bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigating astrocytes as mediators of tau spread
Authors: Reid Matthew J ,   Wendy Noble Research Group
Published: December 2020

AbstractBackgroundHighly phosphorylated tau aggregates are believed to spread in a prion‐like manner through tauopathy brain. We set out to determine the characteristics of tau deposition in mice expressing wild‐type human 3R and 4R tau, following peripheral injection of tau extracts from different tauopathies. Tau accumulations identified around astrocytes in the experimental mice prompted us to develop a human astrocyte culture model to further investigate tau uptake and spread.MethodTau was isolated from human postmortem control (CTRL), Alzheimer’s disease (AD), progressive supranuclear palsy (PSP) and Pick’s disease (PiD) brain. Extracts were injected intraperitoneally into 4‐month old wild‐type and htau mice, and at 18 month‐of‐age tissue was collected for biochemical and immunohistochemical assessment.Human iPSCs were directed into neural progenitor cells and terminally plated as astrocytes using a previously established protocol. Astrocytes were characterised using RT‐qPCR and immunocytochemical assessment. Cultures were spiked with the previously derived pathogenic tau isolated from human tissue. Cells were analysed immunocytochemically for tau uptake.ResultWe found that peripheral injection of brain extracts from AD, PSP and PiD brain results in regional differences in the patterns of tau aggregate accumulation in the mouse brain. Some tau pathology was associated with ‘activated’ astrocytes, similar to the pathology observed in the corresponding human postmortem brain. Cultures of human astrocytes that express mature cell markers were established.ConclusionOur data suggests that neurons in different regions are susceptible to different species of tau aggregates. It is possible that this might hint towards selective vulnerability in different tauopathies. The association of tau pathology with astrocytes in some cases suggests that astrocytes may play a role in tau spread. Our human astrocyte cultures will provide a model to determine how astrocytes may facilitate the spread of tau and potentially contribute to selective regional vulnerability in tauopathies.
Targeting porphyromonas gingivalis to treat Alzheimer’s disease and comorbid cardiovascular disease
Authors: Ermini Florian , Rojas Paola , Dean Afsah , Stephens Danielle , Patel Michele , Haditsch Ursula , Roth Theresa , Rodriguez Leo , Broce Sean , Raha Debasish , Nguyen Mai , Kapur Shirin , Lynch Casey C , Dominy Stephen S , Holsinger Leslie J , Hasturk Hatice 
Published: December 2020

AbstractBackgroundWe recently demonstrated the presence of the bacterial pathogen, Porphyromonas gingivalis (Pg), and its protease virulence factors, known as gingipains, in greater than 90% of AD brains. Brain gingipain levels significantly correlated with AD diagnosis and tau and ubiquitin pathology. Mechanistic studies in wild type mice demonstrated that Pg invades the brain after infection of the oral cavity, resulting in the development of neuropathology consistent with that of AD. These effects were blocked in mice after oral administration of the gingipain inhibitor COR388. In addition to neuropathology, AD is often accompanied by the comorbidity of cardiovascular disease. Pg has been linked to the development of atherosclerosis and the bacteria are found abundant within atheromatous plaque. We investigated if COR388 was efficacious in treating Pg‐accelerated atherosclerosis in a rabbit model.MethodEighteen New Zealand White rabbits on a 13‐week regimen of 0.5% cholesterol diet to induce atherosclerosis were randomized in the study. Twelve rabbits were orally infected with Pg 3x/week for 6 weeks for oral disease induction and 6 rabbits were sham‐infected. Six Pg –infected rabbits were orally administered COR388 10mg/kg once daily for the entire 13 weeks of the study (prevention protocol), and 6 Pg‐infected rabbits received vehicle for 13 weeks. Six sham‐infected rabbits received vehicle for 13 weeks. At 13 weeks, atherosclerotic plaques were quantified by assessing Sudan IV staining, histology, and ex vivo MRI. Serum levels of C‐reactive protein (CRP) were evaluated as a measure of systemic inflammation.ResultPg‐infected rabbits exhibited accelerated atherosclerotic disease severity than sham‐infected animals. COR388 diminished this atherogenesis compared to vehicle controls as evidenced by significantly less arterial plaque and a lower intima/media ratio. COR388 treatment also significantly reduced systemic levels of CRP.ConclusionCOR388, a novel lysine‐gingipain inhibitor, is currently being tested in a Phase 2/3 clinical trial to target Pg for the treatment of AD. Based on the current preclinical data reported here, COR388 has the potential to attenuate atheroma formation and systemic inflammation in Pg‐ induced atherosclerosis and therefore may have beneficial effects on comorbid cardiovascular disease in Pg‐associated AD.
A patient journey analysis: Identification and treatment of dementia with Lewy bodies
Authors: Abler Victor , Rashid Nazia , Skoog Ben , Halpern Rachel , Bunner Scott , Frazer Monica S. 
Published: December 2020

AbstractBackgroundBetween 3.2%‐7.1% of dementia patients are diagnosed with DLB. There is limited research on the identification and treatment of DLB, indicating an unmet need for this condition.[2] [1] Hogan D, Fiest K, Roberts J, Maxwell C, Dykeman J, Pringsheim T, Jetté N. (2016). The Prevalence and Incidence of Dementia with Lewy Bodies: A Systematic Review. Canadian Journal of Neurological Sciences / Journal Canadien Des Sciences Neurologiques, 43(S1), S83‐S95. doi:10.1017/cjn.2016.2. [2] Monfared A, Meier G, Perry R, Joe D. Burden of disease and current management of Dementia with Lewy Bodies: a literature review. Neurol Ther, 2019, 8:289‐305.MethodThis claims‐data analysis examined commercial and Medicare Advantage with Part D (MAPD) enrollees aged ≥40 years with ≥2 DLB diagnoses from 01Jun2016–31May2018. The earliest DLB diagnosis was the index date. Continuous insurance enrollment was required from 24 months before to 12 months after index. Patient characteristics, diagnoses, medication utilization, symptoms (e.g. behavioral, movement changes), and imaging tests were measured in 6‐month periods pre‐ and post‐index.ResultThe 974 patients identified had mean age of 78.3 years, were 56.6% male, 90.0% were MAPD enrollees, and had a mean Charlson comorbidity score of 2.87 (SD=2.05). Generally, percentages of patients with ≥1 diagnosis in a dementia or symptom change category or with ≥1 pharmacy fill for an antipsychotic or behavioral health (BH) medication (e.g., antidepressants, anxiolytics) trended higher in each 6‐month period prior to index date, were highest in the 6 months beginning on index, and decreased slightly 7‐12 months post‐index. Across periods, 31%‐90% of patients had multiple types of dementia diagnoses. BH medications (52.4%‐63.9% with ≥1 BH medication fill across periods) were prescribed to DLB patients more often than were antipsychotics (14.2%‐31.5% with ≥1 antipsychotic fill). CT scans (10.6%‐27.5%) and MRIs (5.3%‐13.0%) were the most prevalent imaging tests.ConclusionPercentages of patients with imaging tests, DLB symptoms, diagnoses and treatments for DLB increased as patients’ first DLB diagnosis neared and occurred at lower percentages 7‐12 months after initial diagnosis.
Healthcare costs among patients with dementia‐related psychosis: Comparing dementia with Lewy bodies with other dementias
Authors: Abler Victor , Rashid Nazia , Skoog Ben , Halpern Rachel , Bunner Scott , Frazer Monica S 
Published: December 2020

AbstractBackgroundDLB is the second‐most common form of degenerative dementia and it’s unclear whether healthcare costs differ for patients with DLB and Alzheimer’s disease. [1],[2]. The differential presentation of psychosis among dementias[3] may affect healthcare costs. [1] Bostrom F, Jonsson L, Minthon L, Londos E. Patients with Lewy body dementia use more resources than those with Alzheimer’s disease. Int J Geriatr Psychiatry 2007;22(8):713‐719. [2] Zhu CW, Scarmeas N, Stavitsky D, Albert M, Brandt J, Blacker D, Sano M, Stern Y. Comparison of costs of care between patients with Alzheimer’s disease and dementia with Lewy Bodies, Alzheimer’s Dementia, July 2008; 4(4):280‐284. [3] Tzeng R, Tsai C, Wang C, Wang T, Chiu P. Delusions in patients with dementia with Lewy bodies and the associated factors. Behavioural Neurology, 2018:1‐8.MethodThis claims data analysis examined commercial and Medicare Advantage with Part D (MAPD) enrollees aged ≥40 years with evidence of psychosis (antipsychotic (AP) treatment lasting ≥45 days or ≥1 AP pharmacy fill+≥1 psychosis diagnosis) and ≥2 diagnoses for the same type of dementia from 01Jun2016–31May2018. The earliest AP fill was the index date. Continuous insurance enrollment was required for 12 months before and after index. DRP and DLB patients were matched 1:1. Patient characteristics and healthcare costs were analyzed descriptively.ResultMatched DLB and DRP cohorts (n=442 each) had average age of 78.3 years, were 53.6% male, and 89.8% had MAPD coverage. 44% of DRP patients had ≥2 Alzheimer’s diagnoses and 32% had ≥2 unspecified dementia diagnoses. DLB patients had a significant pre‐index to post‐index increase for total all‐cause healthcare costs (from $5,392 to $8,046, p<0.01) while pre/post differences among DRP patients were not significant. DLB patients had significantly higher mean post‐index pharmacy costs for all‐cause ($6,616 vs. $4,515), dementia‐related ($810 vs. $675) and psychosis‐related ($2,344 vs. $623) medications, and higher mean psychosis‐related total healthcare costs ($5,801 vs. $2,687) than DRP.ConclusionDLB patients had higher medication and psychosis‐related costs than DRP patients who had other dementias.
Dually targeting human soluble epoxide hydrolase and P38 kinase to prevent neuroinflammation for the treatment of Alzheimer’s disease
Authors: Liang Zhibin , Zhang Bei , Xu Meng , Morisseau Christophe , Hwang Sung Hee , Hammock Bruce D. , Li Qing X. 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is a complex neurodegenerative disorder with no cures. While many pathological characteristics occur in the AD brain, neuroinflammation is a prevalent pathogenic stress that leads to neuronal death in AD. Targeting the brain inflammation to keep neurons alive is an attractive therapeutic strategy for AD. TPPU is a potent inhibitor of soluble epoxide hydrolase (sEH) and can enter into the brain. It has a good efficacy on many chronic inflammatory diseases in preclinical animal models ranging from mice to nonhuman primates. For central nervous system disorders, TPPU shows therapeutic effects in rodent models of neuropsychiatric syndromes associated with inflammation such as stroke, seizure, depression, and Parkinson’s disease. However, the anti‐neuroinflammatory effects and underlying mechanisms of TPPU for potential AD interventions remain elusive.MethodsWith an aim to develop multi‐targeted therapeutics for AD, TPPU was screened in enzymatic assays against sEHs from different mammalian species and a broad panel of human kinases for potential new targets relevant to neuroinflammation. To elucidate the molecular mechanisms, we established an AD cell model using human differentiated SH‐SY5Y nerve cells exposed to toxic amyloid oligomers and investigated the neuroprotective effects of TPPU. Cell viability was assessed by the MTS assay. The cellular levels of sEH and p38β kinase were evaluated by immunoblotting. Tau hyperphosphorylation and nuclear NF‐κB activation were assessed by ELISA. Mitochondrial function was assessed by the mitochondrial membrane potential assay.ResultsTPPU inhibits both human sEH and p38β kinase, two master regulators of inflammation, with nanomolar potencies and distinct selectivity. TPPU effectively prevents neuronal death by mitigating amyloid toxicity, tau hyperphosphorylation and mitochondrial dysfunction, promoting neurite outgrowth, and suppressing activation and nuclear translocation of NF‐κB for inflammatory responses in human nerve cell culture. Pairwise treatment of different selective inhibitors of sEH and p38 kinase synergizes neuroprotection, the effect of which is comparable to the TPPU treatment alone.ConclusionsThe study supports the argument that sEH is a novel target of AD worth pursuing. It uncovers the potential of TPPU and other sEH/p38β dual inhibitors as disease‐modifying agents targeting neuroinflammation for the treatment of Alzheimer’s disease and related CNS disorders.
Anesthesia and surgery induce age‐dependent changes in postoperative delirium behaviors and microbiota
Authors: Liufu Ning , Liu Ling , Xie Zhongcong , Zhang Yiying 
Published: December 2020

AbstractBackgroundDelirium is the most common postoperative complication in senior patients and is associated with accelerated cognitive decline and Alzheimer's disease and related dementia (ADRD). However, the neuropathogenesis of POD remains mostly unknown and no effective medication to prevent or treat POD. Gut microbiota dysbiosis, a condition of microbiota imbalance or maladaptation inside the gut, which could lead to altered immune functions and associated with disorders of POD. Aging and neuroinflammation may also contribute to the neuropathogenesis of POD. However, while all patients may have neuroinflammation, not all patients develop POD. Thus, neuroinflammation alone (single‐factor model of postoperative delirium) is not sufficient to cause POD. Therefore, the objective of the current study was to test the hypothesis that anesthesia/surgery causes age‐dependent gut microbiota dysbiosis, changes in brain IL‐6 level, and mitochondrial function, leading to postoperative delirium‐like behavior in mice.MethodFemale 9 or 18 months old mice received abdominal surgery under 1.4% isoflurane for two hours. We employed a battery of natural and learned behavioral tests to determine the delirium‐like behavior, assessed the gut microbiota before and after the anesthesia/surgery by gene pyrosequencing of 16S rRNA, and measured levels of brain IL‐6(ELISA), synaptic marker( Western blot ) and mitochondrial function (Seahorse XFp Extracellular Flux Analyzer) as measures of neuroinflammation and cerebral dysfunction. For intervention, intragastric administration of lactobacillus and probiotic were used to mitigate the anesthesia/surgery‐induced above changes.ResultAnesthesia/surgery caused different alterations in gut microbiota, including change rate of reduction in the levels of gut lactobacillus, between the 18 and 9 months old mice. The anesthesia/surgery induced greater postoperative delirium‐like behavior, increased brain IL‐6 levels, decreased PSD‐95 and synaptophysin levels, and mitochondrial dysfunction in 18 than 9 months old mice. Treatments with lactobacillus and probiotic mitigated the anesthesia/surgery‐induced changes.ConclusionWe demonstrated that anesthesia/surgery induces age‐dependent changes in the gut microbiota(reduction in lactobacillus), increases brain levels of IL‐6, decreases levels of synaptic marker, and reduces mitochondrial function while also promoting the development of postoperative delirium‐like behaviors in the mice. Treatment with lactobacillus or probiotic mitigated these detrimental effects, strongly suggesting that abnormalities in the gut microbiota contribute to the development of postoperative delirium.
Cognitive differences between healthy monolingual and bilingual anglophones on the English version of the Dépistage Cognitif de Québec: A new screening tool for atypical dementia
Authors: Lévesque Marianne , Ouellet Marie‐Christine , Meilleur‐Durand Synthia , Bouchard Rémi W. , Verret Louis , Fortin Marie‐Pierre , Nadeau Yannick , Molin Pierre , Caron Stéphanie , Hudon Carol , Masellis Mario , Cunnane Stephen , Villeneuve Sylvia , Gauthier Serge , Callahan Brandy L. , Jarrett Pamela , Hsiung Ging‐Yuek Robin , Laforce Robert 
Published: December 2020

AbstractBackgroundCognitive abilities between monolingual and bilingual individuals may differ, making it important to validate new cognitive screening tools using psychometric testing. Otherwise assessments could be subject to misinterpretation, leading to inaccurate diagnoses. The current project aimed to compare healthy older monolingual and bilingual anglophones on the English version of a new cognitive screening test designed for better recognition of atypical dementia; the Dépistage Cognitif de Québec (DCQ, www.dcqtest.org). The DCQ was developed at la Clinique Interdisciplinaire de mémoire de Québec, and its psychometric properties have been well studied, including its sensitivity and specificity to detect atypical dementia compared to current standardized cognitive screening tests (Laforce et al., 2018; Sellami et al., 2018).MethodsThe DCQ was administered by qualified psychometricians to 85 healthy native English‐speaking participants aged 50 years and over, in various sites across North America. The Montreal Cognitive Assessment (MoCA) was used to determine participants’ eligibility. Language proficiency was established using the Language Experience and Proficiency Questionnaire (LEAP‐Q).ResultsAmidst the anglophone participants recruited, 30 monolingual anglophones and 29 bilingual anglophones met the inclusion criteria. The two groups had similar age, education and MoCA scores. Monolinguals and bilinguals were compared on their total DCQ scores as well as on each of the 5 indexes of the DCQ: Memory, Visuospatial, Executive, Language and Behavioural. Statistical analysis showed a significant advantage for the bilingual participants on the total DCQ scores and on the Language index, which was later washed out following a Bonferroni correction. No significant differences were found between groups on any of the other indexes.ConclusionThis study is the first to explore psychometric properties of the DCQ in older monolingual and bilingual participants tested in their native language. The results highlight the importance of identifying and characterizing linguistic diversity before using new screening tools in clinical settings. The potential cognitive advantages of bilingualism, even in healthy older adults, should be considered when interpreting test data and explicitly discussed in neuropsychological reports. Similar studies should be conducted for all future cognitive screening measures, especially to further examine the differences between groups on language‐related tasks.
Investigating P2X7R‐mediated inflammatory signalling in Alzheimer's disease
Authors: Lobo Paula Beltran , Perez‐Nievas Beatriz G , Noble Wendy 
Published: December 2020

AbstractBackgroundGlial function is altered in Alzheimer’s disease (AD) in response to danger‐associated molecular patterns in the local environment such as the binding of Aβ species to toll‐like and purinergic receptors, including P2X7R. These interactions activate pro‐inflammatory pathways and lead to the release of cytokines and chemokines that participate in damaging inter‐cellular cascades. In vivo AD models have shown beneficial effects following P2X7R inhibition via mechanisms that could prevent pathological tau changes. However, the effects of P2X7R activation and downstream inflammatory signalling on tau‐mediated neurodegeneration in AD remains unknown.MethodWe have used biochemical and immunohistochemical methods in post‐mortem control and AD BA9 prefrontal cortex to examine changes in P2X7R expression, determine the spatial pattern of P2X7R activation relative to Aβ and pathological tau accumulation and evaluate the association between P2X7R and local inflammatory responses. Primaryglial and organotypic slice culturesare being used to model glial responses to physiological Aβ species and the downstream consequences on neurons.ResultWe found elevated levels of P2X7R from Braak stage II relative to controls associated with an increased plaque burden, mislocalization of tau to the synapses and astrocyte reactivity. P2X7R was markedly expressed in astrocytes surrounding AD hallmarks and also in disease‐associated microglia neighbouring Aβ plaques. Investigation of inflammatory mediators linked with P2X7R‐positive glia revealed higher activation of the NLRP3 inflammasome and NFκB pathways with disease progression. Preliminary in vitro and ex vivo models suggest that pathological changes in tau following Aβ stimulation are related to P2X7R‐inflammatory activity.ConclusionThese data suggest that P2X7 receptor expression and activation is altered in the early stages of AD, prior to marked synapse loss. Ongoing studies are aimed at determining if blockade of P2X7R‐mediated inflammatory changes in has benefit in models of AD.
Create music at home: Meeting psycho‐social needs through music interventions for people with dementia and their caregivers
Authors: Ray Kendra , Mittelman Mary S 
Published: December 2020

AbstractBackgroundFor people with dementia and their caregivers, neuro‐psychiatric symptoms of dementia may have a negative affect on quality of life. Some studies have shown positive effects of music listening, singing and other individualized music‐based interventions. This study presents a solution by creating opportunities for family caregivers to provide non‐pharmacological uses of music during caregiving activities in the home setting.MethodA psycho‐educational, music‐based protocol for caregivers to use therapeutic music for their family member with dementia was written. Nine dyads (caregiver and care receiver) were recruited from home‐based settings in the NYC area. Family caregivers were educated with hands‐on education in a classroom setting with a music therapist one time per week for one‐hour for six weeks. Using the Cornell‐Brown Scale for Quality of Life in Dementia, quality of life for the care receiver with dementia was measured pre‐test and post‐test the 6‐week psycho‐educational training.ResultA paired samples t‐test indicated a significant increase in quality of life in care receivers with dementia from baseline to following the 6‐week psycho‐educational, music‐based protocol, p = .003. In this presentation, we will discuss the interventions taught to caregivers to facilitate in the home setting with their care receiver diagnosed with dementia. We will present use of technology to adjust study protocol made due to COVID‐19.ConclusionAlthough this study is ongoing, our findings suggest that caregivers can implement music‐based interventions that may lead to an increase in quality of life for their family member with dementia.