bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deciphering the mechanistic action of phytoformulation against scopolamine‐induced Alzheimers in rodents
Authors: Rajendran Kayalvizhi , Krishnan Uma Maheswari 
Published: December 2020

AbstractBackground
Brahmi Nei (BN), an Indian traditional phytoformulation composed of eleven plant constituents has been traditionally used for treating various psychiatric disorders, hypertension and cerebral palsy. Some of the key phytoconstituents in this formulation have been explored for their potential role in plaque disruption, crossing the blood‐brain barrier, reversing the cognitive deficit and promoting tau dephosphorylation independently as a mono‐drug. Since Alzheimer’s disease (AD) is a multifactorial disorder affecting various signaling pathways, we hypothesize that BN formulation may be an effective option to treat AD.MethodThe major constituents in BN were identified using LC‐MS/MS technique. The Alzheimer’s model was created using scopolamine hydrobromide in animals through intra‐hippocampal injection at a concentration of 10 µg/µL. After seven days of post‐operative care, treatment was started with three different doses BN1 (0.5 of therapeutic dose, n=5), BN2 (Therapeutic dose, n=5), BN3 (twice the therapeutic dose, n=5) for a period of 28 days. The cognition and spatial learning were assessed using Morris water maze, radial arm maze and elevated plus maze. RT‐PCR, Western blots, biochemical assays analysis were performed to evaluate the therapeutic efficacy of BN against various signaling pathways deregulated in AD. Neuritic plaque deposits were detected using Bielchowsky silver staining while dendritic morphology and spine types were studied using Golgi‐Cox staining.ResultOur results reveal that BN treatment influences the working memory and hippocampal‐dependent learning pattern in AD‐induced rodents. BN reduced acetylcholine esterase and malondialdehyde concentration in hippocampal tissues. It significantly regulates dephosphorylation of tau, inflammatory pathway and also inhibits the BBB disruption by activating YAP/TAZ. At the cellular level, synaptic degeneration and hippocampal neuronal loss were reversed by BN treatment which also regenerated neurons and increased spine density that is reflected in the superior cognitive improvement displayed by the BN2 and BN3 treated animals in the behavioral studies.ConclusionThe BN formulation is an efficient therapeutic option in treating the multiple pathways involved in AD when compared to conventional mono‐drug treatment.
In silico study for neurodegenerative diseases diagnosis: A novel gene panel
Authors: Nguyen Thuy Trang , Vo Tuong Kha , Vo Van Giau 
Published: December 2020

AbstractBackgroundGenetic factors are central to the etiology of neurodegeneration, both as monogenic causes of heritable disease and as modifiers of susceptibility to complex, sporadic disorders. Extensive analyses of known the monogenic causes of neurodegenerative diseases by whole‐exome/genome sequencing are technically possible today. We here aimed to compile a comprehensive panel of genes associated with monogenic causes of neurodegenerative diseases (NDs) for use in clinical and research situations.MethodWe systematically searched the publicly available database Online Mendelian Inheritance in Man, and validated the entries against original peer‐reviewed publications in PubMed. First, we selected known pathogenic or putatively pathogenic stroke genes reported in at least one person with the disorders. Then, the diseases phenotype was classified based on each gene into eight subgroups: (1) Alzheimer disease (AD), (2) Parkinson disease (PD), (3) Lewy body dementia (LBD), (4) frontotemporal dementia (FTD), (5) amyotrophic lateral sclerosis (ALS), (6) Huntington disease (HD), (7) prion diseases and other genes related to brain disorders, but without any documented the patient description.ResultWe identified in total 177 genes: 45 associated with AD, 29 associated with PD, 25 associated with LBD, 24 associated with FTD, 23 associated with ALS, 10 associated with HD, 1 may cause prion diseases, and 20 other‐related genes from uncleared brain disorders. We described these 177 genes and the clinical NDs subtype(s) associated with each of them. The resulting gene panel can be used to interpret exome sequencing results regarding monogenic NDs.ConclusionThe genetic testing panel is applicable to NPs clinical areas and has important implications for family testing.
β‐amyloidopathy in the pathogenesis of age‐related macular degeneration in correlation with Alzheimer’s disease in the aspect of autophagy anomalies
Authors: Ermilov Victor Vladimirovich , Zagrebin Valeriy , Smirnov Alexey Vladimirovich , Markelov Vadim Vladislavovich 
Published: December 2020

AbstractBackgroundRecent data of molecular analysis leading to the key role of certain proteins in the etiology and pathogenesis of a group of neurodegenerative diseases (NDD) including age‐related macular degeneration (AMD) gave an impulse to the development of new concepts that allocate separate versions of proteinopathies such as tauopathy, synucleinopathy, amyloidopathy. To study the clinical and morphological features of amyloidogenesis in AMD as a manifestation of the commonality of proteinopathy and β‐amyloidopathy of pathological processes in brain for Alzheimer's disease (AD) and in the eye for AMD, a common fact is described that extra‐ and intracellular stimuli from pathological protein deposits are able to modulate the macroautophagic response, which plays a role in homeostasis of the retinal pigment epithelium (RPE).Method111 eyes with morphological signs of “dry” and “wet” forms of AMD and the brain taken from 56 cadavers were examined, using selective methods of amyloid detection.ResultThe amyloid deposits in the patients with AMD were found in 42.3% of cases in all the structural elements of fundus. β‐amyloidopathy was identified in 39% and 80% cases separately in dry and wet form of AMD. The combined accumulation of β‐amyloid in both the eye and the brain was found in 50.6% of cases. β‐amyloid was specific to drusen in eyes with AMD and to senile plaques in brain tissue in the patients with AD. The decrease in RPE nuclei is connected with the process of autophagy.ConclusionThe authors have demonstrated that the keynote of AMD and AD pathogenesis is β‐amyloidopathy as a manifestation of proteinopathy activated by the amyloid deposits. This view on the problem creates the preconditions for new strategies of treatments, targeting on the pathogenesis of β‐amyloid formation and pathological aggregation, as malfunctioning of autophagy has been related to accelerating aging of RPE cells.
Association between cerebrospinal fluid neurofilament light chain and markers of neurofibrillary pathophysiology: Findings from the Knight Alzheimer Disease Research Center
Authors: Schultz Stephanie A. , Schindler Suzanne E. , Chen Charles , Sutphen Courtney L. , Morris John C. , Fagan Anne M. , Gordon Brian A. , Benzinger Tammie L.S. 
Published: December 2020

AbstractBackgroundThe objective of this study was to examine the relationship between cerebrospinal fluid (CSF) neurofilament light (NfL) chain levels and established biomarkers of neurofibrillary tangle (NFT) pathophysiology. Secondarily, we assessed the discordance of beta‐amyloid, NFT, and neurodegeneration markers.Method236 individuals (207 cognitively normal and 29 cognitively impaired) were selected based on completion of CSF collection and AV1451 and AV45 PET imaging within 1 year, and measurement of CSF NfL, beta‐amyloid‐42, total‐tau, and phosphorylated‐tau181 (p‐tau). Using covariate‐adjusted linear regressions we compared log‐transformed CSF NfL to AV1451 summary SUVRs and CSF p‐tau. Using Gaussian mixture models, we determined positivity thresholds in markers of beta‐amyloid (CSF beta‐amyloid‐42 and AV45), NFT (CSF p‐tau and AV1451), and neurodegeneration (CSF total‐tau and CSF NfL), and assessed discordant results between related biomarkers.ResultCSF NfL was highly associated with CSF p‐tau (p=9.83e‐10), whereas CSF NfL was marginally associated with AV1451 (p=0.006). CSF p‐tau and AV1451 were only moderately correlated (r=0.457). The differences in relationship between tau and NfL markers may be due to effects of age on these three biomarkers of interest. Age was minimally correlated with AV1451 (r=0.326) and moderately correlated with CSF p‐tau and NfL (r=0.410 and 0.512, respectively). Secondarily, we found that our sample was 18.2% discordant between beta‐amyloid markers, 18.7% discordant between NFT markers, and 17.8% discordant between neurodegeneration markers.ConclusionThe relationship between CSF NfL and NFT pathophysiology differed depending on the NFT biomarker that was considered and may be related to elevations in certain CSF biomarkers as a function of age. Currently, CSF p‐tau and AV1451 are often considered interchangeable measures of NFT pathophysiology. These results suggest more careful consideration and assessment of biomarkers should be taken when choosing markers of beta‐amyloid, NFT, and neurodegeneration.
Association of cognitive health status with happiness, helplessness and hopelessness in different races
Authors: Umucu Emre , Wyman Mary F , Lee Beatrice , Zuelsdorff Megan , Lambrou Nickolas H , Johnson Adrienne L , Bouges Shenikqua , James Taryn T , Salazar Hector , Simó Carola A Ferrer , Carter Fabu P , Asthana Sanjay , Gleason Carey E 
Published: December 2020

AbstractBackgroundCognitive impairments are linked to changes in positive and negative affect. However, it remains unclear whether some dimensions of positive and negative affect are associated with cognitive health status (CHS) and the relationships between pillars of positive and negative affects and CHS function similarly across racial groups. In this study, we tested whether (a) happiness, helplessness, and hopelessness are linked to CHS and (b) if these relationships are similar among blacks and whites.MethodsParticipants were 755 enrollees in the Wisconsin ADRC who had normal cognition, MCI, and dementia at baseline. The majority of participants were female (59.2%) and Caucasian (81.5%). The average age at baseline was 64.23 (SD=10.40).CHS was categorized as cognitively normal, mild cognitive impairment, and dementia. Happiness, helplessness, and hopelessness were measures with three items from the 15‐item Geriatric Depression Scale. For question (a), all races were included in the analyses. For question (b), blacks and whites are subgrouped and all other races were excluded. Chi‐square or Fisher’s Exact tests were conducted to test our research hypotheses.ResultsChi‐square test results revealed that (a) an association between happiness and CHS, χ
2(2)=6.06, p<.05, (b) an association between helplessness and CHS, χ
2(2)=6.44, p<.05, and (c) an association between hopelessness and CHS, χ
2(2)=14.11,p<.01. The association of happiness with CHS remained significant in blacks (Fisher’s exact=.03), but not in whites, χ
2(2)=1.04, p=.59. The association of helplessness with CHS was not significant for blacks (Fisher’s exact = 1.00), but was significant for whites, χ
2(2)=8.47,p< .05. Finally, the relationship between hopelessness and CHS was not associated in blacks (Fisher’s exact=.19), but was in whites, χ
2(2)=16.31,p<.01.ConclusionRace differences in the association of CHS and happiness, helplessness, and hopelessness were found. For blacks, only happiness was significantly associated with CHS, whereas, for whites, CHS was associated with helplessness and hopelessness, but not with happiness. These findings can inform the development of culturally‐tailored interventions to prevent cognitive decline for specific races.
Impact of blood biomarkers on cost and wait time in diagnosing treatment‐eligible patients for Alzheimer’s disease: A simulation study
Authors: Mattke Soeren , Cho Sang Kyo , Bittner Tobias , Hlavka Jakub , Hanson Mark 
Published: December 2020

AbstractBackgroundRecent trial results give hope that a disease‐modifying treatment (DMT) for Alzheimer’s disease (AD) might become available, but concerns have been raised that the large number of patients might overwhelm the healthcare system, in particular because of limited capacity of dementia specialists. Blood based biomarker (BBBM) tests for the biologic hallmarks of the disease are a promising tool to improve triaging at the primary care level. We projected their impact on cost and wait times with a simulation model.MethodWe simulate the U.S. population age 50+ over 30 years combining a disease progression model (Cognitively normal to MCI due to AD or due to other causes to dementia) and a system dynamics model for capacity constraints (specialist cognitive testing and confirmatory biomarker testing with PET or CSF). We compare four scenarios for primary care evaluation (1) cognitive screening only (MMSE), (2) BBBM only, (3) MMSE followed by BBBM if positive and (4) BBBM followed by MMSE if positive. Parameter for patient pools, costs and capacity were derived from published data and assumptions.ResultUsing either MMSE or BBBM alone would result in a number of specialist referrals that is projected to continuously exceed capacity from 2020 to 2050. Combining MMSE and BBBM in either order would eliminate wait lists after the first three years. (Figure) The projected number of correctly identified cases (i.e., true positive for MCI due to AD) will increase from ∼480,000 for either MMSE or BBBM alone to ∼600.000 for MMSE and BBBM combined on average each year. Average total cost per year would be an estimated $7.2 billion for MMSE alone, $7.7 billion for BBBM alone, and $6.9 billion for MMSE and BBBM combined, and cost per correctly identified case will decline from ∼$15,000 for MMSE or BBBM alone to∼$11,000 for a combination of MMSE and BBBM.ConclusionCombining BBBM with MMSE is projected to increase the efficiency and value of the triage process for eligibility for a DMT at the primary care level, as the addition of a BBBM would reduce wait times for specialist visits and diagnostic yield dramatically without increasing net cost.
Chitosan nanoparticles alleviate Alzheimer’s disease in zebrafish by adopting a dual strategy
Authors: Saleem Suraiya 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disease. It is the most prevalent form of dementia in the world affecting almost 47 million people worldwide. The main pathological hallmark of AD is progressive memory loss. Zebrafish possess 70% similarity with the human genome. Zebrafish have been used extensively in developmental biology and molecular genetics. Zebrafish are being widely used as a predominant model for studying neurodegenerative diseases. In this current study, we have attempted to establish Aβ induced model of AD in Zebrafish. Validation of this model is done by behavioral analysis.MethodThe various assays performed to test memory were spatial memory testing, preference for light and dark environments and their ability to recognize novel objects from the previous objects. SEM, TEM, FTIR, AFM and particle size analysis were performed to validate the nanoparticles thus formed. Amyloid beta was injected mid ventrally into the zebrafish brain, which were previously given Chrysin by oral gavage.ResultThe various assays performed are spatial memory testing, preference for light and dark environments and their ability to recognize novel objects, which revealed the drastic changes in the behavior of Aβ injected fishes. Further validation of the Aβ model was done using immunohistochemical (IHC) staining of brain sections of Aβ injected fish, which confirmed the presence of Aβ with Aβ antibody. The present study establishes a model of AD in zebrafish which will be useful for therapeutic drug intervention in future. Chitosan nanoparticles loaded with the naturally occurring flavonoid, chrysin, were synthesized. The nanoparticles were validated on the basis of their physical and chemical properties. It was also observed that the chrysin loaded chitosan nanoparticles led to protection and restoration of synapses of the amyloid beta treated zebrafish. Chitosan also possessed the ability to disintegrate the amyloid plaques in vivo.
ConclusionThis study provides insight into the dual strategy by which Chrysin‐ Chitosan nanoparticles alleviate Alzheimer’s like condition. This dual strategy adopted by the Chrysin‐ Chitosan nanoparticles therefore holds potential to serve as a therapeutic strategy to treat AD.
Amyloid‐β CSF/PET discordance vs tau load 5 years later: It takes two to tangle
Authors: Reimand Juhan , Collij Lyduine , Scheltens Philip , Bouwman Femke H. , Ossenkoppele Rik ,   and the Alzheimer's Disease Neuroimaging Initiative
Published: December 2020

AbstractBackgroundAmyloid‐β pathology assessed in vivo using CSF and PET results in discordance (CSF+/PET‐ or CSF‐/PET+) in 10‐20% of cases. An amyloid‐β CSF+/PET‐ profile has been proposed to mark the pathological beginnings of amyloid‐β accumulation (Palmqvist et al., 2016), providing a powerful model to study the interplay between amyloid‐β and tau at the earliest stages of Alzheimer’s disease.MethodsWe included 730 participants without dementia (282 cognitively normal, 448 MCI) from the Alzheimer’s Disease Neuroimaging Initiative database with available baseline [18F]florbetapir PET and CSF Aβ42 within one year. Established cut‐offs were used to determine amyloid‐β CSF/PET status. We used linear mixed modelling to study the association between amyloid‐β CSF/PET status and tau pathology measured in CSF and cognitive performance (both available at baseline) or by using [18F]flortaucipir tau‐PET (performed 5.2±1.2 years later). Using Kaplan‐Meier estimates and Cox regression, we investigated the association between amyloid‐β CSF/PET status and progression of syndromic diagnosis. Additionally, we calculated the proportion of CSF+/PET‐ participants who during follow‐up (i) progressed to amyloid‐β CSF+/PET+, and/or (ii) became tau‐positive based on [18F]flortaucipir PET.ResultsMean age of the participants was 73±7 years, 52% were male and mean MMSE was 28.4±1.6. (Table 1). Amyloid‐β CSF+/PET+ (N=318) participants had elevated CSF (p)tau levels and worse cognitive performance at baseline, while CSF+/PET‐ (N=80) participants were overall similar to the CSF‐/PET‐ (N=306) group (Figure 1). Five years after baseline, [18F]flortaucipir PET uptake in the CSF+/PET‐ group (1.20±0.13) did not differ from CSF‐/PET‐ (1.18±0.08, p=0.69), but was substantially lower than CSF+/PET+ (1.48±0.44, p<0.001). Progression of syndromic diagnosis occurred less often in amyloid‐β CSF+/PET‐ (14%, hazard ratio [HR]=0.22[0.12,0.41], p<0.001), CSF‐/PET+ (8%, HR=0.10[0.02,0.41], p=0.001) and CSF‐/PET‐ (10%, HR=0.16[0.11,0.24], p<0.001) participants, compared to the CSF+/PET+ (44%) group (Figure 2). Of the CSF+/PET‐ subjects, 21/64 (33%) progressed to amyloid‐β CSF+/PET+, whereas only one (3%, difference p<0.05) became tau‐positive based on [18F]flortaucipir PET.ConclusionsSufficient amyloid‐β load detectable by both CSF and PET is required before substantial tau deposition emerges. Compared to participants with abnormal amyloid‐β levels on PET and CSF, the discordant CSF/PET groups have a distinctly better prognosis.
How prepared are the EU‐5 countries’ health systems to deliver a disease‐modifying treatment for Alzheimer’s?
Authors: Mattke Soeren , Wang Mo , Ullrich Andreas 
Published: December 2020

AbstractBackgroundPrior research suggests that health systems are unprepared for a potential disease‐modifying treatment (DMT) for Alzheimer’s disease and projected substantial delays in access. We analyzed whether and to what degree changes to institutional arrangements (e.g., policies, incentives and regulations) could improve capacity and readiness in five countries.MethodDesk research and expert interviews in France, Germany, Italy, Spain, and the U.K. focusing on planning for and coverage of memory services, ability of providers to adapt to a surge in demand and provider capabilities along the patient journey from diagnosis to treatment.ResultNo country has a government‐led plan to prepare for the advent of a DMT or advance planning to budget for the expected increase spending. Spain and the U.K. have expert‐led initiatives to inform the policy dialog. Screening for cognitive decline is not recommended or covered in any of the countries. While all cover initial evaluation of memory complaints in primary care settings, it is often not performed because of limited knowledge, lack of tools and fatalistic attitude.Patients with suspected cognitive decline have access to specialist memory services in all five countries, led by geriatric psychiatrists (Germany and U.K.) or neurologists (France, Italy and Spain). Scale and scope vary substantially within and across countries, with only France and the U.K. attempting to standardize services. Only Italy and Spain cover biomarker testing based on PET scans or CSF tests for routine care. Memory services operate at capacity in all countries with wait times of at least two months, and limited flexibility to scale up due to low numbers of dementia specialists, lack of budget and complex planning processes. Psychiatry‐led services tend to be less prepared for the medicalized requirements of a DMT delivery.ConclusionInstitutional preparedness and funding for a DMT needs to be improved in all five countries, particularly by strengthening primary care with training and tools, such as simple cognitive tests and blood‐based tests for Alzheimer’s biomarkers, as workforce and budget constraints limit the ability to scale up specialist services. Such improvements would also improve access to and quality of memory care in the absence of a DMT.