 weekly 1-hour sessions (358 total: ACT-Plan n = 173, control n = 185). Dementia, cardiopulmonary resuscitation (CPR), mechanical ventilation (MV), and tube feeding (TF) treatments were discussed in ACT-Plan classes. Participants completed assessments before the initial class, after the final class (week 4), and at week 20. Repeated measures models were used to test the intervention effect on changes in outcomes across time, adjusting for covariates as needed.

RESULTS: Knowledge of CPR, MV, TF, and self-efficacy to make EOL treatment decisions increased significantly more in the ACT-Plan group at weeks 4 and 20. Knowledge of dementia also increased more in the ACT-Plan group at both points, reaching statistical significance only at week 20. Intentions to make EOL treatment decisions and actually an advance care plan were similar between treatment arms.

DISCUSSION AND IMPLICATIONS: Findings demonstrate promise for ACT-Plan to increase informed EOL treatment decisions for African American caregivers of individuals with dementias.}, } @article {pmid32307772, year = {2020}, author = {Chiu, YW and Hori, Y and Ebinuma, I and Sato, H and Hara, N and Ikeuchi, T and Tomita, T}, title = {Identification of calcium and integrin-binding protein 1 as a novel regulator of production of amyloid β peptide using CRISPR/Cas9-based screening system.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {34}, number = {6}, pages = {7661-7674}, doi = {10.1096/fj.201902966RR}, pmid = {32307772}, issn = {1530-6860}, support = {JP18dm0207014//Japan Agency for Medical Research and Development (AMED)/ ; JP20dm0207073//Japan Agency for Medical Research and Development (AMED)/ ; 15H02492//Japan Society for the Promotion of Science (JSPS)/ ; 19H01015//Japan Society for the Promotion of Science (JSPS)/ ; 16K18871//Japan Society for the Promotion of Science (JSPS)/ ; 17J10935//Japan Society for the Promotion of Science (JSPS)/ ; }, abstract = {The aberrant metabolism of amyloid β peptide (Aβ) has been implicated in the etiology of Alzheimer disease (AD). Aβ is produced via the sequential cleavage of amyloid precursor protein (APP) by β- and γ-secretases. However, the precise regulatory mechanism of Aβ generation still remains unclear. To gain a better understanding of the molecular mechanism of Aβ production, we established a genetic screening method based on the CRISPR/Cas9 system to identify novel regulators of Aβ production. We successfully identified calcium and integrin-binding protein 1 (CIB1) as a potential negative regulator of Aβ production. The disruption of Cib1 significantly upregulated Aβ levels. In addition, immunoprecipitation experiments demonstrated that CIB1 interacts with the γ-secretase complex. Moreover, the disruption of Cib1 specifically reduced the cell-surface localization of mature Nicastrin (Nct), which is a component of the γ-secretase complex, without changing the intrinsic activity of γ-secretase. Finally, we confirmed using the single-cell RNA-seq data in human that CIB1 mRNA level in neuron was decreased in the early stage of AD. Taken together, our results indicate that CIB1 regulates Aβ production via controlling the subcellular localization of γ-secretase, suggesting CIB1 is involved in the development of AD.}, } @article {pmid32306804, year = {2020}, author = {Sen, S and Saxena, R and Vibha, D and Tripathi, M and Sharma, P and Phuljhele, S and Tandon, R and Kumar, P}, title = {Detection of structural and electrical disturbances in macula and optic nerve in Alzheimer's patients and their correlation with disease severity.}, journal = {Seminars in ophthalmology}, volume = {35}, number = {2}, pages = {116-125}, doi = {10.1080/08820538.2020.1748203}, pmid = {32306804}, issn = {1744-5205}, abstract = {Aim: To evaluate and compare structural and functional changes in macula and optic nerve in Alzheimer disease (AD) patients and healthy subjects.Methods: Both eyes of 20 AD patients and 40 age-matched healthy controls were evaluated. All subjects were evaluated by cognitive testing and comprehensive ophthalmological examination, including visual acuity, visual fields, color vision, contrast sensitivity, anterior, and posterior segment examination, optical coherence tomography, multifocal electroretinography (mfERG), and pattern-reversal visual evoked potential (pVEP).Results: AD patients showed significantly reduced contrast sensitivity, thinner nerve fiber layer, ganglion cell layer andmacular volume. Multifocal ERG wave amplitudes were significantly reduced with delayed implicit times, which correlated significantly with the inner retinal layer thinning and poorer disease severity scores. The correlation with structural changes and disease severity was highest for pVEP, which showed significant derangement in AD patients.Conclusion: Subclinical visual dysfunction may be present in AD patients, which may be detected as inner retinal thinning. A probable photoreceptor abnormality may also form a part of the AD disease process.}, } @article {pmid32305596, year = {2020}, author = {González-Mundo, I and Pérez-Vielma, NM and Gómez-López, M and Fleury, A and Correa-Basurto, J and Rosales-Hernández, MC and Sixto-López, Y and Martínez-Godinez, MLÁ and Domínguez-López, A and Miliar-García, A}, title = {DNA methylation of the RE-1 silencing transcription factor in peripheral blood mononuclear cells and gene expression of antioxidant enzyme in patients with late-onset Alzheimer disease.}, journal = {Experimental gerontology}, volume = {136}, number = {}, pages = {110951}, doi = {10.1016/j.exger.2020.110951}, pmid = {32305596}, issn = {1873-6815}, abstract = {Late-onset Alzheimer disease (LOAD) is the most frequent cause of dementia in elderly adults. However, the factors determining disease onset remain unclear. In the elderly, the activation and expression of the gene encoding RE-1 silencing transcription factor (REST) may be a determinant of neuroprotective mechanisms and good amyloidogenic pathway management. In the present study, the minimal promoter region of REST1 was genetically and epigenetically analyzed in blood samples from 21 subjects with LOAD and 20 cognitively healthy elderly subjects. Genomic DNA was isolated, treated with bisulfite and pyrosequenced, and gene expression was determined using real-time PCR. Notably, subjects with LOAD exhibited hypermethylation and significantly diminished expression of REST1 compared with healthy subjects (p = 0.001). In the LOAD group, the gene expression of CAT, SOD2 and GPX also showed a significant decrease and an increase in malondialdehyde. A docking analysis revealed that the first zinc finger protein Sp1 recognized and bound the methylated sequence in subjects with LOAD differently than the binding observed in control subjects. These results reveal that in patients with LOAD the methylation of specific sites in the promoter sequence of REST suppresses its expression and this could be regulating the decreased expression of CAT, SOD and GPX, besides interfering with the action of transcription factors as Sp1.}, } @article {pmid32304374, year = {2020}, author = {Mock, C and Teylan, M and Beecham, G and Besser, L and Cairns, NJ and Crary, JF and Katsumata, Y and Nelson, PT and Kukull, W}, title = {The Utility of the National Alzheimer's Coordinating Center's Database for the Rapid Assessment of Evolving Neuropathologic Conditions.}, journal = {Alzheimer disease and associated disorders}, volume = {34}, number = {2}, pages = {105-111}, pmid = {32304374}, issn = {1546-4156}, support = {P50 AG005142/AG/NIA NIH HHS/United States ; P30 AG010133/AG/NIA NIH HHS/United States ; P50 AG005146/AG/NIA NIH HHS/United States ; P50 AG047266/AG/NIA NIH HHS/United States ; P30 AG008017/AG/NIA NIH HHS/United States ; P30 AG010161/AG/NIA NIH HHS/United States ; P50 AG005133/AG/NIA NIH HHS/United States ; P50 AG005138/AG/NIA NIH HHS/United States ; P50 AG047366/AG/NIA NIH HHS/United States ; P30 AG019610/AG/NIA NIH HHS/United States ; R01 AG062695/AG/NIA NIH HHS/United States ; P30 AG028383/AG/NIA NIH HHS/United States ; R01 AG054008/AG/NIA NIH HHS/United States ; P30 AG013854/AG/NIA NIH HHS/United States ; P30 AG053760/AG/NIA NIH HHS/United States ; P30 AG062428/AG/NIA NIH HHS/United States ; P30 AG010124/AG/NIA NIH HHS/United States ; P50 AG023501/AG/NIA NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; P30 AG035982/AG/NIA NIH HHS/United States ; P50 AG008702/AG/NIA NIH HHS/United States ; U01 AG016976/AG/NIA NIH HHS/United States ; P30 AG008051/AG/NIA NIH HHS/United States ; P50 AG005681/AG/NIA NIH HHS/United States ; P30 AG013846/AG/NIA NIH HHS/United States ; P50 AG047270/AG/NIA NIH HHS/United States ; P30 AG062429/AG/NIA NIH HHS/United States ; P50 AG005136/AG/NIA NIH HHS/United States ; P30 AG049638/AG/NIA NIH HHS/United States ; P30 AG012300/AG/NIA NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; P50 AG016573/AG/NIA NIH HHS/United States ; R01 NS095252/NS/NINDS NIH HHS/United States ; P50 AG025688/AG/NIA NIH HHS/United States ; P30 AG062715/AG/NIA NIH HHS/United States ; P30 AG010129/AG/NIA NIH HHS/United States ; }, abstract = {The field of dementia research is rapidly evolving, especially with regards to our understanding of the diversity of neuropathologic changes that underlie cognitive decline. Definitions and criteria for known conditions are being periodically revised and refined, and new findings are being made about neuropathologic features associated with dementia status. The database maintained by the National Alzheimer's Coordinating Center (NACC) offer researchers a robust, rapid, and statistically well-powered method to evaluate the implications of newly identified neuropathologic conditions with regards to comorbidities, demographic associations, cognitive status, neuropsychologic tests, radiographic findings, and genetics. NACC data derive from dozens of excellent US Alzheimer disease research centers, which collectively follow thousands of research volunteers longitudinally. Many of the research participants are autopsied using state-of-the-art methods. In this article, we describe the NACC database and give examples of its use in evaluating recently revised neuropathologic diagnoses, including primary age-related tauopathy (PART), limbic predominant age-related TDP-43 encephalopathy (LATE), and the preclinical stage of Alzheimer disease neuropathologic change, based on the National Institute on Aging-Alzheimer's Association consensus guidelines. The dementia research community is encouraged to make use of this readily available database as new neuropathologic changes are recognized and defined in this rapidly evolving field.}, } @article {pmid32301497, year = {2020}, author = {Stasiulis, E and Rapoport, MJ and Sivajohan, B and Naglie, G}, title = {The Paradox of Dementia and Driving Cessation: "It's a Hot Topic," "Always on the Back Burner".}, journal = {The Gerontologist}, volume = {}, number = {}, pages = {}, doi = {10.1093/geront/gnaa034}, pmid = {32301497}, issn = {1758-5341}, abstract = {BACKGROUND AND OBJECTIVES: Despite the well-recognized difficulty that persons with dementia and family carers experience in the decision making and transition to nondriving, there are few interventions and resources to support them. As part of our ongoing research to develop a driving cessation toolkit that addresses this gap, we sought to examine the context-specific factors relevant to its effective implementation in settings that support older adults with dementia.

RESEARCH DESIGN AND METHODS: A qualitative descriptive approach was used to explore the perspectives of Alzheimer Society (AS) staff in their work of supporting people with dementia and family carers within the context of driving cessation. Individual in-depth interviews were conducted with 15 AS staff members in 4 Canadian provinces. Data were examined using interpretative thematic analysis.

RESULTS: The study results revealed an overarching paradox that despite the importance of driving cessation in people with dementia, it continues to be largely avoided at the individual and system levels. This is explored via the themes of (a) paradox of importance and avoidance identified in AS settings; (b) lack of awareness and understanding about dementia and driving among people with dementia and family carers; (c) distress and avoidance rooted in ongoing system issues; and (d) moving driving cessation to the "front burner."

DISCUSSION AND IMPLICATIONS: Viewed through the emerging social health paradigm, which focuses on the social and emotional consequences of dementia, our results highlight the urgent need to mobilize our communities, medical education systems, and transportation authorities to finally resolve the dementia and driving cessation paradox.}, } @article {pmid32301334, year = {2020}, author = {Souza, VC and Morais, GS and Henriques, AD and Machado-Silva, W and Perez, DIV and Brito, CJ and Camargos, EF and Moraes, CF and Nóbrega, OT}, title = {Whole-Blood Levels of MicroRNA-9 Are Decreased in Patients With Late-Onset Alzheimer Disease.}, journal = {American journal of Alzheimer's disease and other dementias}, volume = {35}, number = {}, pages = {1533317520911573}, doi = {10.1177/1533317520911573}, pmid = {32301334}, issn = {1938-2731}, abstract = {Recent evidence suggests changes in circulating microRNA levels may be promising biomarkers for the clinical diagnosis of Alzheimer disease (AD). We hypothesized that whole-blood microRNAs may be useful to identify individuals with established AD. For this purpose, a sample of community-dwelling women (≥55 years old) carrying the ApoE ∊4 allele were clinically evaluated using the American Psychiatric Association/Diagnostic and Statistical Manual of Mental Disorders, Fourth edition and the Alzheimer Disease Assessment Scale-Cognitive Subscale criteria to diagnose probable AD, and the Clinical Dementia Rating scale to stage the dementia. A set of 25 mature microRNAs was rationally selected for evaluation based on experimental evidence of interaction with genes linked to the late-onset AD neuropathology. Whole-blood concentrations were determined by quantitative real-time polymerase chain reaction. Compared to patients without dementia, a median 3-fold decrease in miR-9 levels was found among patients with AD (P = .001). Our findings support blood-borne miR-9 as a candidate biomarker for probable AD, embodied by evidence from the literature of its implication in amyloidogenesis.}, } @article {pmid32301028, year = {2020}, author = {Gangemi, A and Colombo, B and Fabio, RA}, title = {Effects of short- and long-term neurostimulation (tDCS) on Alzheimer's disease patients: two randomized studies.}, journal = {Aging clinical and experimental research}, volume = {}, number = {}, pages = {}, doi = {10.1007/s40520-020-01546-8}, pmid = {32301028}, issn = {1720-8319}, abstract = {BACKGROUND: Non-invasive brain stimulation is an effective treatment for Alzheimer's disease.

AIMS: The purpose of the two studies presented here is to compare the short- and long-term effects of transcranial direct current stimulation (t-DCS) on two samples of advanced AD patients.

METHODS: In Study 1 26 patients were involved in a 10-day anodal vs. sham tDCS intervention stimulating the left frontotemporal cortex. A pre-post test assessment was run using two different neurocognitive tests and EEG data. The same protocol was used in Study 2, which involved 18 different patients who underwent the same intervention 10 days a month for 8 months.

RESULTS: Results confirmed how the t-DCS intervention was effective both in the short- and the long-term to slow down the progression of AD on specific neurophysiological domains and, to a certain extent, on neurophysiological activity. Discussion tDCS appear to be effective and to affect differently neurocognitive and neurophysiological functions when comparing short and long-term outcomes. Conclusions Anodal-tDCS is an effective way to slow down the progression of Alzheimer's both in the short and long term. It can also affect the EEG patterns, but this requires a more protracted intervention.}, } @article {pmid32297166, year = {2020}, author = {Kaur, A and Nigam, K and Bhatnagar, I and Sukhpal, H and Awasthy, S and Shankar, S and Tyagi, A and Dang, S}, title = {Treatment of Alzheimer's diseases using donepezil nanoemulsion: an intranasal approach.}, journal = {Drug delivery and translational research}, volume = {}, number = {}, pages = {}, doi = {10.1007/s13346-020-00754-z}, pmid = {32297166}, issn = {2190-3948}, support = {BT/PR19580/BIC/101/865/2016//Department of Biotechnology , Ministry of Science and Technology/ ; }, abstract = {Alzheimer disease (AD) is very common among the older people. There are few medications available as oral and suspension dosage forms for the management of AD. Due to the rising cases of AD and the associated risks of the existing line of treatment, oil in water (o/w) nanoemulsion (NE) loaded with donepezil was prepared to explore intranasal route of administration. The NE was prepared using labrasol (10%), cetyl pyridinium chloride (1% in 80% water), and glycerol (10%), with a drug concentration of 1 mg/ml. The developed NE was characterized for particle size, polydispersity index (PDI), and zeta potential. In vitro release studies were conducted to observe the release of drug. Further in vivo studies of developed NE were done on Sprague Dawley rats using technetium pertechnetate (99mTc) labeled formulations to investigate the nose to brain drug delivery pathway. The nanoemulsion showed particle size of 65.36 nm with a PDI of 0.084 and zeta potential of -10.7 mV. In vitro release studies showed maximum release of 99.22% in 4 h in phosphate-buffered saline, 98% in 2 h in artificial cerebrospinal fluid, and 96% in 2 h in simulated nasal fluid. The cytotoxicity and antioxidant activity of the NE showed dose-dependent cytotoxicity and % radical scavenging activity (%RSA). The images of giemsa staining also confirmed that the developed formulation has no impact on the morphology of cells. Scintigrams showed maximum uptake of NE in the brain. The findings suggested that the developed NE loaded with donepezil hydrochloride could serve as a new approach for the treatment of Alzheimer via nose to brain drug delivery. Graphical abstract.}, } @article {pmid32297026, year = {2020}, author = {Heysieattalab, S and Sadeghi, L}, title = {Effects of Delphinidin on Pathophysiological Signs of Nucleus Basalis of Meynert Lesioned Rats as Animal Model of Alzheimer Disease.}, journal = {Neurochemical research}, volume = {45}, number = {7}, pages = {1636-1646}, doi = {10.1007/s11064-020-03027-w}, pmid = {32297026}, issn = {1573-6903}, abstract = {Alzheimer's disease (AD) is an advanced neurodegenerative disorder greatly accompanied by cognitive deficits, oxidative stress, inflammation, amyloid plaques deposition, and acetylcholinesterase (AChE) hyper-activation. Growing evidence suggests natural compounds with antioxidant and anti-inflammatory features improve pathophysiological signs of AD. The present study was designed to investigate the effects of Delphinidin (25, 50 mg/kg) as an anthocyanidin on spatial memory impairment and AD hallmarks such as hippocampal AChE activity, amyloid plaques deposition, oxidative stress and expression of amyloid precursor protein (APP), AChE, and amyloid beta (Aβ) proteins in nucleus basalis of Meynert (NBM) lesioned rats as the most prevalent animal model of AD. Interestingly, Delphinidin-treated animals showed a significant decrease in escape latency and distance moved. Furthermore, in probe test, NBM lesioned rats treated with both doses of Delphinidin spent more time in the target quadrant zone in Morris water maze task. It could also interact with catalytic site of AChE enzyme and inhibits acetylcholine hydrolysis in in vitro and in vivo conditions. In addition, Delphinidin could scavenge additional produced reactive oxygen molecules dose dependently. Our immunoblotting analysis confirmed high dose of Delphinidin reduced AChE, APP and Aβ contents in AD model. Staining of hippocampus tissue revealed that Delphinidin treatment decreased amyloid plaques formation in NBM lesion rats. It seems that Delphinidin is a plate-like molecule intercalated between β-plated sheets related to Aβ molecules and inhibited amyloid fibril formation. Altogether, Delphinidin and Delphinidin-rich fruits could be suggested as a therapeutic adjuvant in AD and other related cognitive disorders.}, } @article {pmid32296844, year = {2020}, author = {Choi, JY and Cho, SJ and Park, JH and Yun, SM and Jo, C and Kim, EJ and Huh, GY and Park, MH and Han, C and Koh, YH}, title = {Elevated Cerebrospinal Fluid and Plasma N-Cadherin in Alzheimer Disease.}, journal = {Journal of neuropathology and experimental neurology}, volume = {79}, number = {5}, pages = {484-492}, doi = {10.1093/jnen/nlaa019}, pmid = {32296844}, issn = {1554-6578}, abstract = {N-cadherin is a synaptic adhesion molecule stabilizing synaptic cell structure and function. Cleavage of N-cadherin by γ-secretase produces a C-terminal fragment, which is increased in the brains of Alzheimer disease (AD) patients. Here, we investigated the relationship between fluid N-cadherin levels and AD pathology. We first showed that the cleaved levels of N-cadherin were increased in homogenates of postmortem brain from AD patients compared with that in non-AD patients. We found that cleaved N-cadherin levels in the cerebrospinal fluid were increased in AD dementia compared with that in healthy control. ELISA results revealed that plasma levels of N-cadherin in 76 patients with AD were higher than those in 133 healthy control subjects. The N-cadherin levels in the brains of an AD mouse model, APP Swedish/PS1delE9 Tg (APP Tg) were reduced compared with that in control. The N-terminal fragment of N-cadherin produced by cleavage at a plasma membrane was detected extravascularly, accumulated in senile plaques in the cortex of an APP Tg mouse. In addition, N-cadherin plasma levels were increased in APP Tg mice. Collectively, our study suggests that alteration of N-cadherin levels might be associated with AD pathology.}, } @article {pmid32296772, year = {2020}, author = {Abd-Elrahman, KS and Hamilton, A and Albaker, A and Ferguson, SSG}, title = {mGluR5 Contribution to Neuropathology in Alzheimer Mice Is Disease Stage-Dependent.}, journal = {ACS pharmacology & translational science}, volume = {3}, number = {2}, pages = {334-344}, pmid = {32296772}, issn = {2575-9108}, abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disease and is characterized by a progressive cognitive decline in affected individuals. Current therapeutic strategies are limited in their efficacy and some have proven to be even less effective at later disease stages or after extended use. We previously demonstrated that chronic inhibition of mGluR5 signaling using the selective negative allosteric modulator (NAM) CTEP in APPswe/PS1ΔE9 mice can rescue cognitive function, activating the ZBTB16-mediated autophagy pathway to reduce Aβ, the principal neurotoxic species in AD brains. Here, we evaluated the efficacy of long-term treatment with CTEP in 6 month old APPswe/PS1ΔE9 mice for either 24 or 36 weeks. CTEP maintained its efficacy in reversing working and spatial memory deficits and mitigating neurogliosis in APPswe/PS1ΔE9 mice when administered for 24 weeks. This was paralleled by a significant reduction in Aβ oligomer and plaque load as a result of autophagy activation via ZBTB16 and mTOR-dependent pathways. However, further extension of CTEP treatment for 36 weeks was found ineffective in reversing memory deficit, neurogliosis, or Aβ-related pathology. We found that this loss in CTEP efficacy in 15 month old APPswe/PS1ΔE9 mice was due to the abolished contribution of ZBTB16 and mTOR-mediated signaling to AD neuropathology at this advanced disease stage. Our findings indicate that the contribution of pathological mGluR5-signaling to AD may shift as the disease progresses. Thus, we provide the first evidence that the underlying pathophysiological mechanism(s) of AD may unfold along the course of the disease and treatment strategies should be modified accordingly to ensure maximal therapeutic outcomes.}, } @article {pmid32296300, year = {2020}, author = {Muddapu, VR and Dharshini, SAP and Chakravarthy, VS and Gromiha, MM}, title = {Neurodegenerative Diseases - Is Metabolic Deficiency the Root Cause?.}, journal = {Frontiers in neuroscience}, volume = {14}, number = {}, pages = {213}, pmid = {32296300}, issn = {1662-4548}, abstract = {Neurodegenerative diseases, including Alzheimer, Parkinson, Huntington, and amyotrophic lateral sclerosis, are a prominent class of neurological diseases currently without a cure. They are characterized by an inexorable loss of a specific type of neurons. The selective vulnerability of specific neuronal clusters (typically a subcortical cluster) in the early stages, followed by the spread of the disease to higher cortical areas, is a typical pattern of disease progression. Neurodegenerative diseases share a range of molecular and cellular pathologies, including protein aggregation, mitochondrial dysfunction, glutamate toxicity, calcium load, proteolytic stress, oxidative stress, neuroinflammation, and aging, which contribute to neuronal death. Efforts to treat these diseases are often limited by the fact that they tend to address any one of the above pathological changes while ignoring others. Lack of clarity regarding a possible root cause that underlies all the above pathologies poses a significant challenge. In search of an integrative theory for neurodegenerative pathology, we hypothesize that metabolic deficiency in certain vulnerable neuronal clusters is the common underlying thread that links many dimensions of the disease. The current review aims to present an outline of such an integrative theory. We present a new perspective of neurodegenerative diseases as metabolic disorders at molecular, cellular, and systems levels. This helps to understand a common underlying mechanism of the many facets of the disease and may lead to more promising disease-modifying therapeutic interventions. Here, we briefly discuss the selective metabolic vulnerability of specific neuronal clusters and also the involvement of glia and vascular dysfunctions. Any failure in satisfaction of the metabolic demand by the neurons triggers a chain of events that precipitate various manifestations of neurodegenerative pathology.}, } @article {pmid32293915, year = {2020}, author = {Kaur, A and Nigam, K and Srivastava, S and Tyagi, A and Dang, S}, title = {Memantine nanoemulsion: a new approach to treat Alzheimer's disease.}, journal = {Journal of microencapsulation}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/02652048.2020.1756971}, pmid = {32293915}, issn = {1464-5246}, abstract = {Aim: A nanoemulsion loaded with memantine for intranasal delivery to bypass the blood-brain barrier for the treatment of Alzheimer disease.Method: The nanoemulsion was prepared using homogenisation and ultrasonication methods. The developed nanoemulsion was characterised, in vitro release and antioxidant potential was analysed. The in vivo studies were carried out by radiolabelling the memantine with technetium pertechnetate.Results: The finalised NE showed particle-size of ∼11 nm and percentage transmittance of ∼99%. The in vitro release studies showed 80% drug release in simulated nasal fluid. The nanoemulsion showed 98% cell viability and antioxidative assays confirmed that the encapsulation of memantine in a nanoemulsion sustained its antioxidative potential. Gamma images and biodistribution results also confirmed higher uptake of formulation with %radioactivity of 3.6 ± 0.18%/g at 1.5 h in brains of rats administered intranasally.Conclusion: The developed nanoemulsion could be used as a potential carrier of memantine for a direct nose to brain delivery.}, } @article {pmid32293551, year = {2020}, author = {Sosunov, A and Wu, X and McGovern, R and Mikell, C and McKhann, GM and Goldman, JE}, title = {Abnormal mitosis in reactive astrocytes.}, journal = {Acta neuropathologica communications}, volume = {8}, number = {1}, pages = {47}, pmid = {32293551}, issn = {2051-5960}, support = {P30 CA013696/CA/NCI NIH HHS/United States ; K08-NS048064/NH/NIH HHS/United States ; Klingenstein Foundation Fellowship//Esther A. and Joseph Klingenstein Fund/ ; }, abstract = {Although abnormal mitosis with disarranged metaphase chromosomes or many micronuclei in astrocytes (named "Alzheimer I type astrocytes" and later "Creutzfeldt-Peters cells") have been known for nearly 100 years, the origin and mechanisms of this pathology remain elusive. In experimental brain insults in rats, we show that abnormal mitoses that are not followed by cytokinesis are typical for reactive astrocytes. The pathology originates due to the inability of the cells to form normal mitotic spindles with subsequent metaphase chromosome congression, which, in turn may be due to shape constraints aggravated by cellular enlargement and to the accumulation of large amounts of cytosolic proteins. Many astrocytes escape from arrested mitosis by producing micronuclei. These polyploid astrocytes can survive for long periods of time and enter into new cell cycles.}, } @article {pmid32291951, year = {2020}, author = {Niu, Z and Sarkar, R and Aichler, M and Wester, HJ and Yousefi, BH and Reif, B}, title = {Mapping the Binding Interface of PET Tracer Molecules and Alzheimer Disease Aβ Fibrils by Using MAS Solid-State NMR Spectroscopy.}, journal = {Chembiochem : a European journal of chemical biology}, volume = {}, number = {}, pages = {}, doi = {10.1002/cbic.202000143}, pmid = {32291951}, issn = {1439-7633}, support = {//Center for Integrated Protein Science Munich (CIPS-M)/ ; //Helmholtz-Gemeinschaft/ ; //China Scholarship Council (CSC)/ ; }, abstract = {Positron emission tomography (PET) tracer molecules like thioflavin T specifically recognize amyloid deposition in brain tissue by selective binding to hydrophobic or aromatic surface grooves on the β-sheet surface along the fibril axis. The molecular basis of this interaction is, however, not well understood. We have employed magic angle spinning (MAS) solid-state NMR spectroscopy to characterize Aβ-PET tracer complexes at atomic resolution. We established a titration protocol by using bovine serum albumin as a carrier to transfer hydrophobic small molecules to Aβ(1-40) fibrillar aggregates. The same Aβ(1-40) amyloid fibril sample was employed in subsequent titrations to minimize systematic errors that potentially arise from sample preparation. In the experiments, the small molecules 13 C-methylated Pittsburgh compound B (PiB) as well as a novel Aβ tracer based on a diarylbithiazole (DABTA) scaffold were employed. Classical 13 C-detected as well as proton-detected spectra of protonated and perdeuterated samples with back-substituted protons, respectively, were acquired and analyzed. After titration of the tracers, chemical-shift perturbations were observed in the loop region involving residues Gly25-Lys28 and Ile32-Gly33, thus suggesting that the PET tracer molecules interact with the loop region connecting β-sheets β1 and β2 in Aβ fibrils. We found that titration of the PiB derivatives suppressed fibril polymorphism and stabilized the amyloid fibril structure.}, } @article {pmid32291295, year = {2020}, author = {Vilaplana, E and Rodriguez-Vieitez, E and Ferreira, D and Montal, V and Almkvist, O and Wall, A and Lleó, A and Westman, E and Graff, C and Fortea, J and Nordberg, A}, title = {Cortical microstructural correlates of astrocytosis in autosomal-dominant Alzheimer disease.}, journal = {Neurology}, volume = {94}, number = {19}, pages = {e2026-e2036}, doi = {10.1212/WNL.0000000000009405}, pmid = {32291295}, issn = {1526-632X}, abstract = {OBJECTIVE: To study the macrostructural and microstructural MRI correlates of brain astrocytosis, measured with 11C-deuterium-L-deprenyl (11C-DED)-PET, in familial autosomal-dominant Alzheimer disease (ADAD).

METHODS: The total sample (n = 31) comprised ADAD mutation carriers (n = 10 presymptomatic, 39.2 ± 10.6 years old; n = 3 symptomatic, 55.5 ± 2.0 years old) and noncarriers (n = 18, 44.0 ± 13.7 years old) belonging to families with mutations in either the presenilin-1 or amyloid precursor protein genes. All participants underwent structural and diffusion MRI and neuropsychological assessment, and 20 participants (6 presymptomatic and 3 symptomatic mutation carriers and 11 noncarriers) also underwent 11C-DED-PET.

RESULTS: Vertex-wise interaction analyses revealed a differential relationship between carriers and noncarriers in the association between 11C-DED binding and estimated years to onset (EYO) and between cortical mean diffusivity (MD) and EYO. These differences were due to higher 11C-DED binding in presymptomatic carriers, with lower binding in symptomatic carriers compared to noncarriers, and to lower cortical MD in presymptomatic carriers, with higher MD in symptomatic carriers compared to noncarriers. Using a vertex-wise local correlation approach, 11C-DED binding was negatively correlated with cortical MD and positively correlated with cortical thickness.

CONCLUSIONS: Our proof-of-concept study is the first to show that microstructural and macrostructural changes can reflect underlying neuroinflammatory mechanisms in early stages of Alzheimer disease (AD). The findings support a role for neuroinflammation in AD pathogenesis, with potential implications for the correct interpretation of neuroimaging biomarkers as surrogate endpoints in clinical trials.}, } @article {pmid32290675, year = {2020}, author = {Bartfai, T and Lees, GV}, title = {Alzheimer Drug Trials: Combination of Safe and Efficacious Biologicals to Break the Amyloidosis-Neuroinflammation Vicious Cycle.}, journal = {ASN neuro}, volume = {12}, number = {}, pages = {1759091420918557}, pmid = {32290675}, issn = {1759-0914}, } @article {pmid32290556, year = {2020}, author = {Gambardella, J and Lombardi, A and Morelli, MB and Ferrara, J and Santulli, G}, title = {Inositol 1,4,5-Trisphosphate Receptors in Human Disease: A Comprehensive Update.}, journal = {Journal of clinical medicine}, volume = {9}, number = {4}, pages = {}, pmid = {32290556}, issn = {2077-0383}, support = {R00 DK107895/DK/NIDDK NIH HHS/United States ; R01 DK123259/DK/NIDDK NIH HHS/United States ; R01-DK033823/NH/NIH HHS/United States ; P30 DK020541/DK/NIDDK NIH HHS/United States ; R01-HL146691/NH/NIH HHS/United States ; R01 HL146691/HL/NHLBI NIH HHS/United States ; }, abstract = {Inositol 1,4,5-trisphosphate receptors (ITPRs) are intracellular calcium release channels located on the endoplasmic reticulum of virtually every cell. Herein, we are reporting an updated systematic summary of the current knowledge on the functional role of ITPRs in human disorders. Specifically, we are describing the involvement of its loss-of-function and gain-of-function mutations in the pathogenesis of neurological, immunological, cardiovascular, and neoplastic human disease. Recent results from genome-wide association studies are also discussed.}, } @article {pmid32289286, year = {2020}, author = {Dong, YT and Cao, K and Xiang, J and Shan, L and Guan, ZZ}, title = {Silent Mating-Type Information Regulation 2 Homolog 1 Attenuates the Neurotoxicity Associated with Alzheimer Disease via a Mechanism Which May Involve Regulation of Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-α.}, journal = {The American journal of pathology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ajpath.2020.03.015}, pmid = {32289286}, issn = {1525-2191}, abstract = {To investigate whether silent mating-type information regulation 2 homolog 1 (SIRT1) plays a neuroprotective role in connection with Alzheimer disease (AD), brain tissues from patients with AD and APP/PS1 mice as well as primary rat neurons exposed to oligomers of amyloid-β peptide were used. The animals were treated with resveratrol (RSV) or suramin for 2 months; cell cultures were treated with RSV, suramin, the peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) stimulator ZLN005; and transient transfection was treated with PGC-1α RNA silence. The level of SIRT1 in brain tissues from patients with AD and APP/PS1 mice, as well as in primary neurons exposed to oligomers of amyloid-β peptide, was decreased, including SIRT1 proteins in nuclear or mitochondria. Overexpression of APP/PS1 exhibited impaired learning and memory of mice; more senile plaques, disrupted membranes, and broken or absent cristae of mitochondria in the brain; decreased levels of A disintegrin and metallopeptidase domain 10, beta-secretase 2, 8-oxoguanine DNA glycosylase-1, PGC-1α, and NAD+; and increased levels of beta-secretase 1and apoptosis. Interestingly, these changes were attenuated significantly by treatment with RSV but enhanced by suramin. By activating PGC-1α but inhibiting SIRT1, the extent of apoptotic death in cells was significantly decreased; however, by activating SIRT1 but inhibiting PGC-1α with small interfering PGC-1α, these levels remained unchanged. These findings indicate that SIRT1 may protect against the neurotoxicity associated with AD, which might involve the regulation of PGC-1α.}, } @article {pmid32287048, year = {2020}, author = {Jutkowitz, E and Gozalo, P and Trivedi, A and Mitchell, L and Gaugler, JE}, title = {The Effect of Physical and Cognitive Impairments on Caregiving.}, journal = {Medical care}, volume = {58}, number = {7}, pages = {601-609}, pmid = {32287048}, issn = {1537-1948}, support = {R01 AG060871/AG/NIA NIH HHS/United States ; R21 AG059623/AG/NIA NIH HHS/United States ; U01 AG009740/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: Many older adults receive caregiving; however, less is known about how a change in a care recipient's functional activity limitations [instrumental activities of daily living (IADL) and basic activities of daily living (ADL)] as well as their cognitive impairment influence the amount of caregiving received.

METHODS: Using the Health and Retirement Study (2002-2014) we identified community-dwelling respondents with Alzheimer disease and related dementias (ADRD; n=674), cognitive impairment no dementia (CIND; n=530), and no cognitive impairment (n=6126). We estimated a series of two-part regression models to identify the association between care recipients' level of cognitive impairment, change in total number of IADL/ADL limitations and amount of caregiving received.

RESULTS: Persons with ADRD received 235.8 (SD=265.6) monthly hours of care compared with 26.0 (SD=92.6) and 6.0 (SD=40.7) for persons with CIND and no cognitive impairment, respectively. An increase in one IADL/ADL limitation resulted in persons with ADRD and CIND receiving 4.90 (95% confidence interval: 3.40-6.39) and 1.43 (95% confidence interval: 0.17-2.69) more hours of caregiving than persons with no cognitive impairment. Increases in total IADL/ADL limitations were associated with persons with ADRD, but not CIND, receiving more days of caregiving and having more caregivers than persons with no cognitive impairment.

CONCLUSIONS: Compared with persons with no cognitive impairment, increases in IADL/ADL limitations disproportionally increases the caregiving received for persons with ADRD. Policies and programs must pay attention to functional impairments among those living with ADRD.}, } @article {pmid32286939, year = {2020}, author = {Monteiro, KLC and Alcântara, MGDS and de Aquino, TM and da Silva-Júnior, EF}, title = {Tau Protein Aggregation in Alzheimer's Disease: Recent Advances in the Development of Novel Therapeutic Agents.}, journal = {Current pharmaceutical design}, volume = {26}, number = {15}, pages = {1682-1692}, doi = {10.2174/1381612826666200414164038}, pmid = {32286939}, issn = {1873-4286}, abstract = {Major research in Alzheimer's disease (AD) related to disease-modifying agents is concentrated on pharmacological approaches related to diagnostic markers, neurofibrillary tangles and amyloid plaques. Although most studies focus on anti-amyloid strategies, investigations on tau protein have produced significant advances in the modulation of the pathophysiology of several neurodegenerative diseases. Since the discovery of phenothiazines as tau protein aggregation inhibitors (TAGIs), many additional small molecule inhibitors have been discovered and characterized in biological model systems, which exert their interaction effects by covalent and noncovalent means. In this paper, we summarize the latest advances in the discovery and development of tau aggregation inhibitors using a specialized approach in their chemical classes. The design of new TAGIs and their encouraging use in in vivo and clinical trials support their potential therapeutic use in AD.}, } @article {pmid32286632, year = {2020}, author = {Abbasi, J}, title = {Alzheimer Blood Test Using Tau Biomarker Is in Development.}, journal = {JAMA}, volume = {323}, number = {14}, pages = {1336}, doi = {10.1001/jama.2020.4542}, pmid = {32286632}, issn = {1538-3598}, mesh = {Alzheimer Disease/blood/*diagnosis ; Biomarkers/blood ; Hematologic Tests ; Humans ; tau Proteins/*blood ; }, } @article {pmid32285366, year = {2020}, author = {Andrzejewska, A and Janowski, M}, title = {Microfluidic Systems in CNS Studies.}, journal = {Advances in experimental medicine and biology}, volume = {1230}, number = {}, pages = {87-95}, doi = {10.1007/978-3-030-36588-2_6}, pmid = {32285366}, issn = {0065-2598}, mesh = {Brain ; *Central Nervous System ; Humans ; *Lab-On-A-Chip Devices ; *Microfluidic Analytical Techniques ; *Tissue Array Analysis ; }, abstract = {Current technological progress facilitates the introduction of micro-devices into biotechnology research including studies on central nervous system. Wide range of micro-chambers with diversity of channel systems and multiple compartments enable users to create models which closely mimic nervous tissue structure which nowadays is often called as brain-on-a-chip technology. Heretofore experiments showing the influence of substance gradients, cell interactions, spatial conditions, neuroinflammation, stem cells migration, drug delivery, mechanisms controlling progression of diseases like Alzheimer, Parkinson, multiple sclerosis or nerve injury were performed in microfluidic devices. Moreover, the integration of bio-sensors and development of dedicated software for microfluidic studies can enable performing high throughput and good quality automated experiments investigating regeneration and degeneration processes in models well emulating central nervous system structures.}, } @article {pmid32284705, year = {2020}, author = {Castillo-Barnes, D and Su, L and Ramírez, J and Salas-Gonzalez, D and Martinez-Murcia, FJ and Illan, IA and Segovia, F and Ortiz, A and Cruchaga, C and Farlow, MR and Xiong, C and Graff-Radford, NR and Schofield, PR and Masters, CL and Salloway, S and Jucker, M and Mori, H and Levin, J and Gorriz, JM and , }, title = {Autosomal Dominantly Inherited Alzheimer Disease: Analysis of genetic subgroups by Machine Learning.}, journal = {An international journal on information fusion}, volume = {58}, number = {}, pages = {153-167}, pmid = {32284705}, issn = {1566-2535}, support = {U01 AG058922/AG/NIA NIH HHS/United States ; U19 AG032438/AG/NIA NIH HHS/United States ; }, abstract = {Despite subjects with Dominantly-Inherited Alzheimer's Disease (DIAD) represent less than 1% of all Alzheimer's Disease (AD) cases, the Dominantly Inherited Alzheimer Network (DIAN) initiative constitutes a strong impact in the understanding of AD disease course with special emphasis on the presyptomatic disease phase. Until now, the 3 genes involved in DIAD pathogenesis (PSEN1, PSEN2 and APP) have been commonly merged into one group (Mutation Carriers, MC) and studied using conventional statistical analysis. Comparisons between groups using null-hypothesis testing or longitudinal regression procedures, such as the linear-mixed-effects models, have been assessed in the extant literature. Within this context, the work presented here performs a comparison between different groups of subjects by considering the 3 genes, either jointly or separately, and using tools based on Machine Learning (ML). This involves a feature selection step which makes use of ANOVA followed by Principal Component Analysis (PCA) to determine which features would be realiable for further comparison purposes. Then, the selected predictors are classified using a Support-Vector-Machine (SVM) in a nested k-Fold cross-validation resulting in maximum classification rates of 72-74% using PiB PET features, specially when comparing asymptomatic Non-Carriers (NC) subjects with asymptomatic PSEN1 Mutation-Carriers (PSEN1-MC). Results obtained from these experiments led to the idea that PSEN1-MC might be considered as a mixture of two different subgroups including: a first group whose patterns were very close to NC subjects, and a second group much more different in terms of imaging patterns. Thus, using a k-Means clustering algorithm it was determined both subgroups and a new classification scenario was conducted to validate this process. The comparison between each subgroup vs. NC subjects resulted in classification rates around 80% underscoring the importance of considering DIAN as an heterogeneous entity.}, } @article {pmid32283669, year = {2020}, author = {Ciavatta, ML and Lefranc, F and Vieira, LM and Kiss, R and Carbone, M and van Otterlo, WAL and Lopanik, NB and Waeschenbach, A}, title = {The Phylum Bryozoa: From Biology to Biomedical Potential.}, journal = {Marine drugs}, volume = {18}, number = {4}, pages = {}, pmid = {32283669}, issn = {1660-3397}, abstract = {Less than one percent of marine natural products characterized since 1963 have been obtained from the phylum Bryozoa which, therefore, still represents a huge reservoir for the discovery of bioactive metabolites with its ~6000 described species. The current review is designed to highlight how bryozoans use sophisticated chemical defenses against their numerous predators and competitors, and which can be harbored for medicinal uses. This review collates all currently available chemoecological data about bryozoans and lists potential applications/benefits for human health. The core of the current review relates to the potential of bryozoan metabolites in human diseases with particular attention to viral, brain, and parasitic diseases. It additionally weighs the pros and cons of total syntheses of some bryozoan metabolites versus the synthesis of non-natural analogues, and explores the hopes put into the development of biotechnological approaches to provide sustainable amounts of bryozoan metabolites without harming the natural environment.}, } @article {pmid32282020, year = {2020}, author = {Belloy, ME and Napolioni, V and Han, SS and Le Guen, Y and Greicius, MD and , }, title = {Association of Klotho-VS Heterozygosity With Risk of Alzheimer Disease in Individuals Who Carry APOE4.}, journal = {JAMA neurology}, volume = {}, number = {}, pages = {}, pmid = {32282020}, issn = {2168-6157}, abstract = {Importance: Identification of genetic factors that interact with the apolipoprotein e4 (APOE4) allele to reduce risk for Alzheimer disease (AD) would accelerate the search for new AD drug targets. Klotho-VS heterozygosity (KL-VSHET+ status) protects against aging-associated phenotypes and cognitive decline, but whether it protects individuals who carry APOE4 from AD remains unclear.

Objectives: To determine if KL-VSHET+ status is associated with reduced AD risk and β-amyloid (Aβ) pathology in individuals who carry APOE4.

This study combined 25 independent case-control, family-based, and longitudinal AD cohorts that recruited referred and volunteer participants and made data available through public repositories. Analyses were stratified by APOE4 status. Three cohorts were used to evaluate conversion risk, 1 provided longitudinal measures of Aβ CSF and PET, and 3 provided cross-sectional measures of Aβ CSF. Genetic data were available from high-density single-nucleotide variant microarrays. All data were collected between September 2015 and September 2019 and analyzed between April 2019 and December 2019.

Main Outcomes and Measures: The risk of AD was evaluated through logistic regression analyses under a case-control design. The risk of conversion to mild cognitive impairment (MCI) or AD was evaluated through competing risks regression. Associations with Aβ, measured from cerebrospinal fluid (CSF) or brain positron emission tomography (PET), were evaluated using linear regression and mixed-effects modeling.

Results: Of 36 530 eligible participants, 13 782 were excluded for analysis exclusion criteria or refusal to participate. Participants were men and women aged 60 years and older who were non-Hispanic and of Northwestern European ancestry and had been diagnosed as being cognitively normal or having MCI or AD. The sample included 20 928 participants in case-control studies, 3008 in conversion studies, 556 in Aβ CSF regression analyses, and 251 in PET regression analyses. The genotype KL-VSHET+ was associated with reduced risk for AD in individuals carrying APOE4 who were 60 years or older (odds ratio, 0.75 [95% CI, 0.67-0.84]; P = 7.4 × 10-7), and this was more prominent at ages 60 to 80 years (odds ratio, 0.69 [95% CI, 0.61-0.79]; P = 3.6 × 10-8). Additionally, control participants carrying APOE4 with KL-VS heterozygosity were at reduced risk of converting to MCI or AD (hazard ratio, 0.64 [95% CI, 0.44-0.94]; P = .02). Finally, in control participants who carried APOE4 and were aged 60 to 80 years, KL-VS heterozygosity was associated with higher Aβ in CSF (β, 0.06 [95% CI, 0.01-0.10]; P = .03) and lower Aβ on PET scans (β, -0.04 [95% CI, -0.07 to -0.00]; P = .04).

Conclusions and Relevance: The genotype KL-VSHET+ is associated with reduced AD risk and Aβ burden in individuals who are aged 60 to 80 years, cognitively normal, and carrying APOE4. Molecular pathways associated with KL merit exploration for novel AD drug targets. The KL-VS genotype should be considered in conjunction with the APOE genotype to refine AD prediction models used in clinical trial enrichment and personalized genetic counseling.}, } @article {pmid32282012, year = {2020}, author = {Dubal, DB and Yokoyama, JS}, title = {Longevity Gene KLOTHO and Alzheimer Disease-A Better Fate for Individuals Who Carry APOE ε4.}, journal = {JAMA neurology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaneurol.2020.0112}, pmid = {32282012}, issn = {2168-6157}, } @article {pmid32281389, year = {2020}, author = {Bramboeck, V and Moeller, K and Marksteiner, J and Kaufmann, L}, title = {Loneliness and Burden Perceived by Family Caregivers of Patients With Alzheimer Disease.}, journal = {American journal of Alzheimer's disease and other dementias}, volume = {35}, number = {}, pages = {1533317520917788}, doi = {10.1177/1533317520917788}, pmid = {32281389}, issn = {1938-2731}, abstract = {BACKGROUND: The present study aimed at investigating loneliness and burden experienced by family members caring for relatives diagnosed with Alzheimer disease.

METHODS: Participants were 40 caregivers of inpatients with Alzheimer disease. Correlation and multiple regression analyses were conducted to investigate whether caregivers' loneliness (uni- and multidimensional) and burden are associated with and predicted by (1) specific caregiver characteristics and/or (2) patients' dementia severity and neuropsychiatric symptoms.

RESULTS: Loneliness was significantly correlated with caregivers' sex, age, and living circumstances, while burden was significantly correlated with caregivers' education solely. Regression analyses revealed that caregivers' sex and living circumstances contributed significantly to variance explanation of loneliness (but not burden), while the additional consideration of patient variables did not improve model fit.

CONCLUSIONS: Loneliness reported by caregivers of relatives diagnosed with dementia is significantly modulated by caregiver (but not patient) characteristics. Notably, both uni- and multidimensional loneliness scales seem to be sensitive diagnostic tools.}, } @article {pmid32280087, year = {2020}, author = {Hunter, S and Hokkanen, SRK and Keage, HAD and Fleming, J and Minett, T and Polvikoski, T and Allinson, K and Brayne, C and , }, title = {TDP-43 Related Neuropathologies and Phosphorylation State: Associations with Age and Clinical Dementia in the Cambridge City over-75s Cohort.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {75}, number = {1}, pages = {337-350}, doi = {10.3233/JAD-191093}, pmid = {32280087}, issn = {1875-8908}, abstract = {Pathologies associated with the Tar-DNA binding protein 43 KDa (TDP-43) are associated with neurodegenerative diseases and aging. Phosphorylation of cellular proteins is a well-accepted mechanism of biological control and can be associated with disease pathways. Phosphorylation state associated with TDP-43 associated pathology has not been investigated with respect to dementia status in a population representative sample. TDP-43 immunohistochemistry directed toward phosphorylated (TDP-43P) and unphosphorylated (TDP-43U) was assessed in sections of hippocampus and temporal cortex from 222 brains donated to the population representative Cambridge City over-75s Cohort. Relationships between dementia status and age at death for TDP-43 immunoreactive pathologies by phosphorylation state were investigated. TDP-43 pathologies are common in the oldest old in the population and often do not conform to MacKenzie classification. Increasing age is associated with glial (TDP-43P) and neuronal inclusions (TDP-43P and TDP-43U), neurites, and granulovacuolar degeneration (GVD). Dementia status is associated with GVD and glial (TDP-43 P) and neural inclusions (TDP-43 P and U). Dementia severity was associated with glial (TDP-43P) and neuronal inclusions (TDP-43U and TDP-43P), GVD, and neurites. The associations between dementia severity and both glial cytoplasmic inclusions and GVD were independent from other pathologies and TDP-43 neuronal cytoplasmic inclusions. TDP-43 pathology contributes to dementia status and progression in a variety of ways in different phosphorylation states involving both neurons and glia, independently from age and from classic Alzheimer-related pathologies. TDP-43 pathologies as cytoplasmic inclusions in neurons or glia or as GVD contribute independently to dementia.}, } @article {pmid32278747, year = {2020}, author = {Chen, CL and Liang, CK and Yin, CH and Lin, YT and Lee, CC and Chen, NC}, title = {Corrigendum to 'Effects of Socioeconomic Status on Alzheimer Disease Mortality in Taiwan' [The American Journal of Geriatric Psychiatry 28 (2020) 205-216].}, journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jagp.2020.03.004}, pmid = {32278747}, issn = {1545-7214}, } @article {pmid32277437, year = {2020}, author = {Boccardi, V and Carino, S and Marinelli, E and Lapenna, M and Caironi, G and Bianco, AR and Cecchetti, R and Ruggiero, C and Mecocci, P and , }, title = {Uric acid and late-onset Alzheimer's disease: results from the ReGAl 2.0 project.}, journal = {Aging clinical and experimental research}, volume = {}, number = {}, pages = {}, doi = {10.1007/s40520-020-01541-z}, pmid = {32277437}, issn = {1720-8319}, abstract = {BACKGROUND: It has been suggested that oxidative stress may have a role in the pathogenesis of Alzheimer's disease (AD). Serum uric acid (UA) could exert neuroprotective effects via its antioxidant capacities. Many studies investigated serum UA levels in subjects with AD, but to date, results are conflicting and evidence in old age subjects is weak.

AIMS: In this study, we assess whether serum UA levels would be altered in the AD old age subjects compared to those of initial cognitive impairment and healthy controls.

METHODS: This is a retrospective study with data gathered from the ReGAl 2.0 project (Rete Geriatrica Alzheimer-Geriatric Network on Alzheimer's disease), a large Italian multicentric clinical-based study. A cohort of 232 subjects, including 65 (healthy controls HC), 95 mild cognitive impairment (MCI), and 72 AD, were included in the study. Serum UA was measured in all subjects by routine laboratory method.

RESULTS: The sample population includes 232 subjects, mostly women with a mean age of 79.16 ± 5.64 (range 66-93) years. No significant difference was found in gender distribution between groups. No significant correlation was found in all populations between age and uric acid levels. AD group had significantly lower UA levels as compared with HC. The association of uric acid with AD presence after adjusting for age, gender, body mass index (BMI) and creatinine levels showed that uric acid level was independently associated with the diagnosis of AD.

CONCLUSIONS: These data indicate that serum UA is reduced in AD, supporting that UA may have a potential protective role against AD in old age.}, } @article {pmid32276479, year = {2020}, author = {González-Sánchez, M and Jiménez, J and Narváez, A and Antequera, D and Llamas-Velasco, S and Martín, AH and Arjona, JAM and Munain, AL and Bisa, AL and Marco, MP and Rodríguez-Núñez, M and Pérez-Martínez, DA and Villarejo-Galende, A and Bartolome, F and Domínguez, E and Carro, E}, title = {Kynurenic Acid Levels are Increased in the CSF of Alzheimer's Disease Patients.}, journal = {Biomolecules}, volume = {10}, number = {4}, pages = {}, pmid = {32276479}, issn = {2218-273X}, support = {PI18/00118//Instituto de Salud Carlos III/ ; S2017/BMD-3700//Consejería de Educación e Investigación/ ; CTQ2011-29163-C03-01//Ministerio de Ciencia e Innovación/ ; }, abstract = {Kynurenic acid (KYNA) is a product of the tryptophan (TRP) metabolism via the kynurenine pathway (KP). This pathway is activated in neurodegenerative disorders, such as Alzheimer´s disease (AD). KYNA is primarily produced by astrocytes and is considered neuroprotective. Thus, altered KYNA levels may suggest an inflammatory response. Very recently, significant increases in KYNA levels were reported in cerebrospinal fluid (CSF) from AD patients compared with normal controls. In this study, we assessed the accuracy of KYNA in CSF for the classification of patients with AD, cognitively healthy controls, and patients with a variety of other neurodegenerative diseases, including frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and progressive supranuclear palsy (PSP). Averaged KYNA concentration in CSF was higher in patients with AD when compared with healthy subjects and with all the other differentially diagnosed groups. There were no significant differences in KYNA levels in CSF between any other neurodegenerative groups and controls. These results suggest a specific increase in KYNA concentration in CSF from AD patients not seen in other neurodegenerative diseases.}, } @article {pmid32276339, year = {2020}, author = {Vinciguerra, F and Graziano, M and Hagnäs, M and Frittitta, L and Tumminia, A}, title = {Influence of the Mediterranean and Ketogenic Diets on Cognitive Status and Decline: A Narrative Review.}, journal = {Nutrients}, volume = {12}, number = {4}, pages = {}, pmid = {32276339}, issn = {2072-6643}, abstract = {Alzheimer's disease (AD) is the most common form of senile dementia, accounting for up to 70% of dementia cases. AD is a slowly progressive disease, which causes global mental deterioration by affecting various cognitive areas. A growing body of evidence has demonstrated that lifestyle habits and nutritional patterns could delay the natural course of the neurodegeneration process. There is no single dietary pattern unequivocally proven to prevent AD. Nevertheless, epidemiological data suggest that by adopting several dietary habits, especially if accompanied with a healthy lifestyle, the negative consequences of AD could potentially be delayed. Alongside with others, two specific eating patterns have been well investigated concerning their potential beneficial effect on cognitive status: the Mediterranean diet (MedDi) and the Ketogenic Diet (KD). Despite the different underlying mechanisms, both of them have demonstrated a fairly profitable role in reducing or delaying cognitive impairment. The aim of the present narrative review is to overview the existing research on the efficacy of MedDi and KD against AD-related cognitive decline, focusing on the proposed protective mechanisms of action. Although the current knowledge on this complex topic does not allow us, at this point, to make exhaustive conclusions, this information could be of help in order to better characterize the possible role of MedDi and KD as nonpharmacological therapies in the treatment of AD and, more generically, of neurodegenerative disorders.}, } @article {pmid32275861, year = {2020}, author = {Oikari, LE and Pandit, R and Stewart, R and Cuní-López, C and Quek, H and Sutharsan, R and Rantanen, LM and Oksanen, M and Lehtonen, S and de Boer, CM and Polo, JM and Götz, J and Koistinaho, J and White, AR}, title = {Altered Brain Endothelial Cell Phenotype from a Familial Alzheimer Mutation and Its Potential Implications for Amyloid Clearance and Drug Delivery.}, journal = {Stem cell reports}, volume = {14}, number = {5}, pages = {924-939}, pmid = {32275861}, issn = {2213-6711}, abstract = {The blood-brain barrier (BBB) presents a barrier for circulating factors, but simultaneously challenges drug delivery. How the BBB is altered in Alzheimer disease (AD) is not fully understood. To facilitate this analysis, we derived brain endothelial cells (iBECs) from human induced pluripotent stem cells (hiPSCs) of several patients carrying the familial AD PSEN1 mutation. We demonstrate that, compared with isogenic PSEN1 corrected and control iBECs, AD-iBECs exhibit altered tight and adherens junction protein expression as well as efflux properties. Furthermore, by applying focused ultrasound (FUS) that transiently opens the BBB and achieves multiple therapeutic effects in AD mouse models, we found an altered permeability to 3-5 kDa dextran as a model cargo and the amyloid-β (Aβ) peptide in AD-iBECs compared with control iBECs. This presents human-derived in vitro models of the BBB as a valuable tool to understand its role and properties in a disease context, with possible implications for drug delivery.}, } @article {pmid32273431, year = {2020}, author = {Jacobs, HIL and Augustinack, JC and Schultz, AP and Hanseeuw, BJ and Locascio, J and Amariglio, RE and Papp, KV and Rentz, DM and Sperling, RA and Johnson, KA}, title = {The presubiculum links incipient amyloid and tau pathology to memory function in older persons.}, journal = {Neurology}, volume = {94}, number = {18}, pages = {e1916-e1928}, doi = {10.1212/WNL.0000000000009362}, pmid = {32273431}, issn = {1526-632X}, abstract = {OBJECTIVE: To identify the hippocampal subregions linking initial amyloid and tau pathology to memory performance in clinically normal older individuals, reflecting preclinical Alzheimer disease (AD).

METHODS: A total of 127 individuals from the Harvard Aging Brain Study (mean age 76.22 ± 6.42 years, 68 women [53.5%]) with a Clinical Dementia Rating score of 0, a flortaucipir tau-PET scan, a Pittsburgh compound B amyloid-PET scan, a structural MRI scan, and cognitive testing were included. From these images, we calculated neocortical, hippocampal, and entorhinal amyloid pathology; entorhinal and hippocampal tau pathology; and the volumes of 6 hippocampal subregions and total hippocampal volume. Memory was assessed with the selective reminding test. Mediation and moderation analyses modeled associations between regional markers and memory. Analyses included covariates for age, sex, and education.

RESULTS: Neocortical amyloid, entorhinal tau, and presubiculum volume univariately associated with memory performance. The relationship between neocortical amyloid and memory was mediated by entorhinal tau and presubiculum volume, which was modified by hippocampal amyloid burden. With other biomarkers held constant, presubiculum volume was the only marker predicting memory performance in the total sample and in individuals with elevated hippocampal amyloid burden.

CONCLUSIONS: The presubiculum captures unique AD-related biological variation that is not reflected in total hippocampal volume. Presubiculum volume may be a promising marker of imminent memory problems and can contribute to understanding the interaction between incipient AD-related pathologies and memory performance. The modulation by hippocampal amyloid suggests that amyloid is a necessary, but not sufficient, process to drive neurodegeneration in memory-related regions.}, } @article {pmid32273407, year = {2020}, author = {Le Berre, M and Vedel, I}, title = {Diversity considerations in Alzheimer disease and related disorders: How can our national and provincial strategies be inclusive of sexual minorities?.}, journal = {Canadian family physician Medecin de famille canadien}, volume = {66}, number = {4}, pages = {244-246}, pmid = {32273407}, issn = {1715-5258}, } @article {pmid32271912, year = {2020}, author = {Claycombe-Larson, KJ and Alvine, T and Wu, D and Kalupahana, NS and Moustaid-Moussa, N and Roemmich, JN}, title = {Nutrients and Immunometabolism: Role of Macrophage NLRP3.}, journal = {The Journal of nutrition}, volume = {}, number = {}, pages = {}, doi = {10.1093/jn/nxaa085}, pmid = {32271912}, issn = {1541-6100}, abstract = {Inflammation is largely mediated by immune cells responding to invading pathogens, whereas metabolism is oriented toward producing usable energy for vital cell functions. Immunometabolic alterations are considered key determinants of chronic inflammation, which leads to the development of chronic diseases. Studies have demonstrated that macrophages and the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome are activated in key metabolic tissues to contribute to increased risk for type 2 diabetes mellitus, Alzheimer disease, and liver diseases. Thus, understanding the tissue-/cell-type-specific regulation of the NLRP3 inflammasome is crucial for developing intervention strategies. Currently, most of the nutrients and bioactive compounds tested to determine their inflammation-reducing effects are limited to animal models. Future studies need to address how dietary compounds regulate immune and metabolic cell reprograming in humans.}, } @article {pmid32271152, year = {2020}, author = {Sedrak, MS and Soto-Perez-De-Celis, E and Nelson, RA and Liu, J and Waring, ME and Lane, DS and Paskett, ED and Chlebowski, RT}, title = {Online Health Information-Seeking Among Older Women With Chronic Illness: Analysis of the Women's Health Initiative.}, journal = {Journal of medical Internet research}, volume = {22}, number = {4}, pages = {e15906}, doi = {10.2196/15906}, pmid = {32271152}, issn = {1438-8871}, support = {K12 CA001727/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Understanding how older patients with chronic illnesses use the internet to obtain health information is relevant for the design of digital interventions aimed at improving the health and well-being of adults aged 65 years and older; this cohort represents the sickest, most expensive, and fastest-growing segment of the US population.

OBJECTIVE: The objective of our study was to describe online health information-seeking behavior among older patients with chronic illnesses and to compare the characteristics of patients who report using the internet to obtain health information with those who do not.

METHODS: The study population included 72,806 women aged 65 years and older enrolled in the Women's Health Initiative (WHI), a national cohort study, who completed a 2014 supplemental questionnaire assessing everyday technology use and internet use for researching health conditions. Comparisons were made between participants with and without a history of chronic illness and between users and nonusers of online sources for health information. Multivariate logistic regression was used to estimate odds ratios (ORs) and 95% CIs.

RESULTS: Of the total, 59% (42,887/72,806) of older women used the internet for health information. Compared with women who did not use the internet to obtain health information, those who used the internet were younger (median age: 76 vs 81 years), more likely to be non-Hispanic white (90% [38,481/42,887] vs 87% [26,017/29,919]), earned a higher income (over $US 50,000: 55% [23,410/42,887] vs 33% [9991/29,919]), achieved a higher educational level (more than high school: 87% [37,493/42,887] vs 75% [22,377/29,919]), and were more likely to live with a partner (52% [22,457/42,887] vs 36% [10,759/29,919]) (all P<.001). Women with Alzheimer disease were least likely to report online health information-seeking compared to those without the disease (OR 0.41, 95% CI 0.38-0.43). In contrast, women with a recent diagnosis of cancer, within the previous 2 years (OR 1.23, 95% CI 1.11-1.36) or 2-5 years ago (OR 1.09, 95% CI 1.00-1.19), were most likely to use the internet for health information.

CONCLUSIONS: Nearly 6 in 10 older women participating in the WHI reported using the internet to obtain health information. Patients recently diagnosed with cancer are more likely to be looking for health information online, even after adjustment for age, suggesting that these patients may have a greater need for digital health resources.}, } @article {pmid32270504, year = {2020}, author = {Navarro-Triviño, FJ and Ruiz-Villaverde, R}, title = {Allergic contact dermatitis caused by 2-ethylhexyl acrylate in a rivastigmine transdermal therapeutic system.}, journal = {Contact dermatitis}, volume = {}, number = {}, pages = {}, doi = {10.1111/cod.13551}, pmid = {32270504}, issn = {1600-0536}, } @article {pmid32269937, year = {2020}, author = {Kim, S and Lee, Y and Jeon, CY and Kim, K and Jeon, Y and Jin, YB and Oh, S and Lee, C}, title = {Quantitative magnetic susceptibility assessed by 7T magnetic resonance imaging in Alzheimer's disease caused by streptozotocin administration.}, journal = {Quantitative imaging in medicine and surgery}, volume = {10}, number = {3}, pages = {789-797}, pmid = {32269937}, issn = {2223-4292}, abstract = {Streptozotocin treatment has emerged as an alternative model of sporadic Alzheimer's disease (SAD). Streptozotocin-induced alterations in iron and calcium levels reflect magnetic susceptibility changes, while susceptibility distribution in the cerebral regions has not been reported yet. This study aimed to investigate susceptibility distribution in the limbic system after streptozotocin administration to cynomolgus monkeys for exploring informative SAD biomarkers. Quantitative susceptibility mapping (QSM) using 7T magnetic resonance imaging (MRI) was utilized to quantitatively compare the susceptibility distributions in monkeys with sporadic Alzheimer disease and age-matched healthy controls. Compared to healthy controls, overall susceptibility values differed in the SAD models. Notable substantial susceptibility changes were observed in the hypothalamus with a 4.38-time decrease (AD: -47.45±12.19 ppb, healthy controls: 14.02±9.51 ppb) and in the posterior parts of the corpus callosum with a 2.83-times increase (AD: 31.49±15.90 ppb; healthy controls: 11.13±4.02 ppb). These susceptibility alterations may reflect neuronal death, and could serve as key biomarkers in the SAD. These results may be useful for specifying AD pathologies such as cognitive and non-cognitive symptoms.}, } @article {pmid32269835, year = {2019}, author = {Hunsberger, HC and Pinky, PD and Smith, W and Suppiramaniam, V and Reed, MN}, title = {The role of APOE4 in Alzheimer's disease: strategies for future therapeutic interventions.}, journal = {Health psychology and behavioral medicine}, volume = {3}, number = {2}, pages = {NS20180203}, pmid = {32269835}, issn = {2164-2850}, abstract = {Alzheimer's disease (AD) is the leading cause of dementia affecting almost 50 million people worldwide. The ε4 allele of Apolipoprotein E (APOE) is the strongest known genetic risk factor for late-onset AD cases, with homozygous APOE4 carriers being approximately 15-times more likely to develop the disease. With 25% of the population being APOE4 carriers, understanding the role of this allele in AD pathogenesis and pathophysiology is crucial. Though the exact mechanism by which ε4 allele increases the risk for AD is unknown, the processes mediated by APOE, including cholesterol transport, synapse formation, modulation of neurite outgrowth, synaptic plasticity, destabilization of microtubules, and β-amyloid clearance, suggest potential therapeutic targets. This review will summarize the impact of APOE on neurons and neuronal signaling, the interactions between APOE and AD pathology, and the association with memory decline. We will then describe current treatments targeting APOE4, complications associated with the current therapies, and suggestions for future areas of research and treatment.}, } @article {pmid32268543, year = {2020}, author = {Jara-Guajardo, P and Cabrera, P and Celis, F and Soler, M and Berlanga, I and Parra-Muñoz, N and Acosta, G and Albericio, F and Guzman, F and Campos, M and Alvarez, A and Morales-Zavala, F and Kogan, MJ}, title = {Gold Nanoparticles Mediate Improved Detection of β-amyloid Aggregates by Fluorescence.}, journal = {Nanomaterials (Basel, Switzerland)}, volume = {10}, number = {4}, pages = {}, pmid = {32268543}, issn = {2079-4991}, support = {1513001//Fondap/ ; 1170929//Fondecyt/ ; 1161775//Fondecyt/ ; }, abstract = {The early detection of the amyloid beta peptide aggregates involved in Alzheimer's disease is crucial to test new potential treatments. In this research, we improved the detection of amyloid beta peptide aggregates in vitro and ex vivo by fluorescence combining the use of CRANAD-2 and gold nanorods (GNRs) by the surface enhancement fluorescence effect. We synthetized GNRs and modified their surface with HS-PEG-OMe and HS-PEG-COOH and functionalized them with the D1 peptide, which has the capability to selectively bind to amyloid beta peptide. For an in vitro detection of amyloid beta peptide, we co-incubated amyloid beta peptide aggregates with the probe CRANAD-2 and GNR-PEG-D1 observing an increase in the intensity of the fluorescence signal attributed to surface enhancement fluorescence. Furthermore, the surface enhancement fluorescence effect was observed in brain slices of transgenic mice with Alzheimer´s disease co-incubated with CRANAD-2 and GNR-PEG-D1. An increase in the fluorescence signal was observed allowing the detection of aggregates that cannot be detected with the single use of CRANAD-2. Gold nanoparticles allowed an improvement in the detection of the amyloid aggregated by fluorescence in vitro and ex vivo.}, } @article {pmid32265696, year = {2020}, author = {Husna Ibrahim, N and Yahaya, MF and Mohamed, W and Teoh, SL and Hui, CK and Kumar, J}, title = {Pharmacotherapy of Alzheimer's Disease: Seeking Clarity in a Time of Uncertainty.}, journal = {Frontiers in pharmacology}, volume = {11}, number = {}, pages = {261}, pmid = {32265696}, issn = {1663-9812}, abstract = {Alzheimer's disease (AD) is recognized as a major health hazard that mostly affects people older than 60 years. AD is one of the biggest medical, economic, and social concerns to patients and their caregivers. AD was ranked as the 5th leading cause of global deaths in 2016 by the World Health Organization (WHO). Many drugs targeting the production, aggregation, and clearance of Aβ plaques failed to give any conclusive clinical outcomes. This mainly stems from the fact that AD is not a disease attributed to a single-gene mutation. Two hallmarks of AD, Aβ plaques and neurofibrillary tangles (NFTs), can simultaneously induce other AD etiologies where every pathway is a loop of consequential events. Therefore, the focus of recent AD research has shifted to exploring other etiologies, such as neuroinflammation and central hyperexcitability. Neuroinflammation results from the hyperactivation of microglia and astrocytes that release pro-inflammatory cytokines due to the neurological insults caused by Aβ plaques and NFTs, eventually leading to synaptic dysfunction and neuronal death. This review will report the failures and side effects of many anti-Aβ drugs. In addition, emerging treatments targeting neuroinflammation in AD, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and receptor-interacting serine/threonine protein kinase 1 (RIPK1), that restore calcium dyshomeostasis and microglia physiological function in clearing Aβ plaques, respectively, will be deliberately discussed. Other novel pharmacotherapy strategies in treating AD, including disease-modifying agents (DMTs), repurposing of medications used to treat non-AD illnesses, and multi target-directed ligands (MTDLs) are also reviewed. These approaches open new doors to the development of AD therapy, especially combination therapy that can cater for several targets simultaneously, hence effectively slowing or stopping AD.}, } @article {pmid32265650, year = {2020}, author = {Hornung, S and Dutta, S and Bitan, G}, title = {CNS-Derived Blood Exosomes as a Promising Source of Biomarkers: Opportunities and Challenges.}, journal = {Frontiers in molecular neuroscience}, volume = {13}, number = {}, pages = {38}, pmid = {32265650}, issn = {1662-5099}, abstract = {Eukaryotic cells release different types of extracellular vesicles (EVs) including exosomes, ectosomes, and microvesicles. Exosomes are nanovesicles, 30-200 nm in diameter, that carry cell- and cell-state-specific cargo of proteins, lipids, and nucleic acids, including mRNA and miRNA. Recent studies have shown that central nervous system (CNS)-derived exosomes may carry amyloidogenic proteins and facilitate their cell-to-cell transfer, thus playing a critical role in the progression of neurodegenerative diseases, such as tauopathies and synucleinopathies. CNS-derived exosomes also have been shown to cross the blood-brain-barrier into the bloodstream and therefore have drawn substantial attention as a source of biomarkers for various neurodegenerative diseases as they can be isolated via a minimally invasive blood draw and report on the biochemical status of the CNS. However, although isolating specific brain-cell-derived exosomes from the blood is theoretically simple and the approach has great promise, practical details are of crucial importance and may compromise the reproducibility and utility of this approach, especially when different laboratories use different protocols. In this review we discuss the role of exosomes in neurodegenerative diseases, the usefulness of CNS-derived blood exosomes as a source of biomarkers for these diseases, and practical challenges associated with the methodology of CNS-derived blood exosomes and subsequent biomarker analysis.}, } @article {pmid32265533, year = {2020}, author = {Lemprière, S}, title = {New tools could improve Alzheimer disease diagnosis from structural MRI.}, journal = {Nature reviews. Neurology}, volume = {16}, number = {6}, pages = {297}, doi = {10.1038/s41582-020-0357-z}, pmid = {32265533}, issn = {1759-4766}, } @article {pmid32265300, year = {2020}, author = {Tambini, MD and D'Adamio, L}, title = {Knock-in rats with homozygous PSEN1L435F Alzheimer mutation are viable and show selective γ-secretase activity loss causing low Aβ40/42 and high Aβ43.}, journal = {The Journal of biological chemistry}, volume = {295}, number = {21}, pages = {7442-7451}, pmid = {32265300}, issn = {1083-351X}, abstract = {Familial forms of Alzheimer's disease (FAD) are caused by mutations in the gene encoding amyloid precursor protein, whose processing can result in formation of β-amyloid (Aβ). FAD can also result from mutations in the presenilin 1/2 (PSEN1/2) genes, whose protein products partially compose the γ-secretase complex that cleaves Aβ from amyloid precursor protein fragments. Psen1 KO mice and knock-in (KI) mice with homozygous FAD-associated L435F mutations (Psen1LF/LF) are embryonic and perinatally lethal, precluding a more rigorous examination of the effect of Alzheimer's disease-causing Psen1 mutations on neurodegeneration. Given that the rat is a more suitable model organism with regard to surgical interventions and behavioral testing, we generated a rat KI model of the Psen1LF mutation. In this study, we focused on young Psen1LF rats to determine potential early pathogenic changes caused by this mutation. We found that, unlike Psen1LF/LF mice, Psen1LF/LF rats survive into adulthood despite loss of γ-secretase activity. Consistent with loss of γ-secretase function, Psen1LF/LF rats exhibited low levels of Aβ38, Aβ40, and Aβ42 peptides. In contrast, levels of Aβ43, a longer and potentially more amyloidogenic Aβ form, were significantly increased in Psen1LF/LF and Psen1LF/w rats. The longer survival of these KI rats affords the opportunity to examine the effect of homozygous Psen1 Alzheimer's disease-associated mutations on neurodegeneration in older animals.}, } @article {pmid32259666, year = {2020}, author = {Li, JM and Zhao, Y and Sun, Y and Kong, LD}, title = {Potential effect of herbal antidepressants on cognitive deficit: Pharmacological activity and possible molecular mechanism.}, journal = {Journal of ethnopharmacology}, volume = {257}, number = {}, pages = {112830}, doi = {10.1016/j.jep.2020.112830}, pmid = {32259666}, issn = {1872-7573}, abstract = {Cognitive symptom is a "core" symptom of major depressive disorder (MDD) patients with clear deficit in memory, social and occupational function, and may persist during the remitting phase. Therefore, the remission of cognitive symptom has been considered as one of the main objectives in the treatment of MDD. Herbal antidepressants have been used to treat MDD, and there has been great advances in the understanding of the ability of these herbs to improve cognitive deficit linked to brain injury and various diseases including depression, Alzheimer disease, diabetes and age-related disorders. This systematic review summarizes the evidence from preclinical studies and clinical trials of herbal antidepressants with positive effects on cognitive deficit. The potential mechanisms by which herbal antidepressants prevent cognitive deficit are also reviewed. This review will facilitate further research and applications.

MATERIALS AND METHODS: We conducted an open-ended, English restricted search of MEDLINE (PubMed), Web of Science and Scopus for all available articles published or online before 31 December 2019, using terms pertaining to medical herb/phytomedicine/phytochemical/Chinese medicine and depression/major depressive disorder/antidepressant and/or cognitive impairment/cognitive deficit/cognitive dysfunction.

RESULTS: 7 prescriptions, more than 30 individual herbs and 50 phytochemicals from China, Japan, Korea and India with positive effects on the depressive state and cognitive deficit are reviewed herein. The evidence from preclinical studies and clinical trials proves that these herbal antidepressants exhibit positive effects on one or more aspects of cognitive defect including spatial, episodic, aversive, and short- and long-term memory. The action mode of the improvement of cognitive deficit by these herbal antidepressants is mediated mainly through two pathways. One pathway is to promote hippocampal neurogenesis through activating brain derived neurotrophic factor-tropomyosin-related kinase B signaling. The other pathway is to prevent neuronal apoptosis through the inhibition of neuro-inflammation and neuro-oxidation.

CONCLUSION: These herbal antidepressants, having potential therapy for cognitive deficit, may prevent pathological processes of neurodegenerative diseases. Furthermore, these herbal medicines should provide a treasure trove, which will accelerate the development of new antidepressants that can effectively improve cognitive symptom in MDD. Studies on their molecular mechanisms may provide more potential targets and therapeutic approaches for new drug discovery.}, } @article {pmid32255379, year = {2020}, author = {Agnello, L and Piccoli, T and Vidali, M and Cuffaro, L and Lo Sasso, B and Iacolino, G and Giglio, VR and Lupo, F and Alongi, P and Bivona, G and Ciaccio, M}, title = {Diagnostic accuracy of cerebrospinal fluid biomarkers measured by chemiluminescent enzyme immunoassay for Alzheimer disease diagnosis.}, journal = {Scandinavian journal of clinical and laboratory investigation}, volume = {}, number = {}, pages = {1-5}, doi = {10.1080/00365513.2020.1740939}, pmid = {32255379}, issn = {1502-7686}, abstract = {In the last decades, an important role of cerebrospinal fluid (CSF) biomarkers for Alzheimer disease (AD) diagnosis has emerged. The evaluation of the triad consisting of 42 aminoacid-long amyloid-beta peptide (Aβ42), total Tau (tTau) and Tau phosphorylated at threonine 181 (pTau) have been recently integrated into the research diagnostic criteria of AD. For a long time, the enzyme-linked immunosorbent assay (ELISA) has represented the most commonly used method for the measurement of CSF biomarkers levels. This study aimed to assess the diagnostic accuracy of CSF biomarkers, namely Aβ42, tTau and pTau and their ratio, measured by fully automated CLEIA assay (Lumipulse). We included 96 patients clinically diagnosed as AD (48) and non-AD (48). All CSF biomarkers levels were measured on Lumipulse G1200 fully automated platform (Fujirebio Inc. Europe, Gent, Belgium). Aβ42 levels, 42/40 ratio, 42/tTau ratio, 42/PTau ratio were significantly reduced, and tTau and PTau levels were significantly increased in AD patients in comparison with non-AD patients. The receiving operator curve (ROC) analysis showed good diagnostic accuracy of all CSF biomarkers and their ratios for discriminating AD patients from non-AD patients, with 42/40 ratio having the best AUC (0.724, 95%CI 0.619-0.828; p < 0.001). Our findings support the use of CSF biomarkers measured by CLEIA method on a fully automated platform for AD diagnosis.}, } @article {pmid32255227, year = {2020}, author = {Ferrer, I and Andrés-Benito, P}, title = {White matter alterations in Alzheimer's disease without concomitant pathologies.}, journal = {Neuropathology and applied neurobiology}, volume = {}, number = {}, pages = {}, doi = {10.1111/nan.12618}, pmid = {32255227}, issn = {1365-2990}, support = {PI17/000809//Instituto de Salud Carlos III/ ; IFI15/00035//Instituto de Salud Carlos III/ ; LCF/PR/HR19/52160007//La caixa foundation/ ; //European Regional Development Fund/ ; //CERCA Programme/ ; //Generalitat de Catalunya/ ; }, abstract = {AIMS: Most individuals with AD neuropathological changes have co-morbidities which have an impact on the integrity of the WM. This study analyses oligodendrocyte and myelin markers in the frontal WM in a series of AD cases without clinical or pathological co-morbidities.

METHODS: From a consecutive autopsy series, 206 cases had neuropathological changes of AD; among them, only 33 were AD without co-morbidities. WM alterations were first evaluated in coronal sections of the frontal lobe in every case. Then, RT-qPCR and immunohistochemistry were carried out in the frontal WM of AD cases without co-morbidities to analyse the expression of selected oligodendrocyte and myelin markers.

RESULTS: WM demyelination was more marked in AD with co-morbidities when compared with AD cases without co-morbidities. Regarding the later, mRNA expression levels of MBP, PLP1, CNP, MAG, MAL, MOG and MOBP were preserved at stages I-II/0-A when compared with middle-aged (MA) individuals, but significantly decreased at stages III-IV/0-C. This was accompanied by reduced expression of NG2 and PDGFRA mRNA, reduced numbers of NG2-, Olig2- and HDAC2-immunoreactive cells and reduced glucose transporter immunoreactivity. Partial recovery of some of these markers occurred at stages V-VI/B-C.

CONCLUSIONS: The present observations demonstrate that co-morbidities have an impact on WM integrity in the elderly and in AD, and that early alterations in oligodendrocytes and transcription of genes linked to myelin proteins in WM occur in AD cases without co-morbidities. These are followed by partial recovery attempts at advanced stages. These observations suggest that oligodendrocytopathy is part of AD.}, } @article {pmid32253270, year = {2020}, author = {Duguay, BA and Lu, L and Arizmendi, N and Unsworth, LD and Kulka, M}, title = {The Possible Uses and Challenges of Nanomaterials in Mast Cell Research.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {204}, number = {8}, pages = {2021-2032}, doi = {10.4049/jimmunol.1800658}, pmid = {32253270}, issn = {1550-6606}, abstract = {Mast cells are tissue-resident immune cells that are involved in inflammation and fibrosis but also serve beneficial roles, including tissue maintenance, angiogenesis, pathogen clearance, and immunoregulation. Their multifaceted response and the ability of their mediators to target multiple organs and tissues means that mast cells play important roles in numerous conditions, including asthma, atopic dermatitis, drug sensitivities, ischemic heart disease, Alzheimer disease, arthritis, irritable bowel syndrome, infections (parasites, bacteria and viruses), and cancer. As a result, mast cells have become an important target for drug discovery and diagnostic research. Recent work has focused on applying novel nanotechnologies to explore cell biology. In this brief review, we will highlight the use of nanomaterials to modify mast cell functions and will discuss the potential of these technologies as research tools for understanding mast cell biology.}, } @article {pmid32252825, year = {2020}, author = {Xu, G and Fromholt, SE and Chakrabarty, P and Zhu, F and Liu, X and Pace, MC and Koh, J and Golde, TE and Levites, Y and Lewis, J and Borchelt, DR}, title = {Diversity in Aβ deposit morphology and secondary proteome insolubility across models of Alzheimer-type amyloidosis.}, journal = {Acta neuropathologica communications}, volume = {8}, number = {1}, pages = {43}, pmid = {32252825}, issn = {2051-5960}, support = {R01 AG049456/AG/NIA NIH HHS/United States ; P50 AG047266/AG/NIA NIH HHS/United States ; A20141085//BrightFocus Foundation/International ; }, abstract = {A hallmark pathology of Alzheimer's disease (AD) is the formation of amyloid β (Aβ) deposits that exhibit diverse localization and morphologies, ranging from diffuse to cored-neuritic deposits in brain parenchyma, with cerebral vascular deposition in leptomeningeal and parenchymal compartments. Most AD brains exhibit the full spectrum of pathologic Aβ morphologies. In the course of studies to model AD amyloidosis, we have generated multiple transgenic mouse models that vary in the nature of the transgene constructs that are expressed; including the species origin of Aβ peptides, the levels and length of Aβ that is deposited, and whether mutant presenilin 1 (PS1) is co-expressed. These models recapitulate features of human AD amyloidosis, but interestingly some models can produce pathology in which one type of Aβ morphology dominates. In prior studies of mice that primarily develop cored-neuritic deposits, we determined that Aβ deposition is associated with changes in cytosolic protein solubility in which a subset of proteins become detergent-insoluble, indicative of secondary proteome instability. Here, we survey changes in cytosolic protein solubility across seven different transgenic mouse models that exhibit a range of Aβ deposit morphologies. We find a surprisingly diverse range of changes in proteome solubility across these models. Mice that deposit human Aβ40 and Aβ42 in cored-neuritic plaques had the most robust changes in proteome solubility. Insoluble cytosolic proteins were also detected in the brains of mice that develop diffuse Aβ42 deposits but to a lesser extent. Notably, mice with cored deposits containing only Aβ42 had relatively few proteins that became detergent-insoluble. Our data provide new insight into the diversity of biological effects that can be attributed to different types of Aβ pathology and support the view that fibrillar cored-neuritic plaque pathology is the more disruptive Aβ pathology in the Alzheimer's cascade.}, } @article {pmid32252616, year = {2020}, author = {Hajizadeh Moghaddam, A and Ahmadnia, H and Jelodar, SK and Ranjbar, M}, title = {Hesperetin nanoparticles attenuate anxiogenic-like behavior and cerebral oxidative stress through the upregulation of antioxidant enzyme expression in experimental dementia of Alzheimer's type.}, journal = {Neurological research}, volume = {42}, number = {6}, pages = {477-486}, doi = {10.1080/01616412.2020.1747716}, pmid = {32252616}, issn = {1743-1328}, abstract = {Background: In this study, we investigate the neuroprotective effects of Hesperetin (Hst) and Nano-Hst on anxiogenic-like behavior and cerebral antioxidant defenses at transcriptional and enzymatic levels in a streptozotocin (STZ)-induced Alzheimer rat model.Methods: Wistar rats were administrated with Hst and Nano-Hst (10 and 20 mg/kg/d) for three weeks. The elevated plus-maze test assessed anxiogenic-like behavior. After behavioral test, activity and gene expression of catalase (CAT), superoxide dismutase (SOD), glutathione reductase (GRx) enzymes, as well as malondialdehyde (MDA) and glutathione (GSH) levels, were measured in the cerebral cortex.Results: Based on our results, a rat model of Alzheimer's disease (AD) exhibited anxiogenic-like behavior, activity and gene expression of cerebral antioxidant enzymes and GSH level was decreased while the MDA level was increased. Hst and Nano-Hst treatment reversed anxiogenic-like behavior, and the activities of antioxidant enzymes were elevated. Hst and Nano-Hst effects on the gene expression of CAT, SOD and GRx were confirmed by quantitative real-time PCR (qRT-PCR) in which the expression levels of these genes in the cerebral brain were significantly increased compared to STZ group.Conclusions: These findings indicated that the administration of Hst and Nano-Hst may be used to treat anxiety -related to AD via an up-regulation of cerebral antioxidant enzyme gene.}, } @article {pmid32252546, year = {2020}, author = {Dyer, AH and Murphy, C and Lawlor, B and Kennelly, SP and Study Group For The Nilvad, }, title = {Social networks in mild-to-moderate Alzheimer disease: longitudinal relationships with dementia severity, cognitive function, and adverse events.}, journal = {Aging & mental health}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/13607863.2020.1745146}, pmid = {32252546}, issn = {1364-6915}, abstract = {Objectives: Poor social networks are associated with a greater likelihood of cognitive decline, dementia, and other adverse health outcomes in later life. However, these relationships have been poorly explored in those with established Alzheimer Disease (AD), who may represent a particularly vulnerable group.Methods: Analysis of data from the NILVAD study. We assessed social networks (Lubben Social Network Scale [LSNS]), cognition (Alzheimer's disease Assessment Scale [ADAS-Cog]) and dementia severity (Clinical Dementia Rating, Sum of Boxes [CDR-Sb]) in older adults with mild-moderate AD at baseline and at 18 months.Results: 464 participants with mild-to-moderate AD were included (73.1 ± 8.3 years; 61.9% female). At baseline, a poor social network was significantly associated with a greater dementia severity, but not greater cognitive impairment. Rather than a poor social network predicting greater cognitive decline over 18 months, a greater baseline dementia severity predicted a decline in social network over 18 months (β: -0.22, -0.42 - -0.02, p = 0.034). Finally, a poor social network was associated with a significantly increased likelihood of experiencing serious adverse events (IRR: 1.41, 1.06-1.89, p = 0.019).Discussion: As dementia progresses, older adults with AD are more likely to experience a decline in social network. Further, having a poor social network was associated with a greater likelihood of experiencing serious adverse events. These findings add novel insight into the complex relationship between social networks, dementia progression and adverse events in AD, and underscore the importance of developing and maintaining social networks in AD.}, } @article {pmid32252450, year = {2020}, author = {Kuo, FH and Chung, JF and Hsu, MY and Lee, CY and Huang, JY and Hsieh, MJ and Yang, SF}, title = {Impact of the Severities of Glaucoma on the Incidence of Subsequent Dementia: A Population-Based Cohort Study.}, journal = {International journal of environmental research and public health}, volume = {17}, number = {7}, pages = {}, pmid = {32252450}, issn = {1660-4601}, abstract = {The aim of the present study was to survey the relationship between the severity of glaucoma and subsequent dementia using the National Health Insurance Research Database (NHIRD) in Taiwan. Subjects with glaucoma were selected into the study group after an exclusion process, and each subject in the study group was propensity score-matched to another non-glaucoma patient that constituted the control group. The Cox proportional hazard regression that considered multiple potential risk factors of dementia was used to yield the adjusted hazard ratios (aHR) of dementia in different severities of glaucoma. There were 1185 (5.63 percent) subjects in the study group and 1119 (5.32 percent) patients in the control group that developed dementia. After adjusting for multiple confounders, there were no differences in the rate of any dementia (aHR: 0.961, 95% CI: 0.886-1.043, p = 0.3443), vascular dementia (aHR: 0.928, 95% CI: 0.846-1.018, p = 0.1154), Alzheimer's disease (aHR: 1.018, 95% CI: 0.761-1.362, p = 0.9025) or Parkinson's disease (aHR: 1.021, 95% CI: 0.886-1.176, p = 0.7744) between the study and the control groups. Regarding the disease severity of glaucoma, no difference was found in any type of dementia whether the glaucoma patients received less than two medical treatments, received more than two medical treatments, received drainage surgeries or received destructive surgeries. In conclusion, the different severities of glaucoma do not alter the incidence of subsequent dementia.}, } @article {pmid32252271, year = {2020}, author = {Martín-Belmonte, A and Aguado, C and Alfaro-Ruíz, R and Moreno-Martínez, AE and de la Ossa, L and Martínez-Hernández, J and Buisson, A and Shigemoto, R and Fukazawa, Y and Luján, R}, title = {Density of GABAB Receptors Is Reduced in Granule Cells of the Hippocampus in a Mouse Model of Alzheimer's Disease.}, journal = {International journal of molecular sciences}, volume = {21}, number = {7}, pages = {}, pmid = {32252271}, issn = {1422-0067}, support = {RTI2018-095812-B-I00; BFU2015-63769-R//Ministerio de Ciencia, Innovación y Universidades/ ; SBPLY/17/180501/000229; SBPLY/17/180501/000493//Junta de Comunidades de Castilla-La Mancha/ ; 16H04662, 17K19446, and 18H05120//Japan Society for the Promotion of Science/ ; }, abstract = {Metabotropic γ-aminobutyric acid (GABAB) receptors contribute to the control of network activity and information processing in hippocampal circuits by regulating neuronal excitability and synaptic transmission. The dysfunction in the dentate gyrus (DG) has been implicated in Alzheimer´s disease (AD). Given the involvement of GABAB receptors in AD, to determine their subcellular localisation and possible alteration in granule cells of the DG in a mouse model of AD at 12 months of age, we used high-resolution immunoelectron microscopic analysis. Immunohistochemistry at the light microscopic level showed that the regional and cellular expression pattern of GABAB1 was similar in an AD model mouse expressing mutated human amyloid precursor protein and presenilin1 (APP/PS1) and in age-matched wild type mice. High-resolution immunoelectron microscopy revealed a distance-dependent gradient of immunolabelling for GABAB receptors, increasing from proximal to distal dendrites in both wild type and APP/PS1 mice. However, the overall density of GABAB receptors at the neuronal surface of these postsynaptic compartments of granule cells was significantly reduced in APP/PS1 mice. Parallel to this reduction in surface receptors, we found a significant increase in GABAB1 at cytoplasmic sites. GABAB receptors were also detected at presynaptic sites in the molecular layer of the DG. We also found a decrease in plasma membrane GABAB receptors in axon terminals contacting dendritic spines of granule cells, which was more pronounced in the outer than in the inner molecular layer. Altogether, our data showing post- and presynaptic reduction in surface GABAB receptors in the DG suggest the alteration of the GABAB-mediated modulation of excitability and synaptic transmission in granule cells, which may contribute to the cognitive dysfunctions in the APP/PS1 model of AD.}, } @article {pmid32250387, year = {2020}, author = {Sperling, RA and Donohue, MC and Raman, R and Sun, CK and Yaari, R and Holdridge, K and Siemers, E and Johnson, KA and Aisen, PS and , }, title = {Association of Factors With Elevated Amyloid Burden in Clinically Normal Older Individuals.}, journal = {JAMA neurology}, volume = {}, number = {}, pages = {}, pmid = {32250387}, issn = {2168-6157}, abstract = {Importance: The Anti-Amyloid Treatment in Asymptomatic Alzheimer disease (A4) Study is an ongoing prevention trial in clinically normal older individuals with evidence of elevated brain amyloid. The large number of participants screened with amyloid positron emission tomography (PET) and standardized assessments provides an unprecedented opportunity to evaluate factors associated with elevated brain amyloid.

Objective: To investigate the association of elevated amyloid with demographic and lifestyle factors, apolipoprotein E (APOE), neuropsychological testing, and self- and study partner reports of cognitive function.

This cross-sectional study included screening data in the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study collected from April 2014 to December 2017 and classified by amyloid status. Data were was analyzed from 2018 to 2019 across 67 sites in the US, Canada, Australia, and Japan and included 4486 older individuals (age 65-85 years) who were eligible for amyloid PET (clinically normal [Clinical Dementia Rating = 0] and cognitively unimpaired [Mini-Mental State Examination score, ≥25; logical memory IIa 6-18]).

Main Outcomes and Measures: Screening demographics, lifestyle variables, APOE genotyping, and cognitive testing (Preclinical Alzheimer Cognitive Composite), self- and study partner reports of high-level daily cognitive function (Cognitive Function Index). Florbetapir amyloid PET imaging was used to classify participants as having elevated amyloid (Aβ+) or not having elevated amyloid (Aβ-).

Results: Amyloid PET results were acquired for 4486 participants (mean [SD] age, 71.29 [4.67] years; 2647 women [59%]), with 1323 (29.5%) classified as Aβ+. Aβ+ participants were slightly older than Aβ-, with no observed differences in sex, education, marital or retirement status, or any self-reported lifestyle factors. Aβ+ participants were more likely to have a family history of dementia (3320 Aβ+ [74%] vs 3050 Aβ- [68%]) and at least 1 APOE ε4 allele (2602 Aβ+ [58%] vs 1122 Aβ- [25%]). Aβ+ participants demonstrated worse performance on screening Preclinical Alzheimer Cognitive Composite results and reported higher change scores on the Cognitive Function Index.

Conclusions and Relevance: Among a large group of older individuals screening for an Alzheimer disease (AD) prevention trial, elevated brain amyloid was associated with family history and APOE ε4 allele but not with multiple other previously reported risk factors for AD. Elevated amyloid was associated with lower test performance results and increased reports of subtle recent declines in daily cognitive function. These results support the hypothesis that elevated amyloid represents an early stage in the Alzheimer continuum and demonstrate the feasibility of enrolling these high-risk participants in secondary prevention trials aimed at slowing cognitive decline during the preclinical stages of AD.}, } @article {pmid32249853, year = {2020}, author = {Zhang, C and Li, D and Wang, X}, title = {Role of physical exercise type in olfactory deterioration in ageing.}, journal = {Rhinology}, volume = {58}, number = {2}, pages = {145-150}, doi = {10.4193/Rhin19.274}, pmid = {32249853}, issn = {0300-0729}, abstract = {BACKGROUND: Although ageing and neurodegenerative diseases, including Alzheimer disease, have been associated with olfaction impairment, studies exploring how to ameliorate this impairment are limited. The aim of the present study was to determine the effect of various types of physical exercise on olfaction decline in ageing.

METHODOLOGY: 99 healthy community-dwelling participants (85 women; mean (SD) age, 62.5 (5.7) years) were included. All the participants were required to complete the tests consisting of a questionnaire, cognitive test and olfaction test.

RESULTS: Odor identification scores for participants who exercised regularly for more than 1 year (more than 3 times/wk; more than 30 min each time) were significantly higher than those for non-exercisers, and odor detection threshold scores were significantly higher in the exercisers. Both odor threshold and odor identification scores for those who exercised by practicing taiji (tai chi), dancing, or running were significantly better than those for participants who exercised by walking or who did not exercise.

CONCLUSION: Compared with those among older people who did not exercise, measures of olfaction among older adults who exercised were better, and the type of physical exercise mattered. Therefore, if physical exercise intervention is suggested to prevent or delay olfactory deterioration in older adults, the type of physical exercise should be considered.}, } @article {pmid32249007, year = {2020}, author = {Requena, MDC and Suárez-Álvarez, S}, title = {[Pre-death grief in caregivers of Alzheimer patients. A validation of a guide].}, journal = {Revista espanola de geriatria y gerontologia}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.regg.2020.02.001}, pmid = {32249007}, issn = {1578-1747}, abstract = {INTRODUCTION: The pre-death grief in family caregivers (FC) of people with Alzheimer's disease has not been sufficiently treated in studies on this group. Thus, the design and validation of informative printed materials is relevant due to its important implications for the well-being of these FCs and their training in the proper performance of their role. The objective was to design and validate a booklet aimed at informing FCs about this topic, as well as the procedure for its dissemination and use.

MATERIALS AND METHODS: After a review of the literature, a booklet and a questionnaire were designed to determine the acceptability and dissemination procedure and use of the booklet by 73 professionals working with FCs. With the suggestions made, modifications were made to both the content and format of the booklet.

RESULTS: The questionnaire used presented adequate content validity and reliability in its different sections (α=0.793 and α=0.888). The level of acceptability of the booklet was high by professionals (83.85% of total score). Its dissemination was especially valued in the initial stages of the disease, and its use in therapeutic and supportive group contexts, with professional advice.

CONCLUSIONS: The study made it possible to verify the relevance and acceptability of a booklet as a training resource for FCs about pre-death grief, making it a useful tool for professionals that work in this area of great relevance.}, } @article {pmid32244373, year = {2020}, author = {Obrenovich, M and Tabrez, S and Siddiqui, B and McCloskey, B and Perry, G}, title = {The Microbiota-Gut-Brain Axis-Heart Shunt Part II: Prosaic Foods and the Brain-Heart Connection in Alzheimer Disease.}, journal = {Microorganisms}, volume = {8}, number = {4}, pages = {}, pmid = {32244373}, issn = {2076-2607}, abstract = {There is a strong cerebrovascular component to brain aging, Alzheimer disease, and vascular dementia. Foods, common drugs, and the polyphenolic compounds contained in wine modulate health both directly and through the gut microbiota. This observation and novel findings centered on nutrition, biochemistry, and metabolism, as well as the newer insights we gain into the microbiota-gut-brain axis, now lead us to propose a shunt to this classic triad, which involves the heart and cerebrovascular systems. The French paradox and prosaic foods, as they relate to the microbiota-gut-brain axis and neurodegenerative diseases, are discussed in this manuscript, which is the second part of a two-part series of concept papers addressing the notion that the microbiota and host liver metabolism all play roles in brain and heart health.}, } @article {pmid32242751, year = {2020}, author = {Mandlik Ingawale, DS and Namdeo, AG}, title = {Pharmacological evaluation of Ashwagandha highlighting its healthcare claims, safety, and toxicity aspects.}, journal = {Journal of dietary supplements}, volume = {}, number = {}, pages = {1-44}, doi = {10.1080/19390211.2020.1741484}, pmid = {32242751}, issn = {1939-022X}, abstract = {Withania somnifera, commonly known as "Ashwagandha" or "Indian ginseng" is an essential therapeutic plant of Indian subcontinent regions. It is regularly used, alone or in combination with other plants for the treatment of various illnesses in Indian Systems of Medicine over the period of 3,000 years. Ashwagandha (W. somnifera) belongs to the genus Withania and family Solanaceae. It comprises a broad spectrum of phytochemicals having wide range of biological effects. W. somnifera has demonstrated various biological actions such as anti-cancer, anti-inflammatory, anti-diabetic, anti-microbial, anti-arthritic, anti-stress/adaptogenic, neuro-protective, cardio-protective, hepato-protective, immunomodulatory properties. Furthermore, W. somnifera has revealed the capability to decrease reactive oxygen species and inflammation, modulation of mitochondrial function, apoptosis regulation and improve endothelial function. Withaferin-A is an important phytoconstituents of W. somnifera belonging to the category of withanolides been used in the traditional system of medicine for the treatment of various disorders. In this review, we have summarized the active phytoconstituents, pharmacologic activities (preclinical and clinical), mechanisms of action, potential beneficial applications, marketed formulations and safety and toxicity profile of W. somnifera.}, } @article {pmid32242333, year = {2020}, author = {López, C and Sánchez, JL and Martín, J}, title = {[Exploratory analysis of the influence of cognitive reserve on the benefits of cognitive stimulation therapy in patients with sporadic late-onset Alzheimer's disease].}, journal = {Revista de neurologia}, volume = {70}, number = {8}, pages = {271-281}, doi = {10.33588/rn.7008.2019420}, pmid = {32242333}, issn = {1576-6578}, abstract = {INTRODUCTION: The main objective of cognitive stimulation therapies is to promote the plasticity and learning ability that the individual is still in possession of in old age and to delay the clinical manifestations of neurodegenerative processes such as Alzheimer-type dementia. There are variables that can mediate the benefits of the intervention, such as the cognitive reserve.

AIM: To determine whether there is an interaction between the level of reserve and cognitive stimulation, and if it influences the cognitive performance of subjects with Alzheimer-type dementia.

PATIENTS AND METHODS: Twenty subjects (age: 66-89) with Alzheimer-type dementia who attend a day centre participated in the study. A pretest-posttest controlled design was used. The pilot group took part in the intervention for six months. Patients were classified into two levels of cognitive reserve (high and low) and then a broad neuropsychological battery was applied to perform a comprehensive analysis of cognition. Pre- and post-intervention differences were analysed through a two-factor ANOVA, one with repeated measures (pre- and post-intervention scores) and another with independent measures (level of cognitive reserve).

RESULTS: Interaction was found in the scores on the picture arrangement subtests (WAIS-III), failure to maintain the category and the percentage of errors in the Wisconsin Card Sorting Test.

CONCLUSIONS: The positive effect of the interaction on the executive function has been observed, specifically in the capacities for planning and sequencing, perceptual organisation, response inhibition, logical reasoning and mental flexibility.}, } @article {pmid32241955, year = {2020}, author = {McKeith, IG and Ferman, TJ and Thomas, AJ and Blanc, F and Boeve, BF and Fujishiro, H and Kantarci, K and Muscio, C and O'Brien, JT and Postuma, RB and Aarsland, D and Ballard, C and Bonanni, L and Donaghy, P and Emre, M and Galvin, JE and Galasko, D and Goldman, JG and Gomperts, SN and Honig, LS and Ikeda, M and Leverenz, JB and Lewis, SJG and Marder, KS and Masellis, M and Salmon, DP and Taylor, JP and Tsuang, DW and Walker, Z and Tiraboschi, P and , }, title = {Research criteria for the diagnosis of prodromal dementia with Lewy bodies.}, journal = {Neurology}, volume = {94}, number = {17}, pages = {743-755}, doi = {10.1212/WNL.0000000000009323}, pmid = {32241955}, issn = {1526-632X}, abstract = {The prodromal phase of dementia with Lewy bodies (DLB) includes (1) mild cognitive impairment (MCI), (2) delirium-onset, and (3) psychiatric-onset presentations. The purpose of our review is to determine whether there is sufficient information yet available to justify development of diagnostic criteria for each of these. Our goal is to achieve evidence-based recommendations for the recognition of DLB at a predementia, symptomatic stage. We propose operationalized diagnostic criteria for probable and possible mild cognitive impairment with Lewy bodies, which are intended for use in research settings pending validation for use in clinical practice. They are compatible with current criteria for other prodromal neurodegenerative disorders including Alzheimer and Parkinson disease. Although there is still insufficient evidence to propose formal criteria for delirium-onset and psychiatric-onset presentations of DLB, we feel that it is important to characterize them, raising the index of diagnostic suspicion and prioritizing them for further investigation.}, } @article {pmid32241918, year = {2020}, author = {Wallin, C and Jarvet, J and Biverstål, H and Wärmländer, S and Danielsson, J and Gräslund, A and Abelein, A}, title = {Metal ion coordination delays amyloid-β peptide self-assembly by forming an aggregation-inert complex.}, journal = {The Journal of biological chemistry}, volume = {295}, number = {21}, pages = {7224-7234}, pmid = {32241918}, issn = {1083-351X}, abstract = {A detailed understanding of the molecular pathways for amyloid-β (Aβ) peptide aggregation from monomers into amyloid fibrils, a hallmark of Alzheimer's disease, is crucial for the development of diagnostic and therapeutic strategies. We investigate the molecular details of peptide fibrillization in vitro by perturbing this process through addition of differently charged metal ions. Here, we used a monovalent probe, the silver ion, that, similarly to divalent metal ions, binds to monomeric Aβ peptide and efficiently modulates Aβ fibrillization. On the basis of our findings, combined with our previous results on divalent zinc ions, we propose a model that links the microscopic metal-ion binding to Aβ monomers to its macroscopic impact on the peptide self-assembly observed in bulk experiments. We found that substoichiometric concentrations of the investigated metal ions bind specifically to the N-terminal region of Aβ, forming a dynamic, partially compact complex. The metal-ion bound state appears to be incapable of aggregation, effectively reducing the available monomeric Aβ pool for incorporation into fibrils. This is especially reflected in a decreased fibril-end elongation rate. However, because the bound state is significantly less stable than the amyloid state, Aβ peptides are only transiently redirected from fibril formation, and eventually almost all Aβ monomers are integrated into fibrils. Taken together, these findings unravel the mechanistic consequences of delaying Aβ aggregation via weak metal-ion binding, quantitatively linking the contributions of specific interactions of metal ions with monomeric Aβ to their effects on bulk aggregation.}, } @article {pmid32241302, year = {2020}, author = {Ahmadzadeh, M and Christie, GJ and Cosco, TD and Moreno, S}, title = {Neuroimaging and analytical methods for studying the pathways from mild cognitive impairment to Alzheimer's disease: protocol for a rapid systematic review.}, journal = {Systematic reviews}, volume = {9}, number = {1}, pages = {71}, pmid = {32241302}, issn = {2046-4053}, support = {-//SFU Community Trust Endowment Fund/ ; AW-SPC06-2019//AGE-WELL/ ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder commonly associated with deficits of cognition and changes in behavior. Mild cognitive impairment (MCI) is the prodromal stage of AD that is defined by slight cognitive decline. Not all with MCI progress to AD dementia. Thus, the accurate prediction of progression to Alzheimer's, particularly in the stage of MCI could potentially offer developing treatments to delay or prevent the transition process. The objective of the present study is to investigate the most recent neuroimaging procedures in the domain of prediction of transition from MCI to AD dementia for clinical applications and to systematically discuss the machine learning techniques used for the prediction of MCI conversion.

METHODS: Electronic databases including PubMed, SCOPUS, and Web of Science will be searched from January 1, 2017, to the date of search commencement to provide a rapid review of the most recent studies that have investigated the prediction of conversion from MCI to Alzheimer's using neuroimaging modalities in randomized trial or observational studies. Two reviewers will screen full texts of included papers using predefined eligibility criteria. Studies will be included if addressed research on AD dementia and MCI, explained the results in a way that would be able to report the performance measures such as the accuracy, sensitivity, and specificity. Only studies addressed Alzheimer's type of dementia and its early-stage MCI using neuroimaging modalities will be included. We will exclude other forms of dementia such as vascular dementia, frontotemporal dementia, and Parkinson's disease. The risk of bias in individual studies will be appraised using an appropriate tool. If feasible, we will conduct a random effects meta-analysis. Sensitivity analyses will be conducted to explore the potential sources of heterogeneity.

DISCUSSION: The information gathered in our study will establish the extent of the evidence underlying the prediction of conversion to AD dementia from its early stage and will provide a rigorous and updated synthesis of neuroimaging modalities allied with the data analysis techniques used to measure the brain changes during the conversion process.

PROSPERO,CRD42019133402.}, } @article {pmid32241222, year = {2020}, author = {Fray, S and Rassas, A and Messaoud, T and Belal, S}, title = {Refractory epilepsy in PSEN 1 mutation (I83T).}, journal = {Neurocase}, volume = {26}, number = {3}, pages = {167-170}, doi = {10.1080/13554794.2020.1747632}, pmid = {32241222}, issn = {1465-3656}, abstract = {Mutations in the presenilin-1 gene (PSEN1) on chromosome 14 are the most common cause of autosomal dominant Alzheimer's disease (ADAD), which has a broad clinical phenotype, encompassing not only dementia but a variety of other neurological features. We report the case of a 32 years old man with a family history of early onset AD associated with a PSEN1 mutation in the exon 4 (I83T). The proband's, carrying the mutation, present a refractory epilepsy predating cognitive decline. We discuss the physiopathological mechanisms of epilepsy during AD associated with PSEN 1 mutation, the possibility of linking this epilepsy to the mutation?.}, } @article {pmid32240665, year = {2020}, author = {Strüber, D and Herrmann, CS}, title = {Modulation of gamma oscillations as a possible therapeutic tool for neuropsychiatric diseases: A review and perspective.}, journal = {International journal of psychophysiology : official journal of the International Organization of Psychophysiology}, volume = {152}, number = {}, pages = {15-25}, doi = {10.1016/j.ijpsycho.2020.03.003}, pmid = {32240665}, issn = {1872-7697}, abstract = {Gamma oscillations (30-80 Hz) are well-known for their role in cortical signal transmission and cognitive brain functions. Aberrant gamma activity has been observed in various neuropsychiatric disorders, but the clinical potential of restoring gamma oscillations via noninvasive brain stimulation has been widely neglected. Only recently, therapeutic effects of gamma entrainment were documented in mouse models of Alzheimer's dementia (AD) using rhythmic sensory stimulation. In the present review, we first summarize the current status of the research on gamma entrainment in mouse models of AD and human AD patients. Then, we suggest transcranial alternating current stimulation (tACS) as an alternative brain stimulation technique and review the recent literature on the effects of gamma tACS in healthy volunteers and neuropsychiatric diseases to document the efficacy of gamma tACS in improving cognitive functions. We discuss several advantages of tACS compared to rhythmic sensory stimulation for the entrainment of gamma oscillations in the human brain and emphasize the need for more clinical studies applying tACS to drive gamma oscillations and, in turn, to improve cognitive functioning not only in AD but also in patients suffering from other neuropsychiatric disorders.}, } @article {pmid32238499, year = {2020}, author = {}, title = {Congressional Briefing: Diagnostic Imaging and Alzheimer Disease.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {61}, number = {4}, pages = {12N}, pmid = {32238499}, issn = {1535-5667}, } @article {pmid32238339, year = {2020}, author = {Lancaster, C and Koychev, I and Blane, J and Chinner, A and Wolters, L and Hinds, C}, title = {Evaluating the Feasibility of Frequent Cognitive Assessment Using the Mezurio Smartphone App: Observational and Interview Study in Adults With Elevated Dementia Risk.}, journal = {JMIR mHealth and uHealth}, volume = {8}, number = {4}, pages = {e16142}, pmid = {32238339}, issn = {2291-5222}, abstract = {BACKGROUND: By enabling frequent, sensitive, and economic remote assessment, smartphones will facilitate the detection of early cognitive decline at scale. Previous studies have sustained participant engagement with remote cognitive assessment over a week; extending this to a period of 1 month clearly provides a greater opportunity for measurement. However, as study durations are increased, the need to understand how participant burden and scientific value might be optimally balanced also increases.

OBJECTIVE: This study explored the little but often approach to assessment employed by the Mezurio app when prompting participants to interact every day for over a month. Specifically, this study aimed to understand whether this extended duration of remote study is feasible, and which factors promote sustained participant engagement over such periods.

METHODS: A total of 35 adults (aged 40-59 years) with no diagnosis of cognitive impairment were prompted to interact with the Mezurio smartphone app platform for up to 36 days, completing short, daily episodic memory tasks in addition to optional executive function and language tests. A subset (n=20) of participants completed semistructured interviews focused on their experience of using the app.

RESULTS: Participants complied with 80% of the daily learning tasks scheduled for subsequent tests of episodic memory, with 88% of participants still actively engaged by the final task. A thematic analysis of the participants' experiences highlighted schedule flexibility, a clear user interface, and performance feedback as important considerations for engagement with remote digital assessment.

CONCLUSIONS: Despite the extended study duration, participants demonstrated high compliance with the schedule of daily learning tasks and were extremely positive about their experiences. Long durations of remote digital interaction are therefore definitely feasible but only when careful attention is paid to the design of the users' experience.}, } @article {pmid32236402, year = {2020}, author = {Hooper, C and Coley, N and De Souto Barreto, P and Payoux, P and Salabert, AS and Andrieu, S and Weiner, M and Vellas, B}, title = {Cortical β-Amyloid in Older Adults Is Associated with Multidomain Interventions with and without Omega 3 Polyunsaturated Fatty Acid Supplementation.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {7}, number = {2}, pages = {128-134}, doi = {10.14283/jpad.2020.4}, pmid = {32236402}, issn = {2426-0266}, abstract = {Multidomain lifestyle interventions (including combinations of physical exercise, cognitive training and nutritional guidance) are attracting increasing research attention for reducing the risk of Alzheimer's disease (AD). Here we examined for the first time the cross-sectional relationship between cortical β-amyloid (Aβ) and multidomain lifestyle interventions (nutritional and exercise counselling and cognitive training), omega 3 polyunsaturated fatty acid (n-3 PUFA) supplementation or their combination in 269 participants of the Multidomain Alzheimer Preventive Trial (MAPT). In adjusted multiple linear regression models, compared to the control group (receiving placebo alone), cortical Aβ, measured once during follow-up (mean 512.7 ± 249.6 days post-baseline), was significantly lower in the groups receiving multidomain lifestyle intervention + placebo (mean difference, -0.088, 95 % CI, -0.148,-0.029, p = 0.004) or multidomain lifestyle intervention + n-3 PUFA (-0.100, 95 % CI, -0.160,-0.041, p = 0.001), but there was no difference in the n-3 PUFA supplementation alone group (-0.011, 95 % CI, -0.072,0.051, p = 0.729). Secondary analysis provided mixed results. Our findings suggest that multidomain interventions both with and without n-3 PUFA supplementation might be associated with lower cerebral Aβ. Future trials should investigate if such multidomain lifestyle interventions are causally associated with a reduction or the prevention of the accumulation of cerebral Aβ.}, } @article {pmid32236396, year = {2020}, author = {Lo, IL and Zeng, W and Lei, CI and Lam, C and Lou, HL}, title = {Knowledge, Attitude and Preventive Practice on Dementia Care among Primary Health Professionals in Macao.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {7}, number = {2}, pages = {83-86}, doi = {10.14283/jpad.2020.10}, pmid = {32236396}, issn = {2426-0266}, abstract = {The Macao Dementia Policy was recognized by Alzheimer Disease International as the 27th globally and one of the highest stage 5 to develop dementia friendly community and primary health professionals are in a pivotal position to enhance community-based dementia prevention and care quality. This study aimed to investigate the knowledge, attitude and preventive practice on dementia care among primary health professionals in Macao. A specially designed 30-item questionnaire was developed and validated for the study. The Content Validity Index (CVI) and Cronbach's α of the questionnaire were 0.973 and 0.808. The questionnaires were distributed to all 375 primary health professionals from 8 Health Centers throughout Macao and 234 valid questionnaires (62.4%) were returned. The score for dementia care knowledge was 87.02±14.01; attitude was 69.52±5.83; preventive practice was 77.88±13.18, of which doctors (79.89±13.77) was significantly higher (t=2.29, p=0.023) than nurses (75.91±12.33). There were positive relationships between preventive practice and attitude (r=0.163, p=0.014), and age (r=0.212, p=0.002), and a negative relationship between knowledge and age (r=-0.139, p=0.040). These findings have significant implications that most primary health professionals in Macao had sufficient knowledge, a positive attitude and appropriate preventive practice on dementia care. However, enhanced dementia education to improve knowledge and preventive practice was a strong agenda for the training for senior staff and nurses.}, } @article {pmid32236394, year = {2020}, author = {Takeda, C and Guyonnet, S and Sumi, Y and Vellas, B and Araujo de Carvalho, I}, title = {Integrated Care for Older People and the Implementation in the INSPIRE Care Cohort.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {7}, number = {2}, pages = {70-74}, doi = {10.14283/jpad.2020.8}, pmid = {32236394}, issn = {2426-0266}, abstract = {BACKGROUNDS: The World Health Organization has published the Integrated Care for Older People, ICOPE handbook Guidance on person-centred assessment and pathways in primary care. This is an integrated individual care tool focused on the individual and healthy ageing. The ICOPE tool proposes step by step, a screening, a fine assessment, the development of a personalized care plan, its implementation and follow up and finally the consideration of the caregivers and community. The new Geroscience field is focusing on preventing age-related diseases, and should now investigate with the ICOPE tool the optimal maintenance of intrinsic capacity (IC) through mobility, cognition, psychology, vitality, hearing and vision. This article aims to present this new tool and to presents its innovative implementation at the Toulouse University Hospital through the INSPIRE study. We believe that the ICOPE integrated care program will also be a pragmatic way to maintain cognitive functions and detect early Alzheimer.

OBJECTIVES: The main objective of the INSPIRE study is to build a Bio-resource Research Platform for Healthy Ageing gathering biological, clinical and digital resources in order to identify markers of ageing, age-related diseases and IC evolution. The study will be also testing the implementation and follow up of the ICOPE tool.

METHODS: The Inspire Platform will gather clinical data and bio-specimens from 1000 subjects in the Occitania Region, of different ages (from 30 years and over) over 10 years. Data will be collected annually. Using the ICOPE tool IC domains will be monitored every 4 months. Once IC decline is identified, participants will have a thorough clinical assessment and blood sampling to investigate the response of markers of ageing at the time of decline. The French ethic committee approved the study.

RESULTS: The Inspire platform aims to develop an integrative approach to promote novel new technologies for the assessment and monitoring of functional capacities.}, } @article {pmid32235929, year = {2020}, author = {Wood, H}, title = {Mitochondrial dysfunction manifests in the early stages of Alzheimer disease.}, journal = {Nature reviews. Neurology}, volume = {16}, number = {5}, pages = {242}, doi = {10.1038/s41582-020-0353-3}, pmid = {32235929}, issn = {1759-4766}, } @article {pmid32235904, year = {2020}, author = {Viggiano, D and Wagner, CA and Martino, G and Nedergaard, M and Zoccali, C and Unwin, R and Capasso, G}, title = {Mechanisms of cognitive dysfunction in CKD.}, journal = {Nature reviews. Nephrology}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41581-020-0266-9}, pmid = {32235904}, issn = {1759-507X}, abstract = {Cognitive impairment is an increasingly recognized major cause of chronic disability and is commonly found in patients with chronic kidney disease (CKD). Knowledge of the relationship between kidney dysfunction and impaired cognition may improve our understanding of other forms of cognitive dysfunction. Patients with CKD are at an increased risk (compared with the general population) of both dementia and its prodrome, mild cognitive impairment (MCI), which are characterized by deficits in executive functions, memory and attention. Brain imaging in patients with CKD has revealed damage to white matter in the prefrontal cortex and, in animal models, in the subcortical monoaminergic and cholinergic systems, accompanied by widespread macrovascular and microvascular damage. Unfortunately, current interventions that target cardiovascular risk factors (such as anti-hypertensive drugs, anti-platelet agents and statins) seem to have little or no effect on CKD-associated MCI, suggesting that the accumulation of uraemic neurotoxins may be more important than disturbed haemodynamic factors or lipid metabolism in MCI pathogenesis. Experimental models show that the brain monoaminergic system is susceptible to uraemic neurotoxins and that this system is responsible for the altered sleep pattern commonly observed in patients with CKD. Neural progenitor cells and the glymphatic system, which are important in Alzheimer disease pathogenesis, may also be involved in CKD-associated MCI. More detailed study of CKD-associated MCI is needed to fully understand its clinical relevance, underlying pathophysiology, possible means of early diagnosis and prevention, and whether there may be novel approaches and potential therapies with wider application to this and other forms of cognitive decline.}, } @article {pmid32235574, year = {2020}, author = {Obrenovich, M and Siddiqui, B and McCloskey, B and Reddy, VP}, title = {The Microbiota-Gut-Brain Axis Heart Shunt Part I: The French Paradox, Heart Disease and the Microbiota.}, journal = {Microorganisms}, volume = {8}, number = {4}, pages = {}, pmid = {32235574}, issn = {2076-2607}, abstract = {It has been well established that a vegetarian and polyphenol-rich diet, including fruits, vegetables, teas, juices, wine, indigestible fiber and whole grains, provide health-promoting phytochemicals and phytonutrients that are beneficial for the heart and brain. What is not well-characterized is the affect these foods have when co-metabolized within our dynamic gut and its colonizing flora. The concept of a heart shunt within the microbiota-gut-brain axis underscores the close association between brain and heart health and the so-called "French paradox" offers clues for understanding neurodegenerative and cerebrovascular diseases. Moreover, oxidation-redox reactions and redox properties of so-called brain and heart-protective foods are underappreciated as to their enhanced or deleterious mechanisms of action. Focusing on prodromal stages, and common mechanisms underlying heart, cerebrovascular and neurodegenerative diseases, we may unmask and understanding the means to better treat these related diseases.}, } @article {pmid32233096, year = {2020}, author = {Lee, JC and Kim, HY and Lee, S and Shin, J and Kim, HV and Kim, K and Baek, S and Lee, D and Jeon, H and Kim, D and Yang, SH and Han, G and Park, K and Choi, J and Park, J and Moss, JA and Janda, KD and Kim, Y}, title = {Discovery of Chemicals to Either Clear or Indicate Amyloid Aggregates by Targeting Memory-Impairing Anti-Parallel Aβ Dimers.}, journal = {Angewandte Chemie (International ed. in English)}, volume = {}, number = {}, pages = {}, doi = {10.1002/anie.202002574}, pmid = {32233096}, issn = {1521-3773}, support = {HI18C0836//Korea Health Industry Development Institute/Republic of Korea ; NRF-2018R1A6A1A03023718//National Research Foundation of Korea/ ; NRF-2018R1D1A1B07048857//National Research Foundation of Korea/ ; NRF-2018M3C7A1021858//National Research Foundation of Korea/ ; 2018-22-0022//New Faculty Research Grant of Yonsei University/ ; 2Z05620//Korea Institute of Science and Technology/ ; 2E29562//Korea Institute of Science and Technology/ ; //POSCO Science Fellowship/ ; }, abstract = {Amyloid-β (Aβ) oligomers are implicated in Alzheimer disease (AD). However, their unstable nature and heterogeneous state disrupts elucidation of their explicit role in AD progression, impeding the development of tools targeting soluble Aβ oligomers. Herein parallel and anti-parallel variants of Aβ(1-40) dimers were designed and synthesized, and their pathogenic properties in AD models characterized. Anti-parallel dimers induced cognitive impairments with increased amyloidogenesis and cytotoxicity, and this dimer was then used in a screening platform. Through screening, two FDA-approved drugs, Oxytetracycline and Sunitinib, were identified to dissociate Aβ oligomers and plaques to monomers in 5XFAD transgenic mice. In addition, fluorescent Astrophloxine was shown to detect aggregated Aβ in brain tissue and cerebrospinal fluid samples of AD mice. This screening platform provides a stable and homogeneous environment for observing Aβ interactions with dimer-specific molecules.}, } @article {pmid32232904, year = {2020}, author = {Waller, R and Mandeya, M and Viney, E and Simpson, JE and Wharton, SB}, title = {Histological characterization of interneurons in Alzheimer's disease reveals a loss of somatostatin interneurons in the temporal cortex.}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {}, number = {}, pages = {}, doi = {10.1111/neup.12649}, pmid = {32232904}, issn = {1440-1789}, abstract = {Neuronal dysfunction and synaptic loss are major hallmarks of Alzheimer's disease (AD) which correlate with symptom severity. Impairment of the γ-aminobutyric acid (GABA)ergic inhibitory interneurons, which form around 20% of the total neuronal network, may be an early event contributing to neuronal circuit dysfunction in neurodegenerative diseases. This study examined the expression of two of the main classes of inhibitory interneurons, parvalbumin (PV) and somatostatin (SST) interneurons in the temporal cortex and hippocampus of AD and control cases, using immunohistochemistry. We report a significant regional variation in the number of PV and SST interneurons with a higher number identified per mm2 in the temporal cortex compared to the hippocampus. Fewer SST interneurons, but not PV interneurons, were identified per mm2 in the temporal cortex of AD cases compared to control subjects. Our results support regional neuroanatomical effects on selective interneuron classes in AD, and suggest that impairment of the interneuronal circuit may contribute to neuronal dysfunction and cognitive decline in AD.}, } @article {pmid32232888, year = {2020}, author = {Koga, S and Li, F and Zhao, N and Roemer, SF and Ferman, TJ and Wernick, AI and Walton, RL and Faroqi, AH and Graff-Radford, NR and Cheshire, WP and Ross, OA and Dickson, DW}, title = {Clinicopathologic and genetic features of multiple system atrophy with Lewy body disease.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {}, number = {}, pages = {}, doi = {10.1111/bpa.12839}, pmid = {32232888}, issn = {1750-3639}, support = {U54 NS110435/NS/NINDS NIH HHS/United States ; //Jaye F. and Betty F. Dyer Foundation/ ; //Karin & Sten Mortstedt CBD Solutions/ ; }, abstract = {BACKGROUND: Abnormal aggregates of α-synuclein are pathologic hallmarks of multiple system atrophy (MSA) and Lewy body disease (LBD). LBD sometimes coexists with MSA, but the impact of co-pathology, particularly diffuse LBD, on presentation of MSA has not been studied. We aimed to determine the frequency and clinicopathologic features of MSA with LBD (MSA+LBD).

METHODS: Using hematoxylin & eosin and α-synuclein-immunostained slides, we assessed the distribution and severity of LBD in 230 autopsy-confirmed MSA patients collected from 1998 to 2018. Alzheimer-type pathology was assessed to assign the likelihood of clinical presentations of dementia with Lewy body (DLB) using the consensus criteria for DLB. We reviewed medical records to characterize clinicopathologic features of MSA+LBD. Genetic risk factors for LBD, including APOE ε4 allele and mutations in GBA, SNCA, LRRK2, and VPS35, were analyzed.

RESULTS: LBD was observed in 11 MSA patients (5%); seven were brainstem type, three were transitional type, and one was diffuse type. The latter four had an intermediate or high likelihood of DLB. Three of the four had an antemortem diagnosis of Parkinson's disease with dementia (PDD) or clinically probable DLB. Two patients had neuronal loss in the substantia nigra, but not in striatal or olivocerebellar systems with widespread glial cytoplasmic inclusions, consistent with minimal change MSA. In these cases, LBD was considered the primary pathology, and MSA was considered coincidental. APOE ε4 allele frequency was not different between MSA+LBD and MSA without LBD. Two of nine MSA+LBD patients had a risk variant of GBA (p.T408M and p.E365K).

CONCLUSIONS: Although rare, MSA with transitional or diffuse LBD can develop clinical features of PDD or DLB. Minimal change MSA can be interpreted as a coincidental, but distinct, α-synucleinopathy in a subset of patients with diffuse LBD.}, } @article {pmid32232475, year = {2020}, author = {Lorente-Gea, L and García, B and Martín, C and Ordiales, H and García-Suárez, O and Piña-Batista, KM and Merayo-Lloves, J and Quirós, LM and Fernández-Vega, I}, title = {Heparan Sulfate Proteoglycans Undergo Differential Expression Alterations in Alzheimer Disease Brains.}, journal = {Journal of neuropathology and experimental neurology}, volume = {79}, number = {5}, pages = {474-483}, doi = {10.1093/jnen/nlaa016}, pmid = {32232475}, issn = {1554-6578}, abstract = {Previous studies have reported that heparan sulfate proteoglycans (HSPGs) promote amyloid-beta peptide and tau fibrillization in Alzheimer disease (AD) and provide resistance against proteolytic breakdown. We compared the expression levels of 17 HSPG core proteins in 18 AD cases and 6 controls. RT-PCR was used to analyze transcription levels. Immunohistochemistry was performed to localize HSPGs in the brain tissue. We detected expression of all HSPG genes investigated. SDC1, GPC3, and CD44v3 showed the lowest levels of expression, while SDC3 and GPC1 showed the highest. Remarkably, SDC4 and SRGN were overexpressed in most of the areas analyzed. Immunohistochemistry revealed the presence of both SDC4 and SRGN mostly associated with tau and amyloid-β pathology throughout the AD brains. In conclusion, in view of the involvement of HSPGs in AD pathology, especially SDC4 and SRGN, there would seem to be a relationship between the regulation of core protein expression and the pathological features suggesting HSPGs are potential inducers of the disease.}, } @article {pmid32229636, year = {2020}, author = {Breitner, J and Meyer, PF}, title = {Author response: INTREPAD: A randomized trial of naproxen to slow progress of presymptomatic Alzheimer disease.}, journal = {Neurology}, volume = {94}, number = {13}, pages = {594}, doi = {10.1212/WNL.0000000000009185}, pmid = {32229636}, issn = {1526-632X}, } @article {pmid32229635, year = {2020}, author = {Ashford, JW}, title = {Reader response: INTREPAD: A randomized trial of naproxen to slow progress of presymptomatic Alzheimer disease.}, journal = {Neurology}, volume = {94}, number = {13}, pages = {593-594}, doi = {10.1212/WNL.0000000000009184}, pmid = {32229635}, issn = {1526-632X}, } @article {pmid32229634, year = {2020}, author = {Ganesh, A and Galetta, S}, title = {Editors' note: INTREPAD: A randomized trial of naproxen to slow progress of presymptomatic Alzheimer disease.}, journal = {Neurology}, volume = {94}, number = {13}, pages = {593}, doi = {10.1212/WNL.0000000000009182}, pmid = {32229634}, issn = {1526-632X}, } @article {pmid32229582, year = {2020}, author = {Singh, V and Xu, L and Boyko, S and Surewicz, K and Surewicz, WK}, title = {Zinc promotes liquid-liquid phase separation of tau protein.}, journal = {The Journal of biological chemistry}, volume = {295}, number = {18}, pages = {5850-5856}, pmid = {32229582}, issn = {1083-351X}, abstract = {Tau is a microtubule-associated protein that plays a major role in Alzheimer's disease (AD) and other tauopathies. Recent reports indicate that, in the presence of crowding agents, tau can undergo liquid-liquid phase separation (LLPS), forming highly dynamic liquid droplets. Here, using recombinantly expressed proteins, turbidimetry, fluorescence microscopy imaging, and fluorescence recovery after photobleaching (FRAP) assays, we show that the divalent transition metal zinc strongly promotes this process, shifting the equilibrium phase boundary to lower protein or crowding agent concentrations. We observed no tau LLPS-promoting effect for any other divalent transition metal ions tested, including Mn2+, Fe2+, Co2+, Ni2+, and Cu2+ We also demonstrate that multiple zinc-binding sites on tau are involved in the LLPS-promoting effect and provide insights into the mechanism of this process. Zinc concentration is highly elevated in AD brains, and this metal ion is believed to be an important player in the pathogenesis of this disease. Thus, the present findings bring a new dimension to understanding the relationship between zinc homeostasis and the pathogenic process in AD and related neurodegenerative disorders.}, } @article {pmid32228870, year = {2020}, author = {Pichet Binette, A and Vachon-Presseau, É and Morris, J and Bateman, R and Benzinger, T and Collins, DL and Poirier, J and Breitner, JCS and Villeneuve, S and , and , }, title = {Amyloid and Tau Pathology Associations With Personality Traits, Neuropsychiatric Symptoms, and Cognitive Lifestyle in the Preclinical Phases of Sporadic and Autosomal Dominant Alzheimer's Disease.}, journal = {Biological psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.biopsych.2020.01.023}, pmid = {32228870}, issn = {1873-2402}, support = {U19 AG032438/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: Major prevention trials for Alzheimer's disease (AD) are now focusing on multidomain lifestyle interventions. However, the exact combination of behavioral factors related to AD pathology remains unclear. In 2 cohorts of cognitively unimpaired individuals at risk of AD, we examined which combinations of personality traits, neuropsychiatric symptoms, and cognitive lifestyle (years of education or lifetime cognitive activity) related to the pathological hallmarks of AD, amyloid-β, and tau deposits.

METHODS: A total of 115 older adults with a parental or multiple-sibling family history of sporadic AD (PREVENT-AD [PRe-symptomatic EValuation of Experimental or Novel Treatments for AD] cohort) underwent amyloid and tau positron emission tomography and answered several questionnaires related to behavioral attributes. Separately, we studied 117 mutation carriers from the DIAN (Dominant Inherited Alzheimer Network) study group cohort with amyloid positron emission tomography and behavioral data. Using partial least squares analysis, we identified latent variables relating amyloid or tau pathology with combinations of personality traits, neuropsychiatric symptoms, and cognitive lifestyle.

RESULTS: In PREVENT-AD, lower neuroticism, neuropsychiatric burden, and higher education were associated with less amyloid deposition (p = .014). Lower neuroticism and neuropsychiatric features, along with higher measures of openness and extraversion, were related to less tau deposition (p = .006). In DIAN, lower neuropsychiatric burden and higher education were also associated with less amyloid (p = .005). The combination of these factors accounted for up to 14% of AD pathology.

CONCLUSIONS: In the preclinical phase of both sporadic and autosomal dominant AD, multiple behavioral features were associated with AD pathology. These results may suggest potential pathways by which multidomain interventions might help delay AD onset or progression.}, } @article {pmid32228468, year = {2020}, author = {Dyer, AH and Lawlor, B and Kennelly, SP and , }, title = {Gait speed, cognition and falls in people living with mild-to-moderate Alzheimer disease: data from NILVAD.}, journal = {BMC geriatrics}, volume = {20}, number = {1}, pages = {117}, pmid = {32228468}, issn = {1471-2318}, support = {279093//FP7 Health ()/ ; }, abstract = {BACKGROUND: Previous evidence suggests that slower gait speed is longitudinally associated with cognitive impairment, dementia and falls in older adults. Despite this, the longitudinal relationship between gait speed, cognition and falls in those with a diagnosis of dementia remains poorly explored. We sought to assess this longitudinal relationship in a cohort of older adults with mild to-moderate Alzheimer Disease (AD).

METHODS: Analysis of data from NILVAD, an 18-month randomised-controlled trial of Nilvadipine in mild to moderate AD. We examined: (i) the cross-sectional (baseline) association between slow gait speed and cognitive function, (ii) the relationship between baseline slow gait speed and cognitive function at 18 months (Alzheimer Disease Assessment Scale, Cognitive Subsection: ADAS-Cog), (iii) the relationship between baseline cognitive function and incident slow gait speed at 18 months and finally (iv) the relationship of baseline slow gait speed and incident falls over the study period.

RESULTS: Overall, one-tenth (10.03%, N = 37/369) of participants with mild-to-moderate AD met criteria for slow gait speed at baseline and a further 14.09% (N = 52/369) developed incident slow gait speed at 18 months. At baseline, there was a significant association between poorer cognition and slow gait speed (OR 1.05, 95% CI 1.01-1.09, p = 0.025). Whilst there was no association between baseline slow gait speed and change in ADAS-Cog score at 18 months, a greater cognitive severity at baseline predicted incident slow gait speed over 18 months (OR 1.04, 1.01-1.08, p = 0.011). Further, slow gait speed at baseline was associated with a significant risk of incident falls over the study period, which persisted after covariate adjustment (IRR 3.48, 2.05-5.92, p < 0.001).

CONCLUSIONS: Poorer baseline cognition was associated with both baseline and incident slow gait speed. Slow gait speed was associated with a significantly increased risk of falls over the study period. Our study adds further evidence to the complex relationship between gait and cognition in this vulnerable group and highlights increased falls risk in older adults with AD and slow gait speed.

TRIAL REGISTRATION: Secondary analysis of the NILVAD trial (Clincaltrials.gov NCT02017340; EudraCT number 2012-002764-27). First registered: 20/12/2013.}, } @article {pmid32228421, year = {2020}, author = {Arora, D and Bhatt, S and Kumar, M and Gali, CC and Vattikonda, HDC and Taneja, Y and Jain, V and Joshi, V}, title = {Intranasal Lipid Particulate Drug Delivery Systems: An Update on Clinical Challenges and Biodistribution Studies of Cerebroactive Drugs in Alzheimer's disease.}, journal = {Current pharmaceutical design}, volume = {}, number = {}, pages = {}, doi = {10.2174/1381612826666200331085854}, pmid = {32228421}, issn = {1873-4286}, abstract = {BACKGROUND: Alzheimer is the primary cause of death in the various countries that affects wide strata of the population. The treatment of it is restricted to a few conventional oral medications that act only superficially. It is evident that the delivery of a drug to the brain across the blood-brain barrier is challenging as the BBB is armed with several efflux transporters like the P-glycoprotein as well as nasal mucociliary clearance adds up leading to decreased concentration and reduced therapeutic efficacy. Considering these, the intranasal IN route of drug administration is emerging as an alternative route for systemic delivery of a drug to the brain. The intranasal (IN) administration of lipid nanoparticles loaded with cerebroactive drugs showed promise in treating various neurodegenerative diseases, since the nasal route allows the direct nose to brain delivery by means of solid lipid nanoparticles (SLN's). The tailoring of intranasal lipid particulate drug delivery systems is a pleasing approach to facilitate uptake of therapeutic agents at the desired site of action, particularly when a free drug has poor pharmacokinetics/ biodistribution (PK/BD) or significant off-site toxicities.

OBJECTIVES: 1) In this review, key challenges and physiological mechanisms regulating intranasal brain delivery in Alzheimer's disease, ex-vivo studies, pharmacokinetics parameters including brain uptake and histopathological studies are thoroughly discussed. 2) A thorough understanding of the in vivo behaviour of the intranasal drug carriers will be the elusive goal. 3) The article emphasizes to drag the attention of the research community working in the intranasal field towards the challenges and hurdles of the practical applicability of intranasal delivery of cerebroactive drugs.

METHOD: Various electronic databases, journals like nanotechnology and nanoscience, dove press are reviewed for the collection and compilation of data.

RESULTS: From In-vivo biodistribution studies, pharmacokinetics parameters and gamma scintigraphy images of various drugs it is speculated that intranasal lipid particulates drug delivery system shows better brain targeting efficiency for various CNS disorders in comparison to other routes.

CONCLUSION: Various routes are explored for the delivery of drugs to increase bioavailability in the brain for CNS disorders but intranasal route shows better results that pave way for success in future if properly explored.}, } @article {pmid32228330, year = {2020}, author = {Cruz-Aguilar, MA and Ramírez-Salado, I and Hernández-González, M and Guevara, MA and Del Río, JM}, title = {Melatonin effects on EEG activity during non-rapid eye movement sleep in mild-to-moderate Alzheimer´s disease: a pilot study.}, journal = {The International journal of neuroscience}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/00207454.2020.1750392}, pmid = {32228330}, issn = {1563-5279}, abstract = {Introduction: There is evidence to suggest that melatonin diminishes non-rapid eye movement sleep (NREMS) latency in patients with Alzheimer´s disease (AD). However, melatonin's effects on cortical activity during NREMS in AD have not been studied. The objective of this research was to analyze the effects of melatonin on cortical activity during the stages of NREMS in 8 mild-to-moderate AD patients that received 5-mg of fast-release melatonin.Methods: During a single-blind, placebo-controlled crossover study, polysomnographic recordings were obtained from C3-A1, C4-A2, F7-T3, F8-T4, F3-F4 and O1-O2. Also, the relative power (RP) and EEG coherences of the delta, theta, alpha1, alpha2, beta1, beta2 and gamma bands were calculated during NREMS-1, NREMS-2 and NREMS-3. These sleep latencies and all EEG data were then compared between the placebo and melatonin conditions.Results: During NREMS-2, a significant RP increase was observed in the theta band of the left-central hemisphere. During NREMS-3, significant RP decreases in the beta bands were recorded in the right-central hemisphere, compared to the placebo group. After melatonin administration, significant decreases of EEG coherences in the beta2, beta1 and gamma bands were observed in the right hemisphere during NREMS-3.Discussion: We conclude that short NREMS onset related to melatonin intake in AD patients is associated with a significant RP increase in the theta band and a decrease in RP and EEG coherences in the beta and gamma bands during NREMS-3. These results suggest that the GABAergic pathways are preserved in mild-to-moderate AD.}, } @article {pmid32227181, year = {2020}, author = {Park, S and White, L and Fishman, P and Larson, EB and Coe, NB}, title = {Health Care Utilization, Care Satisfaction, and Health Status for Medicare Advantage and Traditional Medicare Beneficiaries With and Without Alzheimer Disease and Related Dementias.}, journal = {JAMA network open}, volume = {3}, number = {3}, pages = {e201809}, doi = {10.1001/jamanetworkopen.2020.1809}, pmid = {32227181}, issn = {2574-3805}, abstract = {Importance: Compared with traditional Medicare (TM) fee-for-service plans, Medicare Advantage (MA) plans may provide more-efficient care for beneficiaries with Alzheimer disease and related dementias (ADRD) without compromising care quality.

Objective: To determine differences in health care utilization, care satisfaction, and health status for MA and TM beneficiaries with and without ADRD.

A cohort study was conducted of MA and TM beneficiaries with and without ADRD from all publicly available years of the Medicare Current Beneficiary Survey between 2010 and 2016. To address advantageous selection into MA plans, county-level MA enrollment rate was used as an instrument. Data were analyzed between July 2019 and December 2019.

Exposures: Enrollment in MA.

Main Outcomes and Measures: Self-reported health care utilization, care satisfaction, and health status.

Results: The sample included 47 100 Medicare beneficiaries (25 900 women [54.9%]; mean [SD] age, 72.2 [11.4] years). Compared with TM beneficiaries with ADRD, MA beneficiaries with ADRD had lower utilization across the board, including a mean of -22.3 medical practitioner visits (95% CI, -24.9 to -19.8 medical practitioner visits), -2.3 outpatient hospital visits (95% CI, -3.6 to -1.1 outpatient hospital visits), -0.2 inpatient hospital admissions (95% CI, -0.3 to -0.1 inpatient hospital admissions), and -0.1 long-term care facility stays (95% CI, -0.2 to -0.1 long-term care facility stays). A similar trend was observed among beneficiaries without ADRD, but the difference was greater between MA and TM beneficiaries with ADRD than between MA and TM beneficiaries without ADRD (mean, -15.0 medical practitioner visits [95% CI, -18.7 to -11.3 medical practitioner visits], -1.7 outpatient hospital visits [95% CI, -3.0 to -0.3 outpatient hospital visits], and -0.1 inpatient hospital admissions [95% CI, -1.0 to 0.0 inpatient hospital admissions]). Overall, no or negligible differences were detected in care satisfaction and health status between MA and TM beneficiaries with and without ADRD.

Conclusions and Relevance: Compared with TM beneficiaries, MA beneficiaries had lower health care utilization without compromising care satisfaction and health status. This difference was more pronounced among beneficiaries with ADRD. These findings suggest that MA plans may be delivering health care more efficiently than TM, especially for beneficiaries with ADRD.}, } @article {pmid32227176, year = {2020}, author = {Dosa, DM and Trivedi, AN and Mor, V}, title = {Implications of Medicare Advantage for Patients With Alzheimer Disease and Related Dementias.}, journal = {JAMA network open}, volume = {3}, number = {3}, pages = {e201853}, pmid = {32227176}, issn = {2574-3805}, support = {R01 AG060581/AG/NIA NIH HHS/United States ; }, } @article {pmid32223973, year = {2020}, author = {Gündüztepe, Y and Bukan, N and Zorlu, E and Karaman, Y and Andaç Topkan, T and Gurbuz, N and Neşelioğlu, S and Erel, Ö}, title = {The evaluation of thiol-disulfıte balance, ischemıa albumın modıfıcation and seruloplazmine as a new oxidatıve stress in mild cognitive impairment and early stage alzheimer's disease patients.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {75}, number = {}, pages = {188-194}, doi = {10.1016/j.jocn.2019.12.026}, pmid = {32223973}, issn = {1532-2653}, abstract = {BACKGROUND: Alzheimer's Disease (AD) is the most common form of dementia seen in advanced age. It is characterized by progressive deterioration in cognitive functions. The prevalence of Alzheimer's disease increasing day by day due to the increase in the share of the elderly population in the general population due to developing health and living conditions, is limited and early diagnosis and effective treatment possibilities are very limited. From this point of view, a specific biomarker for AD is very important. As a new oxidative stress biomarker, the levels of thiol-disulfide balance, ischemia-modified albumin and seroloplazminin were evaluated. The aim of this study was to determine the serum levels of oxidative stress biomarkers in the early stages of the disease and to compare these oxidative stress markers with patients with mild cognitive impairment as a precursor form of Alzheimer's disease and to determine whether these markers develop at an earlier stage.

METHODS: 30 volunteers with early stage AD according to NINCDS-ARDRA criteria, 19 volunteers with Midl Cognitive İmpairment according to PCA criteria and 30 volunteers with defined criteria were selected from the subjects aged between 55 and 88 who applied to Gazi University Health Research. Statistical analysis of the data showed that there was a significant difference between the endgroups and biomarkers for the early diagnosis of Alzheimer's disease, but this complicated matter has to be investigated in more comprehensive and detailed studie.

RESULTS: In the present study, we investigated oxidative stress parameters, thiol-disulphide balance, ischemia modified abumin and seruloplasmin in parallel with the impairment in cognitive dysfunction from control group to Mild Cognitive Impairment (MCD) and AD group by using a newly-developed method.

CONCLUSIONS: This is the first study in literature comparing Early Stages Alzheimer Disease (ESAD), MCD and healthy volunteer groups. Our study has revealed that these newly developed tests may be candidates as oxidative stress biomarkers in pathgenesis of AD. However it was concluded that more comprehensive and detailed studies are required to enlighten this issue.}, } @article {pmid32223758, year = {2020}, author = {Yamasaki, M and Makino, T and Khor, SS and Toyoda, H and Miyagawa, T and Liu, X and Kuwabara, H and Kano, Y and Shimada, T and Sugiyama, T and Nishida, H and Sugaya, N and Tochigi, M and Otowa, T and Okazaki, Y and Kaiya, H and Kawamura, Y and Miyashita, A and Kuwano, R and Kasai, K and Tanii, H and Sasaki, T and Honda, M and Tokunaga, K}, title = {Sensitivity to gene dosage and gene expression affects genes with copy number variants observed among neuropsychiatric diseases.}, journal = {BMC medical genomics}, volume = {13}, number = {1}, pages = {55}, pmid = {32223758}, issn = {1755-8794}, support = {AMED-17km0405205h0002//Japan Agency for Medical Research and Development/ ; }, abstract = {BACKGROUND: Copy number variants (CNVs) have been reported to be associated with diseases, traits, and evolution. However, it is hard to determine which gene should have priority as a target for further functional experiments if a CNV is rare or a singleton. In this study, we attempted to overcome this issue by using two approaches: by assessing the influences of gene dosage sensitivity and gene expression sensitivity. Dosage sensitive genes derived from two-round whole-genome duplication in previous studies. In addition, we proposed a cross-sectional omics approach that utilizes open data from GTEx to assess the effect of whole-genome CNVs on gene expression.

METHODS: Affymetrix Genome-Wide SNP Array 6.0 was used to detect CNVs by PennCNV and CNV Workshop. After quality controls for population stratification, family relationship and CNV detection, 287 patients with narcolepsy, 133 patients with essential hypersomnia, 380 patients with panic disorders, 164 patients with autism, 784 patients with Alzheimer disease and 1280 healthy individuals remained for the enrichment analysis.

RESULTS: Overall, significant enrichment of dosage sensitive genes was found across patients with narcolepsy, panic disorders and autism. Particularly, significant enrichment of dosage-sensitive genes in duplications was observed across all diseases except for Alzheimer disease. For deletions, less or no enrichment of dosage-sensitive genes with deletions was seen in the patients when compared to the healthy individuals. Interestingly, significant enrichments of genes with expression sensitivity in brain were observed in patients with panic disorder and autism. While duplications presented a higher burden, deletions did not cause significant differences when compared to the healthy individuals. When we assess the effect of sensitivity to genome dosage and gene expression at the same time, the highest ratio of enrichment was observed in the group including dosage-sensitive genes and genes with expression sensitivity only in brain. In addition, shared CNV regions among the five neuropsychiatric diseases were also investigated.

CONCLUSIONS: This study contributed the evidence that dosage-sensitive genes are associated with CNVs among neuropsychiatric diseases. In addition, we utilized open data from GTEx to assess the effect of whole-genome CNVs on gene expression. We also investigated shared CNV region among neuropsychiatric diseases.}, } @article {pmid32223501, year = {2020}, author = {Nogueira, MML and Neto, JPS and Dourado, MCN}, title = {Quality of Life of People With Alzheimer Disease: Comparison Between Dyads Degree of Kinship.}, journal = {Journal of geriatric psychiatry and neurology}, volume = {}, number = {}, pages = {891988720915521}, doi = {10.1177/0891988720915521}, pmid = {32223501}, issn = {0891-9887}, abstract = {The quality of life (QoL) of people with Alzheimer disease (PwAD) may be influenced by the type of relationship between carer and the PwAD. Dyads of 98 PwAD/carers (N = 49 spouse-carers; N = 49 nonspouses carers) were measured about QoL, cognition, dementia severity, awareness of disease, functionality, depression, anxiety, and burden of care. Univariate and multivariate regression analyses were conducted to identify the factors that influenced the spouse and nonspouse self-report PwAD QoL (PQOL) and to compare carers' ratings of PwAD QoL (C-PQOL). The total score of QoL for spouse and nonspouse PwAD showed no significant difference (P = .29). The linear regression demonstrated that higher awareness of disease was significantly related to spouse PQOL (P = .001). Nonspouse PQOL was negatively related to lower depression (P = .007). The total score of QoL for spouse and nonspouse C-PQOL showed no significant difference (P = .14). The linear regression demonstrated that depression of spouse-PwAD (P < .001) and burden of care (P = .001) were negatively related to spouse-dyads' C-PQOL. The nonspouse-dyads C-PQOL was negatively related to depression of nonspouse-PwAD (P < .001), awareness of disease (P = .001), and the mood of the carer (P = .01). Spouse and nonspouse PwAD evaluate PQOL better than carers (C-PQOL). No significant difference was found in the total PQOL and C-PQOL of spouse and nonspouse, but dyads evaluated differently about what is important to assess QoL.}, } @article {pmid32223428, year = {2020}, author = {Evans, N and Boyd, H and Harris, N and Noonan, K and Ingram, T and Jarvis, A and Ridgers, J and Cheston, R}, title = {The experience of using prompting technology from the perspective of people with Dementia and their primary carers.}, journal = {Aging & mental health}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/13607863.2020.1745145}, pmid = {32223428}, issn = {1364-6915}, abstract = {Objectives: People who are living with dementia typically experience difficulties in completing multi-step, everyday tasks. However, digital technology such as touchscreen tablets provide a means of delivering concise personalised prompts that combine audio, text and pictures. This study was one component of a broader, mixed methods study that tested how an application (app) -based prompter running on a touchscreen tablet computer could support everyday activities in individuals with mild to moderate dementia. In this study we set out to understand the experiences of people living with dementia and their primary carer in using the prompter over a four-week period.Method: We collected qualitative data using semi-structured interviews from 26 dyads, composed of a person living with dementia and their carer. Dyads were interviewed at the start and end of this period. Transcripts were then analysed using thematic analysis.Results: The study identified three overarching themes related to: participants' attitudes towards the technology; their judgements about how useful the prompter would be; and the emotional impact of using it.Conclusion: Consistent with the Technology Acceptance Model, carers and participants were influenced by their approaches to technology and determined the usefulness of the prompter according to whether it worked for them and fitted into their routines. In addition, participants' decisions about using the prompter were also determined by the extent to which doing so would impact on their self-identity.}, } @article {pmid32222542, year = {2020}, author = {Quan, H and Koltai, E and Suzuki, K and Aguiar, AS and Pinho, R and Boldogh, I and Berkes, I and Radak, Z}, title = {Exercise, redox system and neurodegenerative diseases.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {1866}, number = {10}, pages = {165778}, doi = {10.1016/j.bbadis.2020.165778}, pmid = {32222542}, issn = {1879-260X}, abstract = {Regular exercise induces a wide range of redox system-associated molecular adaptive responses to the nervous system. The intermittent induction of reactive oxygen species (ROS) during acute exercise sessions and the related upregulation of antioxidant/repair and housekeeping systems are associated with improved physiological function. Exercise-induced proliferation and differentiation of neuronal stem cells are ROS dependent processes. The increased production of brain derived neurotrophic factor (BDNF) and the regulation by regular exercise are dependent upon redox sensitive pathways. ROS are causative and associative factors of neurodegenerative diseases and regular exercise provides significant neuroprotective effects against Alzheimer's disease, Parkinson's disease, and hypoxia/reperfusion related disorders. Regular exercise regulates redox homeostasis in the brain with complex multi-level molecular pathways.}, } @article {pmid32222300, year = {2020}, author = {Soldan, A and Pettigrew, C and Albert, M}, title = {Cognitive Reserve from the Perspective of Preclinical Alzheimer Disease: 2020 Update.}, journal = {Clinics in geriatric medicine}, volume = {36}, number = {2}, pages = {247-263}, doi = {10.1016/j.cger.2019.11.006}, pmid = {32222300}, issn = {1879-8853}, abstract = {The concept of cognitive reserve (CR) was proposed to account for the discrepancy between levels of brain pathologic process or damage and clinical and cognitive function. We provide a detailed review of prospective longitudinal studies that have investigated the interaction between CR and Alzheimer disease (AD) biomarkers on clinical and cognitive outcomes among individuals with normal cognition at baseline. Current evidence is consistent with the view that higher levels of CR are associated with a delay in the onset of symptoms of mild cognitive impairment and that there may be multiple pathways by which CR exerts its protective effects.}, } @article {pmid32221721, year = {2020}, author = {Battistella, V and Camara, VD and Nogueira, CB and Porto, FHG and Jamaci, L and Guillermo, CV and Osvaldo, JMN and Souza, JA}, title = {Transcranial Doppler could help to differentiate the types of dementia? A pilot study when CSF biomarkers are not available.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {127}, number = {6}, pages = {899-904}, doi = {10.1007/s00702-020-02178-y}, pmid = {32221721}, issn = {1435-1463}, abstract = {Our objective was to find a mean flow velocity (MFV) cut-off point to differentiate between normal and cognitive impaired patients using Clinical Dementia Rating (CDR) as a comparison method. To evaluate MFV (in cm/s) and pulsatility index (PI) from the left middle cerebral artery (MCA) and basilar artery using transcranial Doppler in a pilot study from an outpatient cognition unit and compare with cognitively normal older adults (at the age of sixty or older) from the Geriatric Ambulatory of Fluminense Federal University. We hypothesized that there is a MFV and PI cut-off point to potentially distinguish between normal and impaired cognition. Sixty-one patients with cognitive decline, including 18 with amnestic mild cognitive impairment (aMCI), 31 with probable Alzheimer disease (AD), 12 with vascular dementia (VD), and 10 cognitively normal older adults were included in the study. Patients with dementia (both AD and VD, p < 0.01) and aMCI (p < 0.05) had lower MFV than the control group in the MCA (32.2 cm/s, 31.9 cm/s, and 36.6 cm/s, respectively) and dementia patients had higher PI compared to control (AD and VD, both p < 0.05). Basilar MFV showed to be no difference between the patients and the control group. A cut off value of 39.1 cm/s was found in a ROC curve (area under de curve value 0.85, 95% CI 0.75-0.95) for mean MCA MFV to be predictive of cognitive impairment (CDR ≥ 0.5). In this study, the values of MCA MFV below 39.1 cm/s were predictive of cognitive impairment according to CDR. TCD is an inexpensive method that could be used in a clinical scenario to help differentiate normal cognition from cognitive decline. Multicentric and longitudinal studies should be done to validate that.}, } @article {pmid32219988, year = {2020}, author = {Mortazavizadeh, Z and Maercker, A and Roth, T and Savaskan, E and Forstmeier, S}, title = {Quality of the caregiving relationship and quality of life in mild Alzheimer's dementia.}, journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society}, volume = {}, number = {}, pages = {}, doi = {10.1111/psyg.12546}, pmid = {32219988}, issn = {1479-8301}, support = {No number//Hedwig Widmer Foundation, Zurich, Switzerland/ ; 100014_130034/1//Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung/ ; }, abstract = {BACKGROUND: The present study aims to investigate the quality of the dyadic relationship between mild Alzheimer patients and their caregivers. The main objective is to evaluate the consistency, agreement and validity of the German version of the Scale for Quality of the Current Relationship in Caregiving (SQCRC). The secondary objective was to examine the association of relationship quality with quality of life (QOL) in patients with mild Alzheimer's disease (AD) and their caregivers.

METHODS: In this study, a sample of 50 patients diagnosed with mild AD and their primary caregivers were included. Participants underwent a full neuropsychological evaluation. The quality of the relationship between persons with AD and their caregivers was assessed using the SQCRC. Furthermore, other scales of relationship quality, well-being of the person with AD, and well-being of the caregiver were used.

RESULTS: The results showed that the SQCRC has a good internal consistency and high validity. Also, relationship quality as rated by the AD patients (r = 0.37, P < 0.1) and their caregivers (r = 0.51, P < 0.1) was significantly correlated with QOL.

CONCLUSIONS: The findings suggest that many persons with mild AD can rate their relationship quality and that the patient's self-rated relationship quality is a substantial predictor of their QOL.}, } @article {pmid32219727, year = {2020}, author = {Katdare, A and Khunt, D and Thakkar, S and Polaka, SN and Misra, M}, title = {Comparative evaluation of fish oil and butter oil in modulating delivery of galantamine hydrobromide to brain via intranasal route: pharmacokinetic and oxidative stress studies.}, journal = {Drug delivery and translational research}, volume = {}, number = {}, pages = {}, doi = {10.1007/s13346-020-00739-y}, pmid = {32219727}, issn = {2190-3948}, support = {IFA-LSBM-13//Department of science and technology (IN)/ ; EMR/2016/007966/HS//Science and Engineering Research Board (IN)/ ; }, abstract = {The present study investigates the role of fish oil (FO)- and butter oil (BO)-enriched microemulsion-based system of galantamine hydrobromide (GH), an anti-Alzheimer drug, for its potential role in brain permeation enhancement and neuroprotection against oxidative stress. Microemulsion (ME)-based system of GH was prepared using water phase titration. The prepared ME was characterized by several physicochemical parameters like particle size, polydispersity index, and ex vivo drug permeation. Cell-based oxidative stress assays and pharmacokinetic studies were performed using C6 glial cell lines, and Sprague Dawley rats, respectively. The optimized ME comprised 5.3% v/v of Capmul MCM EP (as oil),15.8% v/v of Tween-80 (as surfactant), 5.3% v/v of Transcutol P (as co-surfactant), and 73.6% v/v of water (as aqueous phase). The addition of FO and BO resulted in a slight increase in the droplet size and decrease in transparency of ME. Cell-based anti-oxidative stress assays (glutathione assay, nitrite assay, and lipid peroxidation assay) showed the efficacy of formulation in the order of ME, BO ME, and FO ME, respectively. A similar trend was also observed in in vivo animal studies, wherein GH FO ME showed a comparatively higher percentage of drug reaching the brain when administered by intranasal route than by IV route. The study concluded the potential benefits of co-administering FO- and BO-enriched microemulsion is not only enhancing the permeation of drugs across BBB but also improving efficacy against lipopolysaccharide-induced oxidative stress. Graphical abstract.}, } @article {pmid32218468, year = {2020}, author = {Yang, R and Bogdan, P}, title = {Controlling the Multifractal Generating Measures of Complex Networks.}, journal = {Scientific reports}, volume = {10}, number = {1}, pages = {5541}, pmid = {32218468}, issn = {2045-2322}, abstract = {Mathematical modelling of real complex networks aims to characterize their architecture and decipher their underlying principles. Self-repeating patterns and multifractality exist in many real-world complex systems such as brain, genetic, geoscience, and social networks. To better comprehend the multifractal behavior in the real networks, we propose the weighted multifractal graph model to characterize the spatiotemporal complexity and heterogeneity encoded in the interaction weights. We provide analytical tools to verify the multifractal properties of the proposed model. By varying the parameters in the initial unit square, the model can reproduce a diverse range of multifractal spectrums with different degrees of symmetry, locations, support and shapes. We estimate and investigate the weighted multifractal graph model corresponding to two real-world complex systems, namely (i) the chromosome interactions of yeast cells in quiescence and in exponential growth, and (ii) the brain networks of cognitively healthy people and patients exhibiting late mild cognitive impairment leading to Alzheimer disease. The analysis of recovered models show that the proposed random graph model provides a novel way to understand the self-similar structure of complex networks and to discriminate different network structures. Additionally, by mapping real complex networks onto multifractal generating measures, it allows us to develop new network design and control strategies, such as the minimal control of multifractal measures of real systems under different functioning conditions or states.}, } @article {pmid32218066, year = {2020}, author = {Montoya, Y and Balbim, GM and Glover, CM and Marquez, DX}, title = {"My Parent's Body Is Sacred": Perspectives From Adult Latino Children About Brain Donation for Alzheimer Disease Research.}, journal = {Alzheimer disease and associated disorders}, volume = {}, number = {}, pages = {}, doi = {10.1097/WAD.0000000000000377}, pmid = {32218066}, issn = {1546-4156}, abstract = {INTRODUCTION: Brain donation is a critical part of advancing research addressing Alzheimer disease and related dementias (ADRD). Studies on ADRD with an option for brain donation are reliant on family members to fulfill the research participant's plan for brain donation. Thus, family members play a pivotal role in increasing brain donation rates, particularly among under-represented groups.

METHODS: This study examines knowledge, attitudes, and beliefs about brain donation for research among Latinos. Latino men (N=4) and Latina women (N=11) 18 years of age or older with a parental figure age 65 years and over were invited to participate in a focus group.

RESULTS: Data analyses revealed 3 themes. Two themes focused on factors influencing a family's willingness to support brain donation: (a) social and cultural contexts, and (b) lack of knowledge and information about the brain donation process. The last theme provided recommendations for engaging older Latino adults in ADRD research and brain donation.

DISCUSSION: Results suggest being inclusive of family members during all stages of the research process, from recruitment to dissemination. In addition, addressing information gaps among Latinos about the process and benefits of brain donation may help mitigate mistrust and misperceptions and increase participation rates in brain donation.}, } @article {pmid32217775, year = {2020}, author = {Carvalho, DZ and St Louis, EK and Schwarz, CG and Lowe, VJ and Boeve, BF and Przybelski, SA and Reddy, A and Mielke, MM and Knopman, DS and Petersen, RC and Jack, CR and Vemuri, P}, title = {Witnessed apneas are associated with elevated tau-PET levels in cognitively unimpaired elderly.}, journal = {Neurology}, volume = {94}, number = {17}, pages = {e1793-e1802}, doi = {10.1212/WNL.0000000000009315}, pmid = {32217775}, issn = {1526-632X}, support = {R01 AG056366/AG/NIA NIH HHS/United States ; R01 NS097495/NS/NINDS NIH HHS/United States ; }, abstract = {OBJECTIVE: To assess whether informant-reported apneas during sleep (witnessed apneas) in cognitively unimpaired (CU) elderly persons are associated with higher levels of brain tau.

METHODS: From the population-based Mayo Clinic Study of Aging, we identified 292 CU elderly ≥65 years of age with both AV-1451 tau-PET and Pittsburgh compound B (PiB)-PET scans and whose bed partners and close relatives had completed a questionnaire that assessed whether participants had witnessed apneas during sleep. For this cross-sectional analysis, we selected the entorhinal and inferior temporal cortices as our regions of interest (ROIs) because they are highly susceptible to tau accumulation. PET signal was scaled to the cerebellum crus to calculate standardized uptake value ratio (SUVR). We fit linear models to assess the association between regional tau and witnessed apneas while controlling for age, sex, years of education, body mass index, hypertension, hyperlipidemia, diabetes, reduced sleep, excessive daytime sleepiness, and global PiB.

RESULTS: Forty-three participants (14.7%) were found to have witnessed apneas during sleep. The report of witnessed apneas was associated with higher tau-PET SUVR elevation in our ROIs: 0.049 SUVR (95% confidence interval [CI] 0.010-0.087, p = 0.015) in the entorhinal cortex and 0.037 SUVR (95% CI 0.006-0.067, p = 0.019) in the inferior temporal cortex after controlling for confounders.

CONCLUSION: We identified a significant association between witnessed apneas in CU elderly and elevated tau-PET signal in tau-susceptible brain regions. These results suggest a plausible mechanism that could contribute to cognitive impairment and the development of Alzheimer disease. Longitudinal observations are necessary to determine direction of causality.}, } @article {pmid32216773, year = {2020}, author = {Kouzuki, M and Ichikawa, J and Shirasagi, D and Katsube, F and Kobashi, Y and Matsumoto, H and Chao, H and Yoshida, S and Urakami, K}, title = {Detection and recognition thresholds for five basic tastes in patients with mild cognitive impairment and Alzheimer's disease dementia.}, journal = {BMC neurology}, volume = {20}, number = {1}, pages = {110}, pmid = {32216773}, issn = {1471-2377}, abstract = {BACKGROUND: Patients with Alzheimer's disease dementia (ADD) are thought to exhibit taste disorders; however, this has not been extensively studied. We investigated gustatory functions and factors affecting taste in patients with ADD or mild cognitive impairment (MCI) and in non-demented controls (NDCs) and evaluated associations between cognitive impairment and gustatory functions.

METHODS: We recruited 29 patients with ADD, 43 with MCI, and 14 with NDCs. We obtained medical and medication history, measured salivary secretion volumes, and performed cognitive function tests, blood tests, whole-mouth gustatory tests, and dietary and gustatory questionnaires.

RESULTS: Patients with ADD showed significantly higher recognition threshold values than NDCs (p < 0.05). Many individuals did not recognize umami at the maximum concentration, and this happened more frequently in patients with ADD or MCI than in NDCs. Evaluation items other than cognitive function tests did not show significant differences among the groups, but many individuals had decreased salivation, low serum zinc levels, and were on multiple medications. We found a significant correlation between recognition threshold and age (r = 0.229, p < 0.05) and cognitive function test score (r = 0.268, p < 0.05).

CONCLUSIONS: Patients with ADD showed impairment of gustatory function. Gustatory impairment in patients with MCI could not be confirmed. However, many individuals with MCI did not recognize umami, either. Our results suggest that taste disorders in elderly people with cognitive decline occur independently of factors affecting taste such as salivation, zinc levels, or prescription drugs.

TRIAL REGISTRATION: The study was registered in the UMIN Clinical Trials Registry on February 10, 2017, with reference number UMIN000026087.}, } @article {pmid32215721, year = {2020}, author = {Leblhuber, F and Huemer, J and Steiner, K and Gostner, JM and Fuchs, D}, title = {Knock-on effect of periodontitis to the pathogenesis of Alzheimer's disease?.}, journal = {Wiener klinische Wochenschrift}, volume = {}, number = {}, pages = {}, doi = {10.1007/s00508-020-01638-5}, pmid = {32215721}, issn = {1613-7671}, abstract = {BACKGROUND: Alzheimer's disease has chronic inflammatory components, which can be enhanced by systemic immune activation resulting in inflammation or vice versa. There is growing evidence that chronic periodontitis drives systemic inflammation and finally Alzheimer's disease. Thus, a link might exist between oral pathogens and Alzheimer's disease. This may be of special significance as there is an age-related incidence of chronic periodontitis.

METHODS: In this study, 20 consecutive patients with probable Alzheimer's disease were investigated. Diagnosis was established by cognitive tests, routine laboratory tests and cerebral magnetic resonance tomography. In 35% of these patients with cognitive impairment pathogenic periodontal bacteria were found.

RESULTS: The presence of Porphyromonas gingivalis, the key pathogen and one of the species involved in chronic periodontitis, was found to be associated with lower mini mental state examination scores (p < 0.05) and with a tendency to lower scores in the clock drawing test (p = 0.056). Furthermore, association between lower serum concentrations of the immune biomarker neopterin and the presence of Treponema denticola (p < 0.01) as well as of kynurenine were found in Alzheimer patients positive vs. negative for Tannerella forsytia (p < 0.05).

CONCLUSIONS: Data indicate a possible association of specific periodontal pathogens with cognitive impairment, Treponema denticola and Tannerella forsytia may alter the host immune response in Alzheimer's disease. Albeit still preliminary, findings of the study may point to a possible role of an altered salivary microbiome as a causal link between chronic periodontitis and cognitive impairment in Alzheimer's disease.}, } @article {pmid32215172, year = {2020}, author = {Cai, B and Zhang, Y and Wang, Z and Xu, D and Jia, Y and Guan, Y and Liao, A and Liu, G and Chun, C and Li, J}, title = {Therapeutic Potential of Diosgenin and Its Major Derivatives against Neurological Diseases: Recent Advances.}, journal = {Oxidative medicine and cellular longevity}, volume = {2020}, number = {}, pages = {3153082}, pmid = {32215172}, issn = {1942-0994}, abstract = {Diosgenin (DG), a well-known steroidal sapogenin, is present abundantly in medicinal herbs such as Dioscorea rhizome, Dioscorea villosa, Trigonella foenum-graecum, Smilax China, and Rhizoma polgonati. DG is utilized as a major starting material for the production of steroidal drugs in the pharmaceutical industry. Due to its wide range of pharmacological activities and medicinal properties, it has been used in the treatment of cancers, hyperlipidemia, inflammation, and infections. Numerous studies have reported that DG is useful in the prevention and treatment of neurological diseases. Its therapeutic mechanisms are based on the mediation of different signaling pathways, and targeting these pathways might lead to the development of effective therapeutic agents for neurological diseases. The present review mainly summarizes recent progress using DG and its derivatives as therapeutic agents for multiple neurological disorders along with their various mechanisms in the central nervous system. In particular, those related to therapeutic efficacy for Parkinson's disease, Alzheimer's disease, brain injury, neuroinflammation, and ischemia are discussed. This review article also critically evaluates existing limitations associated with the solubility and bioavailability of DG and discusses imperatives for translational clinical research. It briefly recapitulates recent advances in structural modification and novel formulations to increase the therapeutic efficacy and brain levels of DG. In the present review, databases of PubMed, Web of Science, and Scopus were used for studies of DG and its derivatives in the treatment of central nervous system diseases published in English until December 10, 2019. Three independent researchers examined articles for eligibility. A total of 150 articles were screened from the above scientific literature databases. Finally, a total of 46 articles were extracted and included in this review. Keywords related to glioma, ischemia, memory, aging, cognitive impairment, Alzheimer, Parkinson, and neurodegenerative disorders were searched in the databases based on DG and its derivatives.}, } @article {pmid32213845, year = {2020}, author = {Espinosa-Val, MC and Martín-Martínez, A and Graupera, M and Arias, O and Elvira, A and Cabré, M and Palomera, E and Bolívar-Prados, M and Clavé, P and Ortega, O}, title = {Prevalence, Risk Factors, and Complications of Oropharyngeal Dysphagia in Older Patients with Dementia.}, journal = {Nutrients}, volume = {12}, number = {3}, pages = {}, pmid = {32213845}, issn = {2072-6643}, support = {-//Pla Estratègic de Recerca I Innovació en Salut, Genralitat de Catalunya/ ; -//Centro de Investigación Biomédica en Red en el Área de Enfermedades Hepáticas y Digestivas (CIBERehd), Insitituto de Salud Carlos III/ ; }, abstract = {The prevalence of older patients with dementia and oropharyngeal dysphagia (OD) is rising and management is poor. Our aim was to assess the prevalence, risk factors, and long-term nutritional and respiratory complications during follow-up of OD in older demented patients. We designed a prospective longitudinal quasi-experimental study with 255 patients with dementia. OD was assessed with the Volume-Viscosity Swallowing Test and a geriatric evaluation was performed. OD patients received compensatory treatments based on fluid viscosity and texture modified foods and oral hygiene, and were followed up for 18 months after discharge. Mean age was 83.5 ± 8.0 years and Alzheimer's disease was the main cause of dementia (52.9%). The prevalence of OD was 85.9%. Up to 82.7% patients with OD required fluid thickening and 93.6% texture modification, with poor compliance. OD patients were older (p < 0.007), had worse functionality (p < 0.0001), poorer nutritional status (p = 0.014), and higher severity of dementia (p < 0.001) than those without OD and showed higher rates of respiratory infections (p = 0.011) and mortality (p = 0.0002) after 18 months follow-up. These results show that OD is very prevalent among patients with dementia and is associated with impaired functionality, malnutrition, respiratory infections, and increased mortality. New nutritional strategies should be developed to increase the compliance and therapeutic effects for this growing population of dysphagic patients.}, } @article {pmid32213642, year = {2020}, author = {Ryan, J and Storey, E and Murray, AM and Woods, RL and Wolfe, R and Reid, CM and Nelson, MR and Chong, TTJ and Williamson, JD and Ward, SA and Lockery, JE and Orchard, SG and Trevaks, R and Kirpach, B and Newman, AB and Ernst, ME and McNeil, JJ and Shah, RC and , }, title = {Randomized placebo-controlled trial of the effects of aspirin on dementia and cognitive decline.}, journal = {Neurology}, volume = {}, number = {}, pages = {}, doi = {10.1212/WNL.0000000000009277}, pmid = {32213642}, issn = {1526-632X}, abstract = {OBJECTIVE: To determine the effect of low-dose aspirin vs placebo on incident all-cause dementia, incident Alzheimer disease (AD), mild cognitive impairment (MCI), and cognitive decline in older individuals.

METHODS: Aspirin in Reducing Events in the Elderly (ASPREE) was a double-blind, placebo-controlled trial of low-dose aspirin. In the United States and Australia, community-dwelling individuals aged ≥70 years (US minorities ≥65 years) and free of cardiovascular disease, physical disability, and diagnosed dementia were enrolled. Participants were randomized 1:1-100 mg daily aspirin or placebo. The Modified Mini-Mental State Examination, Hopkins Verbal Learning Test-Revised, Symbol Digit Modalities Test, and Controlled Oral Word Association Test assessed cognition at baseline and over follow-up. Additional cognitive testing was performed in participants with suspected dementia ("trigger") based on within-study assessments or clinical history. Dementia was adjudicated according to DSM-IV criteria. National Institute on Aging-Alzheimer's Association criteria were used for AD and MCI subclassification.

RESULTS: A total of 19,114 participants were followed over a median 4.7 years and 964 triggered further dementia assessments. There were 575 adjudicated dementia cases, and 41% were classified as clinically probable AD. There was no substantial difference in the risk of all dementia triggers (hazard ratio [HR], 1.03; 95% confidence interval [CI], 0.91-1.17), probable AD (HR, 0.96; 95% CI, 0.74-1.24), or MCI (HR, 1.12; 95% CI, 0.92-1.37) between aspirin and placebo. Cognitive change over time was similar in the aspirin and placebo groups.

CONCLUSIONS: There was no evidence that aspirin was effective in reducing risk of dementia, MCI, or cognitive decline. Follow-up of these outcomes after initial exposure is ongoing.

CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for healthy older individuals, low-dose aspirin does not significantly reduce the incidence of dementia, probable AD, MCI, or cognitive decline.

CLINICALTRIALSGOV IDENTIFIER: NCT01038583.}, } @article {pmid32213159, year = {2020}, author = {Cui, W and Fu, W and Lin, Y and Zhang, T and Zhou, R and Zhang, T}, title = {Application of nanomaterials in neurodegenerative diseases.}, journal = {Current stem cell research & therapy}, volume = {}, number = {}, pages = {}, doi = {10.2174/1574888X15666200326093410}, pmid = {32213159}, issn = {2212-3946}, abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Huntington's disease are very harmful brain lesions. Due to the difficulty in obtaining therapeutic drugs, the best treatment for neurodegenerative diseases is often not available. In addition, the blood-brain barrier can effectively prevent the transfer of cells, particles and macromolecules (such as drugs) in the brain, resulting in the failure of the traditional drug delivery system to provide adequate cellular structure repair and connection modes, which are crucial for the functional recovery of neurodegenerative diseases. Nanomaterials are designed to carry drugs across the blood-brain barrier for targets. Nanotechnology uses engineering materials or equipment to interact with biological systems at the molecular level to induce physiological responses through stimulation, response and target site interactions, while minimizing side effects, thus revolutionizing the treatment and diagnosis of neurodegenerative diseases. Some magnetic nanomaterials play a role as imaging agents or nanoprobes for Magnetic Resonance Imaging to assist in the diagnosis of neurodegenerative diseases. Although the current research on nanomaterials is not as useful as expected in clinical applications, it achieves a major breakthrough and guides the future development direction of nanotechnology in the application of neurodegenerative diseases. This review briefly discusses the application and advantages of nanomaterials in neurodegenerative diseases. Data for this review were identified by searches of PubMed, and references from relevant articles published in English between 2015 and 2019 were using the search terms "nanomaterials", "neurodegenerative diseases" and "blood-brain barrier".}, } @article {pmid32213008, year = {2020}, author = {Martínez-Tomé, M and Murcia, MA and Rosario, C and Mariscal-Arcas, M and Jiménez-Monreal, AM}, title = {Different Methods to Assess the Nutritional Status of Alzheimer Patients.}, journal = {Journal of the American College of Nutrition}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/07315724.2020.1737594}, pmid = {32213008}, issn = {1541-1087}, abstract = {Objective: To assess the body composition and nutritional state of patients with Alzheimer's (Global Deterioration Scale GDS-4) using different methods and to investigate the correlation among methods.Methods: A total of 25 Alzheimer GDS-4 patients participated in this transversal descriptive observational study, which used anthropometry, Mini Nutritional Assessment (MNA), the Nutrition Screening Initiative Check List (NSI) and a 24-hour recall questionnaire (R24h).Results: Anthropometric observations pointed to obesity in patients of both sexes. The MNA showed that 76% of the population was "at risk of malnutrition", and the NSI suggested that 32% had a high nutritional risk, 48% had an "average" nutritional risk, and the remaining 20% a low nutritional risk. The Bland-Alman concordance plot between the NSI and MNA tests pointed to a high degree of agreement, meaning that both tests provided similar results for the group of studied subjects. The nutritional analysis, based on the Kruskal-Wallis test, showed there were significant differences between R24h and MNA in the case of ascorbic acid, iron, zinc and potassium (p < 0.05), and between R24h and NSI in the case of the double unsaturation index and vitamin D3 (p < 0.05). These results suggest that both questionnaires are equally valid for evaluating the nutritional status of Alzheimer patients.Conclusion: Although the NSI and MNA tests provide similar results, we recommend an initial nutritional assessment using the NSI since it is short but provides information on any alteration in food intake as a result of restrictions and/or metabolic alterations.}, } @article {pmid32211506, year = {2020}, author = {Kutzsche, J and Jürgens, D and Willuweit, A and Adermann, K and Fuchs, C and Simons, S and Windisch, M and Hümpel, M and Rossberg, W and Wolzt, M and Willbold, D}, title = {Safety and pharmacokinetics of the orally available antiprionic compound PRI-002: A single and multiple ascending dose phase I study.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {6}, number = {1}, pages = {e12001}, pmid = {32211506}, issn = {2352-8737}, abstract = {Introduction: PRI-002 is an orally available anti-amyloid beta (Aβ) prionic compound developed for direct disassembly of toxic Aβ oligomers relevant to Alzheimer's disease.

Methods: Two placebo-controlled clinical phase I trials with oral dosing of PRI-002 were conducted in healthy young subjects: A single ascending dose trial (4, 12, 36, 108, or 320 mg PRI-002 or placebo) in 40 participants followed by a multiple ascending dose study with daily 160 mg PRI-002 for 14 days or 320 mg for 28 days in 24 participants. The main objectives were safety, tolerability, and evaluation of pharmacokinetic (PK) parameters.

Results: PRI-002 was safe and well tolerated after single and multiple oral administration up to the highest doses. PRI-002 was absorbed rapidly and drug exposure increased proportional to dose. During repeated daily administration, the drug accumulated by a factor of about three. Steady-state conditions were reached after 1 to 2 weeks.

Conclusions: The safety and PK results encourage further clinical development of PRI-002.}, } @article {pmid32211499, year = {2020}, author = {Day, GS and Rappai, T and Sathyan, S and Morris, JC}, title = {Deciphering the factors that influence participation in studies requiring serial lumbar punctures.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {12}, number = {1}, pages = {e12003}, pmid = {32211499}, issn = {2352-8729}, support = {P01 AG026276/AG/NIA NIH HHS/United States ; K23 AG064029/AG/NIA NIH HHS/United States ; UF1 AG032438/AG/NIA NIH HHS/United States ; U19 AG032438/AG/NIA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; P50 AG005681/AG/NIA NIH HHS/United States ; }, abstract = {Introduction: Cerebrospinal fluid biomarkers increasingly inform the causes of dementia and may provide objective markers of disease progression. There is a need to decipher participant and procedural factors that promote participation in studies incorporating longitudinal biomarker measures.

Methods: Participant and procedural factors associated with participation in longitudinal biomarker studies were determined in individuals enrolled in studies of memory and aging at the Knight Alzheimer Disease Research Center (Saint Louis, MO, USA).

Results: Complications were encountered following 331 of 1484 lumbar punctures (22.3%; LPs), affecting 280 of 929 participants (30.1%); in >95% complications were minor. Three hundred fifteen of 679 eligible participants (46.4%) completed multiple LPs. Younger age (odds ratio [OR] 2.08 per decade [95% confidence interval (CI) 1.61-2.94]), normal cognition (OR 21.4 [2.85-160.1]), and the absence of heart disease (OR 2.0 [1.01-3.85]) or seizures at study entry identified participants with increased odds of completing three or more LPs.

Discussion: Factors influencing participation may be leveraged to improve recruitment and retention within observational and therapeutic studies requiring serial LPs.}, } @article {pmid32210102, year = {2020}, author = {Martínez-Iglesias, O and Carrera, I and Carril, JC and Fernández-Novoa, L and Cacabelos, N and Cacabelos, R}, title = {DNA Methylation in Neurodegenerative and Cerebrovascular Disorders.}, journal = {International journal of molecular sciences}, volume = {21}, number = {6}, pages = {}, pmid = {32210102}, issn = {1422-0067}, abstract = {DNA methylation is an epigenetic mechanism by which methyl groups are added to DNA, playing a crucial role in gene expression regulation. The aim of the present study is to compare methylation status of healthy subjects with that of patients with Alzheimer's, Parkinson's or Cerebrovascular diseases. We also analyze methylation status of a transgenic Alzheimer's disease mouse model (3xTg-AD). Our results show that both global methylation (n = 141) and hydroxymethylation (n = 131) levels are reduced in DNA samples from buffy coats of patients with neurodegenerative disorders and age-related cerebrovascular disease. The importance of methylation and hydroxymethylation reduction is stressed by the finding that DNMT3a mRNA levels are also downregulated in buffy coats of patients with Dementia (n = 25). Global methylation is also reduced in brain, liver and serum samples of 3xTg-AD vs. wild type mice, such as DNMT3a mRNA levels that are also decreased in the brain of 3xTg-AD (n = 10). These results suggest that the use of global methylation and hydroxymethylation levels, together with the study of DNMT3a expression, could be useful as a new diagnostic biomarker for these prevalent disorders.}, } @article {pmid32209796, year = {2019}, author = {Kaskikallio, A and Karrasch, M and Koikkalainen, J and Lötjönen, J and Rinne, JO and Tuokkola, T and Parkkola, R and Grönholm-Nyman, P}, title = {White Matter Hyperintensities and Cognitive Impairment in Healthy and Pathological Aging: A Quantified Brain MRI Study.}, journal = {Dementia and geriatric cognitive disorders}, volume = {48}, number = {5-6}, pages = {297-307}, doi = {10.1159/000506124}, pmid = {32209796}, issn = {1421-9824}, abstract = {BACKGROUND: Brain changes involving the white matter (WM), often an indication of cerebrovascular pathology, are frequently seen in patients with mild cognitive impairment (MCI) and Alzheimer disease (AD). Few studies have examined possible cognitive domain- or group-specific cognitive effects of WM pathology in old age, MCI, and AD.

OBJECTIVE: Our purpose was to examine the relationship between WM hyperintensities (WMH), a typical marker for WM pathology, and cognitive functioning in healthy old age and pathological aging using quantified MRI data.

METHODS: We utilized multidomain neuropsychological data and quantified MRI data from a sample of 42 cognitively healthy older adults and 44 patients with MCI/AD (total n = 86).

RESULTS: After controlling for age and education, WMH in the temporal and parieto-occipital lobes was associated with impairments in processing speed and parieto-occipital pathology with verbal memory impairment in the whole sample. Additionally, temporal WMH was associated with impaired processing speed in the patient group specifically.

CONCLUSIONS: WM pathology is strongly associated with impaired processing speed, and our results indicate that these impairments arise from WMH in the temporal and parieto-occipital regions. In MCI and AD patients with temporal WMH, processing speed impairments are especially prominent. The results of this study increase our knowledge of cognitive repercussions stemming from temporal and/or parieto-occipital WM pathology in healthy and pathological aging.}, } @article {pmid32209123, year = {2020}, author = {Alber, J and Maruff, P and Santos, CY and Ott, BR and Salloway, SP and Yoo, DC and Noto, RB and Thompson, LI and Goldfarb, D and Arthur, E and Song, A and Snyder, PJ}, title = {Disruption of cholinergic neurotransmission, within a cognitive challenge paradigm, is indicative of Aβ-related cognitive impairment in preclinical Alzheimer's disease after a 27-month delay interval.}, journal = {Alzheimer's research & therapy}, volume = {12}, number = {1}, pages = {31}, pmid = {32209123}, issn = {1758-9193}, support = {None//Pfizer/ ; }, abstract = {BACKGROUND: Abnormal beta-amyloid (Aβ) is associated with deleterious changes in central cholinergic tone in the very early stages of Alzheimer's disease (AD), which may be unmasked by a cholinergic antagonist (J Prev Alzheimers Dis 1:1-4, 2017). Previously, we established the scopolamine challenge test (SCT) as a "cognitive stress test" screening measure to identify individuals at risk for AD (Alzheimer's & Dementia 10(2):262-7, 2014) (Neurobiol. Aging 36(10):2709-15, 2015). Here we aim to demonstrate the potential of the SCT as an indicator of cognitive change and neocortical amyloid aggregation after a 27-month follow-up interval.

METHODS: Older adults (N = 63, aged 55-75 years) with self-reported memory difficulties and first-degree family history of AD completed the SCT and PET amyloid imaging at baseline and were then seen for cognitive testing at 9, 18, and 27 months post-baseline. Repeat PET amyloid imaging was completed at the time of the 27-month exam.

RESULTS: Significant differences in both cognitive performance and in Aβ neocortical burden were observed between participants who either failed vs. passed the SCT at baseline, after a 27-month follow-up period.

CONCLUSIONS: Cognitive response to the SCT (Alzheimer's & Dementia 10(2):262-7, 2014) at baseline is related to cognitive change and PET amyloid imaging results, over the course of 27 months, in preclinical AD. The SCT may be a clinically useful screening tool to identify individuals who are more likely to both have positive evidence of amyloidosis on PET imaging and to show measurable cognitive decline over several years.}, } @article {pmid32207833, year = {2020}, author = {Branigan, GL and Soto, M and Neumayer, L and Rodgers, K and Brinton, RD}, title = {Association Between Hormone-Modulating Breast Cancer Therapies and Incidence of Neurodegenerative Outcomes for Women With Breast Cancer.}, journal = {JAMA network open}, volume = {3}, number = {3}, pages = {e201541}, pmid = {32207833}, issn = {2574-3805}, support = {P01 AG026572/AG/NIA NIH HHS/United States ; R37 AG053589/AG/NIA NIH HHS/United States ; T32 AG061897/AG/NIA NIH HHS/United States ; }, abstract = {Importance: The association between exposure to hormone-modulating therapy (HMT) as breast cancer treatment and neurodegenerative disease (NDD) is unclear.

Objective: To determine whether HMT exposure is associated with the risk of NDD in women with breast cancer.

This retrospective cohort study used the Humana claims data set from January 1, 2007, to March 31, 2017. The Humana data set contains claims from private-payer and Medicare insurance data sets from across the United States with a population primarily residing in the Southeast. Patient claims records were surveyed for a diagnosis of NDD starting 1 year after breast cancer diagnosis for the duration of enrollment in the claims database. Participants were 57 843 women aged 45 years or older with a diagnosis of breast cancer. Patients were required to be actively enrolled in Humana claims records for 6 months prior to and at least 3 years after the diagnosis of breast cancer. The analyses were conducted between January 1 and 15, 2020.

Exposure: Hormone-modulating therapy (selective estrogen receptor modulators, estrogen receptor antagonists, and aromatase inhibitors).

Main Outcomes and Measures: Patients receiving HMT for breast cancer treatment were identified. Survival analysis was used to determine the association between HMT exposure and diagnosis of NDD. A propensity score approach was used to minimize measured and unmeasured selection bias.

Results: Of the 326 485 women with breast cancer in the Humana data set between 2007 and 2017, 57 843 met the study criteria. Of these, 18 126 (31.3%; mean [SD] age, 76.2 [7.0] years) received HMT, whereas 39 717 (68.7%; mean [SD] age, 76.8 [7.0] years) did not receive HMT. Mean (SD) follow-up was 5.5 (1.8) years. In the propensity score-matched population, exposure to HMT was associated with a decrease in the number of women who received a diagnosis of NDD (2229 of 17 878 [12.5%] vs 2559 of 17 878 [14.3%]; relative risk, 0.89; 95% CI, 0.84-0.93; P < .001), Alzheimer disease (877 of 17 878 [4.9%] vs 1068 of 17 878 [6.0%]; relative risk, 0.82; 95% CI, 0.75-0.90; P < .001), and dementia (1862 of 17 878 [10.4%] vs 2116 of 17 878 [11.8%]; relative risk, 0.88; 95% CI, 0.83-0.93; P < .001). The number needed to treat was 62.51 for all NDDs, 93.61 for Alzheimer disease, and 69.56 for dementia.

Conclusions and Relevance: Among patients with breast cancer, tamoxifen and steroidal aromatase inhibitors were associated with a decrease in the number who received a diagnosis of NDD, specifically Alzheimer disease and dementia.}, } @article {pmid32205035, year = {2020}, author = {Butterfield, DA}, title = {BRAIN LIPID PEROXIDATION AND ALZHEIMER DISEASE: SYNERGY BETWEEN THE BUTTERFIELD AND MATTSON LABORATORIES.}, journal = {Ageing research reviews}, volume = {}, number = {}, pages = {101049}, doi = {10.1016/j.arr.2020.101049}, pmid = {32205035}, issn = {1872-9649}, support = {R56 AG055596/AG/NIA NIH HHS/United States ; }, abstract = {Brains from persons with Alzheimer disease (AD) and its earlier stage, amnestic mild cognitive impairment (MCI), exhibit high levels of oxidative damage, including that to phospholipids. One type of oxidative damage is lipid peroxidation, the most important index of which is protein-bound 4-hydroxy-2-trans-nonenal (HNE). This highly reactive alkenal changes the conformations and lowers the activities of brain proteins to which HNE is covalently bound. Evidence exists that suggests that lipid peroxidation is the first type of oxidative damage associated with amyloid β-peptide (Aβ), a 38-42 amino acid peptide that is highly neurotoxic and critical to the pathophysiology of AD. The Butterfield laboratory is one of, if not the, first research group to show that Aβ42 oligomers led to lipid peroxidation and to demonstrate this modification in brains of subjects with AD and MCI. The Mattson laboratory, particularly when Dr. Mattson was a faculty member at the University of Kentucky, also showed evidence for lipid peroxidation associated with Aβ peptides, mostly in in vitro systems. Consequently, there is synergy between our two laboratories. Since this special tribute issue of Aging Research Reviews is dedicated to the career of Dr. Mattson, a review of some aspects of this synergy of lipid peroxidation and its relevance to AD, as well as the role of lipid peroxidation in the progression of this dementing disorder seems germane. Accordingly, this review outlines some of the individual and/or complementary research on lipid peroxidation related to AD published from our two laboratories either separately or jointly.}, } @article {pmid32204915, year = {2020}, author = {Chen, Y and Wang, H and Ying, Z and Gao, Q}, title = {Ibudilast enhances the clearance of SOD1 and TDP-43 aggregates through TFEB-mediated autophagy and lysosomal biogenesis: The new molecular mechanism of ibudilast and its implication for neuroprotective therapy.}, journal = {Biochemical and biophysical research communications}, volume = {526}, number = {1}, pages = {231-238}, doi = {10.1016/j.bbrc.2020.03.051}, pmid = {32204915}, issn = {1090-2104}, abstract = {A key feature of amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders including Alzheimer disease (AD), Parkinson disease (PD) and Huntington's disease (HD) is abnormal aggregation and deposition of misfolded proteins. Previous studies have shown that autophagy plays an important role in the clearance of disease-linked protein aggregates. In the current study, we report that ibudilast, which is a non-selective inhibitor of phosphodiesterases (PDEs) and an anti-inflammation drug, can induce autophagy and lysosomal biogenesis through mammalian target of rapamycin complex 1 - transcription factor EB (mTORC1-TFEB) signaling. We have found that ibudilast significantly enhances the clearance of disease-linked TAR DNA binding protein (TDP-43) and superoxide dismutase 1 (SOD1) protein aggregates in transfected cellular models carrying corresponding gene mutations. The mechanistic study revealed that ibudilast could markedly enhance TFEB nuclear translocation and increase the autolysosomes by inhibiting mTORC1 activity. We have also demonstrated that ibudilast could protect TDP-43-induced cytotoxicity in motor neuron-like NSC-34 cells. Collectively, our study identifies ibudilast as an autophagy enhancer and provides insights into the molecular basis of ibudilast for the potential treatment of several neurodegenerative disorders.}, } @article {pmid32203399, year = {2020}, author = {Peng, C and Trojanowski, JQ and Lee, VM}, title = {Protein transmission in neurodegenerative disease.}, journal = {Nature reviews. Neurology}, volume = {16}, number = {4}, pages = {199-212}, doi = {10.1038/s41582-020-0333-7}, pmid = {32203399}, issn = {1759-4766}, mesh = {Alzheimer Disease/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Axonal Transport ; Brain/*metabolism/pathology ; Cell Communication ; DNA-Binding Proteins/metabolism ; Endocytosis ; Exosomes/metabolism ; Genetic Predisposition to Disease ; Humans ; Huntingtin Protein/metabolism ; Huntington Disease/metabolism/pathology ; Membrane Fusion ; Nanotubes ; Neurodegenerative Diseases/*metabolism/pathology ; Neuroglia/metabolism ; Neurons/metabolism ; Parkinson Disease/metabolism/pathology ; Protein Aggregation, Pathological/*metabolism/pathology ; *Protein Transport ; alpha-Synuclein/metabolism ; tau Proteins/metabolism ; }, abstract = {Most neurodegenerative diseases are characterized by the intracellular or extracellular aggregation of misfolded proteins such as amyloid-β and tau in Alzheimer disease, α-synuclein in Parkinson disease, and TAR DNA-binding protein 43 in amyotrophic lateral sclerosis. Accumulating evidence from both human studies and disease models indicates that intercellular transmission and the subsequent templated amplification of these misfolded proteins are involved in the onset and progression of various neurodegenerative diseases. The misfolded proteins that are transferred between cells are referred to as 'pathological seeds'. Recent studies have made exciting progress in identifying the characteristics of different pathological seeds, particularly those isolated from diseased brains. Advances have also been made in our understanding of the molecular mechanisms that regulate the transmission process, and the influence of the host cell on the conformation and properties of pathological seeds. The aim of this Review is to summarize our current knowledge of the cell-to-cell transmission of pathological proteins and to identify key questions for future investigation.}, } @article {pmid32203395, year = {2020}, author = {Fyfe, I}, title = {Closer to a blood test for Alzheimer disease.}, journal = {Nature reviews. Neurology}, volume = {16}, number = {5}, pages = {241}, doi = {10.1038/s41582-020-0347-1}, pmid = {32203395}, issn = {1759-4766}, } @article {pmid32203153, year = {2020}, author = {Nitsche, A and Arnold, C and Ueberham, U and Reiche, K and Fallmann, J and Hackermüller, J and Horn, F and Stadler, PF and Arendt, T}, title = {Alzheimer-related genes show accelerated evolution.}, journal = {Molecular psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41380-020-0680-1}, pmid = {32203153}, issn = {1476-5578}, support = {SPP1738//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; AR 200/17-1//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; HA 5857/2-1//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; STA 850/19-1//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder of unknown cause with complex genetic and environmental traits. While AD is extremely prevalent in human elderly, it hardly occurs in non-primate mammals and even non-human-primates develop only an incomplete form of the disease. This specificity of AD to human clearly implies a phylogenetic aspect. Still, the evolutionary dimension of AD pathomechanism remains difficult to prove and has not been established so far. To analyze the evolutionary age and dynamics of AD-associated-genes, we established the AD-associated genome-wide RNA-profile comprising both protein-coding and non-protein-coding transcripts. We than applied a systematic analysis on the conservation of splice-sites as a measure of gene-structure based on multiple alignments across vertebrates of homologs of AD-associated-genes. Here, we show that nearly all AD-associated-genes are evolutionarily old and did not originate later in evolution than not-AD-associated-genes. However, the gene-structures of loci, that exhibit AD-associated changes in their expression, evolve faster than the genome at large. While protein-coding-loci exhibit an enhanced rate of small changes in gene structure, non-coding loci show even much larger changes. The accelerated evolution of AD-associated-genes indicates a more rapid functional adaptation of these genes. In particular AD-associated non-coding-genes play an important, as yet largely unexplored, role in AD. This phylogenetic trait indicates that recent adaptive evolution of human brain is causally involved in basic principles of neurodegeneration. It highlights the necessity for a paradigmatic change of our disease-concepts and to reconsider the appropriateness of current animal-models to develop disease-modifying strategies that can be translated to human.}, } @article {pmid32202739, year = {2019}, author = {Stavrovskaya, AV and Voronkov, DN and Shestakova, EA and Gushchina, AS and Olshansky, AS and Yamshikova, NG}, title = {[Streptozocin-induced Alzheimer's disease as an independent risk factor for the development of hyperglycemia in Wistar rats].}, journal = {Problemy endokrinologii}, volume = {65}, number = {5}, pages = {351-361}, doi = {10.14341/probl12126}, pmid = {32202739}, issn = {2308-1430}, abstract = {BACKGROUND: In recent years the theme of the relationship of Alzheimers disease (AD) and metabolic disorders has been widely discussed. Nevertheless, it remains unclear whether AD is a direct cause of carbohydrate metabolism disorders or it is the presence of classical risk factors for type 2 diabetes mellitus (DM 2), primarily obesity, that significantly increases the risk of AD.

AIM: To evaluate the separate contribution of two factors to the development of disorders of carbohydrate metabolism: (1) weight gain due to a high-calorie diet and (2) experimental-induced AD.

METHODS: Male Wistar rats were injected with streptozocin (STZ) in the lateral ventricles of the brain to induce AD or saline (sham operated animals - SO) during stereotactic operations. After 2 weeks, the animals were divided into four groups: 1) the SO group, which was assigned to the normal calorie (NCD) diet (SO NCD); 2) the SO group, which was assigned to the high-calorie diet (SO HCD); 3) the group to which the norm-calorie diet was prescribed after the administration of STZ into the lateral ventricles of the brain (STZ NCD); 4) the group to which the HCD was assigned after the administration of STZ (STZ HCD). The animals were on a diet for 3 months. Intraperitoneal glucose tolerance tests were carried out before the diet and after 3 months. At the end of the study, a morphological assessment of brain tissue, pancreas, and liver was performed.

RESULTS: 3 months after surgical interventions and the appointment of diets, the glycemic curves significantly differed in the 4 studied groups: normoglycemia persisted only in the SO + NCD group, while HCD and the STZ administration were accompanied by the development of hyperglycemia (p = 0.0001). The STZ + NСD group, which represented the isolated effect of AD, was also characterized by impaired carbohydrate metabolism. A morphological study showed that HCD leads to a more pronounced ectopic accumulation of fat in the liver and pancreas tissue than NCD. The administration of STZ, regardless of the diet, led to changes typical for the AD model an increase in the size of the ventricles of the brain, degeneration of white matter, and the accumulation of -amyloid in the hypothalamus.

CONCLUSIONS: The STZ-induced brain damage typical for AD led to impaired carbohydrate metabolism regardless of diet and was an independent risk factor for hyperglycemia.}, } @article {pmid32202593, year = {2020}, author = {André, C and Rehel, S and Kuhn, E and Landeau, B and Moulinet, I and Touron, E and Ourry, V and Le Du, G and Mézenge, F and Tomadesso, C and de Flores, R and Bejanin, A and Sherif, S and Delcroix, N and Manrique, A and Abbas, A and Marchant, NL and Lutz, A and Klimecki, OM and Collette, F and Arenaza-Urquijo, EM and Poisnel, G and Vivien, D and Bertran, F and de la Sayette, V and Chételat, G and Rauchs, G and , }, title = {Association of Sleep-Disordered Breathing With Alzheimer Disease Biomarkers in Community-Dwelling Older Adults: A Secondary Analysis of a Randomized Clinical Trial.}, journal = {JAMA neurology}, volume = {}, number = {}, pages = {}, pmid = {32202593}, issn = {2168-6157}, abstract = {Importance: Increasing evidence suggests that sleep-disordered breathing (SDB) increases the risk of developing Alzheimer clinical syndrome. However, the brain mechanisms underlying the link between SDB and Alzheimer disease are still unclear.

Objective: To determine which brain changes are associated with the presence of SDB in older individuals who are cognitively unimpaired, including changes in amyloid deposition, gray matter volume, perfusion, and glucose metabolism.

This cross-sectional study was conducted using data from the Age-Well randomized clinical trial of the Medit-Ageing European project, acquired between 2016 and 2018 at Cyceron Center in Caen, France. Community-dwelling older adults were assessed for eligibility and were enrolled in the Age-Well clinical trial if they did not meet medical or cognitive exclusion criteria and were willing to participate. Participants who completed a detailed neuropsychological assessment, polysomnography, a magnetic resonance imaging, and florbetapir and fluorodeoxyglucose positron emission tomography scans were included in the analyses.

Main Outcomes and Measures: Based on an apnea-hypopnea index cutoff of 15 events per hour, participants were classified as having SDB or not. Voxelwise between-group comparisons were performed for each neuroimaging modality, and secondary analyses aimed at identifying which SDB parameter (sleep fragmentation, hypoxia severity, or frequency of respiratory disturbances) best explained the observed brain changes and assessing whether SDB severity and/or SDB-associated brain changes are associated with cognitive and behavioral changes.

Results: Of 157 participants initially assessed, 137 were enrolled in the Age-Well clinical trial, and 127 were analyzed in this study. The mean (SD) age of the 127 participants was 69.1 (3.9) years, and 80 (63.0%) were women. Participants with SDB showed greater amyloid burden (t114 = 4.51; familywise error-corrected P = .04; Cohen d, 0.83), gray matter volume (t119 = 4.12; familywise error-corrected P = .04; Cohen d, 0.75), perfusion (t116 = 4.62; familywise error-corrected P = .001; Cohen d, 0.86), and metabolism (t79 = 4.63; familywise error-corrected P = .001; Cohen d, 1.04), overlapping mainly over the posterior cingulate cortex and precuneus. No association was found with cognition, self-reported cognitive and sleep difficulties, or excessive daytime sleepiness symptoms.

Conclusions and Relevance: The SDB-associated brain changes in older adults who are cognitively unimpaired include greater amyloid deposition and neuronal activity in Alzheimer disease-sensitive brain regions, notably the posterior cingulate cortex and precuneus. These results support the need to screen and treat for SDB, especially in asymptomatic older populations, to reduce Alzheimer disease risk.

Trial Registration: ClinicalTrials.gov Identifier: NCT02977819.}, } @article {pmid32201261, year = {2020}, author = {Kakuda, N and Yamaguchi, H and Akazawa, K and Hata, S and Suzuki, T and Hatsuta, H and Murayama, S and Funamoto, S and Ihara, Y}, title = {γ-Secretase Activity Is Associated with Braak Senile Plaque Stages.}, journal = {The American journal of pathology}, volume = {190}, number = {6}, pages = {1323-1331}, doi = {10.1016/j.ajpath.2020.02.009}, pmid = {32201261}, issn = {1525-2191}, abstract = {Amyloid β-proteins (Aβs) Aβ1-42 and Aβ1-43 are converted via two product lines of γ-secretase to Aβ1-38 and Aβ1-40. This parallel stepwise processing model of γ-secretase predicts that Aβ1-42 and Aβ1-43, and Aβ1-38 and Aβ1-40 are proportional to each other, respectively. To obtain further insight into the mechanisms of parenchymal Aβ deposition, these four Aβ species were quantified in insoluble fractions of human brains (Brodmann areas 9 to 11) at various Braak senile plaque (SP) stages, using specific enzyme-linked immunosorbent assays. With advancing SP stages, the amounts of deposited Aβ1-43 in the brain increased proportionally to those of Aβ1-42. Similarly, the amounts of deposited Aβ1-38 correlated with those of Aβ1-40. Surprisingly, the ratios of deposited Aβ1-38/Aβ1-42 and Aβ1-40/Aβ1-43 were proportional and discriminated the Braak SP stages accurately. This result indicates that the generation of Aβ1-38 and Aβ1-40 decreased and the generation of Aβ1-42 and Aβ1-43 increased with advancing SP stages. Thus, Aβs deposition might depend on γ-secretase activity, as it does in the cerebrospinal fluid. Here, the extracted γ-secretase from Alzheimer disease brains generates an amount of Aβ1-42 and Aβ1-43 compared with cognitively normal brains. This refractory γ-secretase localized in detergent-solubilized fractions from brain cortices. But activity modulated γ-secretase, which decreases Aβ1-42 and Aβ1-43 in the cerebrospinal fluid, localized in detergent-insoluble fractions. These drastic alterations reflect Aβ situation in Alzheimer disease brains.}, } @article {pmid32201219, year = {2020}, author = {Tower, J and Pomatto, LCD and Davies, KJA}, title = {Sex differences in the response to oxidative and proteolytic stress.}, journal = {Redox biology}, volume = {31}, number = {}, pages = {101488}, pmid = {32201219}, issn = {2213-2317}, abstract = {Sex differences in diseases involving oxidative and proteolytic stress are common, including greater ischemic heart disease, Parkinson disease and stroke in men, and greater Alzheimer disease in women. Sex differences are also observed in stress response of cells and tissues, where female cells are generally more resistant to heat and oxidative stress-induced cell death. Studies implicate beneficial effects of estrogen, as well as cell-autonomous effects including superior mitochondrial function and increased expression of stress response genes in female cells relative to male cells. The p53 and forkhead box (FOX)-family genes, heat shock proteins (HSPs), and the apoptosis and autophagy pathways appear particularly important in mediating sex differences in stress response.}, } @article {pmid32200213, year = {2020}, author = {Lyu, M and Liu, H and Ye, Y and Yin, Z}, title = {Inhibition effect of thiol-type antioxidants on protein oxidative aggregation caused by free radicals.}, journal = {Biophysical chemistry}, volume = {260}, number = {}, pages = {106367}, doi = {10.1016/j.bpc.2020.106367}, pmid = {32200213}, issn = {1873-4200}, abstract = {This study was aimed to investigate the inhibition effect of thiol-type antioxidants on protein oxidative aggregation caused by free radicals and the underlying mechanisms using six different thiol-type antioxidants (N-acetyl-L-cysteine, methionine, taurine, alpha-lipoic acid, glutathione and thioproline), Cu2+-H2O2 as a free radical generator (mainly a hydroxyl radical generator) and bovine serum albumin as the model protein. The inhibition effect of these antioxidants on protein oxidative aggregation and protective effect against oxidative damage in mouse brain tissues were investigated using SDS-PAGE, intrinsic fluorescence, simultaneous fluorescence, thioflavin T fluorescence, Congo red absorbance and inverted microscope. The results showed that all six antioxidants could inhibit protein oxidative aggregation by scavenging free radicals. In addition, alpha-lipoic acid could also bind to proteins via hydrophobic interactions and thioproline could bind to proteins via hydrogen bonds and van der Waals forces, thereby showing much stronger inhibition effect than others. Moreover, alpha-lipoic acid and thioproline could effectively prevent oxidative damage of mouse brain tissues. These results suggest that alpha-lipoic acid and thioproline can effectively inhibit free radical-induced protein aggregation and brain damage, which are worth testing for further anti-Alzheimer properties.}, } @article {pmid32199815, year = {2020}, author = {Eckert, GP and Eckert, SH and Eckmann, J and Hagl, S and Muller, WE and Friedland, K}, title = {Olesoxime improves cerebral mitochondrial dysfunction and enhances Aβ levels in preclinical models of Alzheimer's disease.}, journal = {Experimental neurology}, volume = {329}, number = {}, pages = {113286}, doi = {10.1016/j.expneurol.2020.113286}, pmid = {32199815}, issn = {1090-2430}, abstract = {BACKGROUND: Approved drugs for Alzheimer's disease (AD) only have a symptomatic effects and do not intervene causally in the course of the disease. Olesoxime (TRO19622) has been tested in AD disease models characterized by improved amyloid precursor protein processing (AβPP) and mitochondrial dysfunction.

METHODS: Three months old Thy-1-AβPPSL (tg) and wild type mice (wt) received TRO19622 (100 mg/kg b.w.) in supplemented food pellets for 15 weeks (tg TRO19622). Mitochondrial membrane potential (MMP) and adenosine triphosphate (ATP) levels were determined in dissociated brain cells (DBC). Respiration was analyzed in mitochondria isolated from brain tissue. Citrate synthase (CS) activity and beta-amyloid peptide (Aβ1-40) levels were determined in brain tissue. Malondialdehyde (MDA) levels were determined as an indicator for lipid peroxidation. DBC and brain homogenates were additionally stressed with Rotenone and FeCl2, respectively. Mitochondrial respiration and Aβ1-40 levels were also determined in HEK-AβPPsw-cells.

RESULTS: Treatment of mice did not affect the body weight. TRO19622 was absorbed after oral treatment (plasma levels: 6,2 μg/ml). Mitochondrial respiration was significantly reduced in brains of tg-mice. Subsequently, DBC isolated from brains of tg-mice showed significantly lower MMP but not ATP levels. TRO19622 increased the activity of respiratory chain complexes and reversed complex IV (CIV) activity and MMP. Moreover, DBC isolated from brains of tg TRO19622 mice were protected from Rotenone induced inhibition of complex I activity. TRO19622 also increased the respiratory activity in HEKsw-cells. MDA basal levels were significantly higher in brain homogenates isolated from tg-mice. TRO19622 treatment had no effects on lipid peroxidation. TRO19622 increased cholesterol levels but did not change membrane fluidity of synaptosomal plasma and mitochondrial membranes isolated from brain of mice. TRO19622 significantly increased levels of Aβ1-40 in both, in brains of tg TRO19622 mice and in HEKsw cells.

CONCLUSIONS: TRO19622 improves mitochondrial dysfunction but enhances Aβ levels in disease models of AD. Further studies must evaluate whether TRO19622 offers benefits at the mitochondrial level despite the increased formation of Aβ, which could be harmful.}, } @article {pmid32198562, year = {2020}, author = {Riancho, J and Sanchez de la Torre, JR and Paz-Fajardo, L and Limia, C and Santurtun, A and Cifra, M and Kourtidis, K and Fdez-Arroyabe, P}, title = {The role of magnetic fields in neurodegenerative diseases.}, journal = {International journal of biometeorology}, volume = {}, number = {}, pages = {}, doi = {10.1007/s00484-020-01896-y}, pmid = {32198562}, issn = {1432-1254}, abstract = {The term neurodegenerative diseases include a long list of diseases affecting the nervous system that are characterized by the degeneration of different neurological structures. Among them, Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS) are the most representative ones. The vast majority of cases are sporadic and results from the interaction of genes and environmental factors in genetically predisposed individuals. Among environmental conditions, electromagnetic field exposure has begun to be assessed as a potential risk factor for neurodegeneration. In this review, we discuss the existing literature regarding electromagnetic fields and neurodegenerative diseases. Epidemiological studies in AD, PD, and ALS have shown discordant results; thus, a clear correlation between electromagnetic exposure and neurodegeneration has not been demonstrated. In addition, we discuss the role of electromagnetic radiation as a potential non-invasive therapeutic strategy for some neurodegenerative diseases, particularly for PD and AD.}, } @article {pmid32196752, year = {2020}, author = {Dyer, AH and Lawlor, B and Kennelly, SP and , }, title = {Sexual dimorphism in the association of APOE ε4 genotype with cognitive decline and dementia progression in mild-to-moderate Alzheimer disease.}, journal = {International journal of geriatric psychiatry}, volume = {35}, number = {6}, pages = {683-686}, doi = {10.1002/gps.5294}, pmid = {32196752}, issn = {1099-1166}, } @article {pmid32195836, year = {2020}, author = {Lektemur Alpan, A and Çalişir, M and Kizildağ, A and Özdede, M and Özmen, Ö}, title = {Effects of a Glycogen Synthase Kinase 3 Inhibitor Tideglusib on Bone Regeneration With Calvarial Defects.}, journal = {The Journal of craniofacial surgery}, volume = {}, number = {}, pages = {}, doi = {10.1097/SCS.0000000000006326}, pmid = {32195836}, issn = {1536-3732}, abstract = {Tideglusib is a glycogen synthase kinase 3 (GSK-3) inhibitor which has shown the effects of bone regeneration, used for the treatment of Alzheimer disease. The aim of the study was to determine the effects of Tideglusib in the apoptosis and the bone regeneration in rats with calvarial defects. Twenty male Wistar rats (aged 11-13 weeks) were used for the study. Full-thickness flap elevated to exposure calvarial bone. Two 5 mm critical size calvarial defects were created on each rat calvarium. The defects were divided into 4 study groups: 1-Control (n = 10); 2- Gelatin sponge+Tideglusib (Gs+TDG; n = 10); 3- Autogenous bone (AB; n = 10); 4-Autogenous bone+Tideglusib (AB+TDG; n = 10). Then, the rats were sacrificed at fourth week. Three-dimensional imaging, histopathologic and immunohistochemical examinations were performed to evaluate the samples. The most increased bone formation and interaction between graft and new bone were observed in AB+TDG group. Bone morphogenic protein-2 (BMP-2), alkaline phosphatase (ALP), collagen type 1 (Col 1) and osteocalcin (OCN) was determined significantly higher in Tideglusib received groups compared with those of Control and AB groups (P < 0.05). Osteoclast numbers found to be higher in Gs+TDG and AB+TDG groups as well as RANKL expression dis not affected in Gs+TDG group but decreased in AB+TDG group comparing those of Control and AB groups. In addition, Tideglusib increased the Bcl-2 levels (P < 0.05) and decreased Bax levels (P > 0.05) in Tideglusib received groups compared with their controls. The administration of Tideglusib in calvarial bone defects increased bone mineral density, new bone area and total bone area by decreasing apoptosis and increasing osteoblastogenesis.}, } @article {pmid32194370, year = {2020}, author = {Giorgio, A and Zhang, J and Costantino, F and De Stefano, N and Frezzotti, P}, title = {Altered Large-Scale Brain Functional Connectivity in Ocular Hypertension.}, journal = {Frontiers in neuroscience}, volume = {14}, number = {}, pages = {146}, pmid = {32194370}, issn = {1662-4548}, abstract = {We hypothesized that assessment of brain connectivity may shed light on the underpinnings of ocular hypertension (OHT), characterized by raised intraocular pressure (IOP) and no typical glaucomatous findings. OHT carries a risk for future glaucoma development, thus representing a model of presymptomatic condition. In previous studies on glaucoma, we showed altered brain connectivity since the early stage and in case of normal IOP. In this pilot study, we used a multimodal MRI approach by modeling voxelwise measures of gray matter volume, anatomical connectivity along white matter(WM) tracts, and large-scale functional connectivity in OHT subjects (n = 18, age: 58.3 ± 9.8 years) and demographically matched normal controls (n = 29). While OHT brain had no structural alterations, it showed significantly decreased functional connectivity in key cognitive networks [default mode network, frontoparietal working memory network (WMN), ventral attention network (VAN), and salience network (SN)] and altered long-range functional connectivity, which was decreased between default mode and SNs and increased between primary and secondary visual networks (VN). Overall, such findings seem to delineate a complex neuroplasticity in the OHT brain, where decreased functional connectivity in non-visual networks may reflect a type of temporarily downregulated functional reserve while increased functional connectivity between VN may be viewed as a very early attempt of adaptive functional reorganization of the visual system.}, } @article {pmid32193491, year = {2020}, author = {Pastore, A and Raimondi, F and Rajendran, L and Temussi, PA}, title = {Why does the Aβ peptide of Alzheimer share structural similarity with antimicrobial peptides?.}, journal = {Communications biology}, volume = {3}, number = {1}, pages = {135}, pmid = {32193491}, issn = {2399-3642}, abstract = {The Aβ peptides causally associated with Alzheimer disease have been seen as seemingly purposeless species produced by intramembrane cleavage under both physiological and pathological conditions. However, it has been increasingly suggested that they could instead constitute an ancient, highly conserved effector component of our innate immune system, dedicated to protecting the brain against microbial attacks. In this antimicrobial protection hypothesis, Aβ aggregation would switch from an abnormal stochastic event to a dysregulated innate immune response. In this perspective, we approach the problem from a different and complementary perspective by comparing the structure and sequence of Aβ(1-42) with those of bona fide antimicrobial peptides. We demonstrate that Aβ(1-42) bears convincing structural similarities with both viral fusion domains and antimicrobial peptides, as well as sequence similarities with a specific family of bacterial bacteriocins. We suggest a model of the mechanism by which Aβ peptides could elicit the immune response against microbes.}, } @article {pmid32190891, year = {2020}, author = {Semba, RD}, title = {Perspective: The Potential Role of Circulating Lysophosphatidylcholine in Neuroprotection against Alzheimer Disease.}, journal = {Advances in nutrition (Bethesda, Md.)}, volume = {}, number = {}, pages = {}, doi = {10.1093/advances/nmaa024}, pmid = {32190891}, issn = {2156-5376}, abstract = {Alzheimer disease (AD), the most common cause of dementia, is a progressive disorder involving cognitive impairment, loss of learning and memory, and neurodegeneration affecting wide areas of the cerebral cortex and hippocampus. AD is characterized by altered lipid metabolism in the brain. Lower concentrations of long-chain PUFAs have been described in the frontal cortex, entorhinal cortex, and hippocampus in the brain in AD. The brain can synthesize only a few fatty acids; thus, most fatty acids must enter the brain from the blood. Recent studies show that PUFAs such as DHA (22:6) are transported across the blood-brain barrier (BBB) in the form of lysophosphatidylcholine (LPC) via a specific LPC receptor at the BBB known as the sodium-dependent LPC symporter 1 (MFSD2A). Higher dietary PUFA intake is associated with decreased risk of cognitive decline and dementia in observational studies; however, PUFA supplementation, with fatty acids esterified in triacylglycerols did not prevent cognitive decline in clinical trials. Recent studies show that LPC is the preferred carrier of PUFAs across the BBB into the brain. An insufficient pool of circulating LPC containing long-chain fatty acids could potentially limit the supply of long-chain fatty acids to the brain, including PUFAs such as DHA, and play a role in the pathobiology of AD. Whether adults with low serum LPC concentrations are at greater risk of developing cognitive decline and AD remains a major gap in knowledge. Preventing and treating cognitive decline and the development of AD remain a major challenge. The LPC pathway is a promising area for future investigators to identify modifiable risk factors for AD.}, } @article {pmid32190507, year = {2020}, author = {Rashid, MH and Zahid, MF and Zain, S and Kabir, A and Hassan, SU}, title = {The Neuroprotective Effects of Exercise on Cognitive Decline: A Preventive Approach to Alzheimer Disease.}, journal = {Cureus}, volume = {12}, number = {2}, pages = {e6958}, pmid = {32190507}, issn = {2168-8184}, abstract = {Alzheimer's disease (AD) is a progressive disorder that causes brain cells to slowly degenerate and die. This leads to a continuous decline in thinking, behavioral and social skills that disrupts a person's ability to function independently. AD is the most common cause of dementia globally. Neuroinflammation caused by intracellular neurofibrillary tangles and extracellular amyloid deposits leads to atrophy of brain cells especially the hippocampus, which is associated with memory formation. This atrophy leads to dementia and cognitive decline. Among the many preventive factors being studied, exercise is thought to play a vital role in not only preventing the pre-clinical stage of AD but also slowing the clinical progression of AD. It is also deployed as a treatment option for late-stage AD along with pharmacological treatment options. Various studies and clinical trials in both human and animal models are of the opinion that exercise slows the onset and progression of cognitive decline in AD patients. Some studies suggest that this effect is due to a decrease in neurofibrillary tangles and amyloid deposits in brain parenchyma. Others suggest that exercise causes an increase in angiogenesis, neurogenesis, and synaptogenesis mainly due to an increase in blood flow, brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), hormones, and second messengers.}, } @article {pmid32190448, year = {2020}, author = {Aljanabi, NM and Mamtani, S and Al-Ghuraibawi, MMH and Yadav, S and Nasr, L}, title = {Alzheimer's and Hyperglycemia: Role of the Insulin Signaling Pathway and GSK-3 Inhibition in Paving a Path to Dementia.}, journal = {Cureus}, volume = {12}, number = {2}, pages = {e6885}, pmid = {32190448}, issn = {2168-8184}, abstract = {In this project, we are trying to review the articles that discuss the relationship between insulin signaling and Alzheimer's disease (AD). Another focus of this project is to find the best treatment regimen that can reduce the progression of AD in patients with impaired glucose metabolism. We used Pubmed database to collect our data and used the following keywords: Alzheimer's disease, insulin signaling pathway, type 3 diabetes, type 2 diabetes, insulin, and insulin resistance in our revision; we included free articles that were published in the last 10 years and excluded articles that were written in any language other than English. We reviewed 68 articles. Forty-nine out of 68 articles were containing materials that are relevant for this project. We found that there is a relation between AD and the insulin signaling pathway. Insulin signaling pathway impairment leads to hyperphosphorylation of Tau protein, which plays a vital role in AD pathology. The effect of insulin on cognition is bidirectional; the intranasal route of insulin showed to have a promising effect on cognition improvement. Subcutaneous and intravenous insulin can increase the risk of dementia. Further studies are encouraged to use a specific anti-diabetic medication that can reduce the progression of AD.}, } @article {pmid32186726, year = {2020}, author = {Gauthreaux, K and Bonnett, TA and Besser, LM and Brenowitz, WD and Teylan, M and Mock, C and Chen, YC and Chan, KCG and Keene, CD and Zhou, XH and Kukull, WA}, title = {Concordance of Clinical Alzheimer Diagnosis and Neuropathological Features at Autopsy.}, journal = {Journal of neuropathology and experimental neurology}, volume = {79}, number = {5}, pages = {465-473}, pmid = {32186726}, issn = {1554-6578}, support = {U01 AG016976/AG/NIA NIH HHS/United States ; }, abstract = {It remains unclear what clinical features inform the accuracy of a clinical diagnosis of Alzheimer disease (AD). Data were obtained from the National Alzheimer's Coordinating Center to compare clinical and neuropathologic features among participants who did or did not have Alzheimer disease neuropathologic changes (ADNC) at autopsy. Participants (1854) had a clinical Alzheimer dementia diagnosis and ADNC at autopsy (Confirmed-AD), 204 participants had an AD diagnosis and no ADNC (AD-Mimics), and 253 participants had no AD diagnosis and ADNC (Unidentified-AD). Compared to Confirmed-AD participants, AD-Mimics had less severe cognitive impairment, while Unidentified-AD participants displayed more parkinsonian signs, depression, and behavioral problems. This study highlights the importance of developing a complete panel of biomarkers as a tool to inform clinical diagnoses, as clinical phenotypes that are typically associated with diseases other than AD may result in inaccurate diagnoses.}, } @article {pmid32186116, year = {2019}, author = {Chi, H and Liu, T and Pan, W and Chen, J and Wu, B and Yu, Z and Chen, C}, title = {Shen-Zhi-Ling oral solution improves learning and memory ability in Alz