bluuebunny/crossref_metadata_2025_split huggingface dataset:
In‐vitro neuronal cell proliferation and in‐vivo neuroprotective activity of pinus roxburghii for memory and cognition
Authors: Sharma Aditi , Goyal Rohit 
Published: December 2020

AbstractBackgroundPinus roxburghii Sarg. is traditionally used as a nerve tonic, hemostatic and anticonvulsant. The present study was aimed to investigate the neuroprotective activity of P. roxburghii stem bark for memory and cognition using in‐vitro and in‐vivo methods.MethodPlant drug was extracted with methanol using Soxhlet extraction. In‐vitro cell viability activity of P. roxburghii was assessed using PC‐12 cell lines. The in‐vivo neuroprotective activity of P. roxburghii was tested on Wistar albino rats (either sex) and ICV‐STZ (3 mg/kg, bilateral) was given to cause memory deficit. HPTLC fingerprinting was performed for the presence of quercetin and gallic acid in the plant extract.ResultThe phytochemical testing of extract revealed the presence of flavonoids, alkaloids, steroids, and tannins. P. roxburghii showed significant cell viability at 10, 50 and 100 µg/ml in an in‐vitro test on PC‐12 cell lines. In the in‐vivo activity, ICV‐STZ caused significant deterioration in memory and cognition, tissue oxidative stress and AchE activity. P. roxburghii 100, 200 and 300 mg/kg, p.o. and donepezil (3 mg/kg, p.o.) significantly (p<0.05) reversed the behavioral changes in rats when tested on morris water maze and elevated plus maze. Increased levels of lipid peroxidation, AchE activity and decreased the level of glutathione were significantly (p<0.05) antagonized by P. roxburghii, similar to donepezil in rat brain. Quercetin and gallic acid were identified quantitatively in the plant extract in HPTLC study.ConclusionThe methanolic extract of P. roxburghii ameliorated ICV‐STZ induced cognitive deficits and memory impairment possibly due to the presence of quercetin and gallic acid.
The implication of SRC family kinases in Alzheimer’s disease
Authors: Beirute‐Herrera Julianne L. , Diouf David , van den Hove Daniel L.A. , Mastroeni Diego F. 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) remains as one of the major challenges for the neuroscientific community today. It affects approximately 50 million cases worldwide, with a total cost estimation of $290 billion in 2019 (Alzheimer’s Association, 2019). The pathophysiological hallmarks of AD are amyloid beta plaques (Aβ) and neurofibrillary tangles (NFTs). Nevertheless, the underlying mechanism have yet to be elucidated (Mehta et al., 2017). Recent efforts have demonstrated that non‐receptor Src‐family tyrosine kinases in AD are potential targets for therapeutic intervention and we show epigenetic mechanisms associated with the expression of non‐receptor Src‐family tyrosine kinase (e.g. methylation), as a mechanism for its dysfunction (Kaufman et al., 2015; Iatrou, Kenis, Rutten, Lunnon & van den Hove, 2017). The current project aims to investigate the proteomic, genomic and epigenomic correlation of c‐ and v‐SRC to PYK2 and Fyn in neuropathologically confirmed AD and nondemented control cases.MethodWestern blots, immunohistochemistry, qPCR and Methylation Specific PCR will be performed in the Medial Temporal Gyrus (MTG) of 10 AD cases in a range of disease states (Braak stage IV, V and VI) and in 10 healthy age matched controls (Braak stage 0‐II). Laser Capture Microdissection will be used prior to qPCR to select neurons and microglia. For the statistical analysis, a 2‐tail student t test and regression analysis of expression profiles will be conducted using IBM SPSS Statistics 25.0 with a significance level of >0.05 and covariates like Braak stage and gender.ResultsPreliminary results already showed a significant upregulation of v‐Src and Fyn in CA1 laser capture neurons in AD cases compared to controls. While immunohistochemistry shows an upregulation of the Src family kinases in the CA1 of the AD cases. We hypothesize that there is an upregulation of c‐Src, v‐Src, Fyn and PYK2 mRNA/protein levels in AD cases, which is correlated to hypomethylation in the promoter regions of the corresponding genes in AD cases. Furthermore, is expected that the same proteins interact in both microglial and neuronal cells following an equivalent pattern.ConclusionV‐Src and Fyn are upregulated in Alzheimer’s disease cases and must be considered to further study the pathophysiology of the disease.
The C99 fragment of APP regulates cholesterol trafficking
Authors: Montesinos Jorge , Pera Marta , Larrea Delfina , Guardia‐Laguarta Cristina , Area‐Gomez Estela 
Published: December 2020

AbstractBackgroundγ‐secretase activity is enriched at mitochondria‐associated ER membranes (MAMs),a lipid‐raft subdomain of the ER, where APP fragment C99 is delivered for its cleavage. Moreover, γ‐secretase activity deficiency linked to AD mutations causes C99 accumulation at MAM, resulting in the upregulation of MAM activities such as sphingomyelin turnover and cholesterol esterification. We now explore whether the interaction of C99 with cholesterol could explain the link between C99 accumulation at MAM and the lipid abnormalities found in AD.MethodUsing cellular models of C99 accumulation versus a cholesterol‐binding deficient C99, we assessed cholesterol uptake dynamics and sub‐cellular distribution along with MAM‐regulated functionalities such as cholesterol esterification, phospholipid synthesis and sphingomyelinase activity. Also, we used a photo click activable cholesterol analog to study the proteins interacting with cholesterol at MAM in both conditions.ResultC99 accumulation at MAM caused an increase in cholesterol uptake, cholesterol esterification, phospholipid synthesis and sphingomyelinase activity accompanied by a sub cellular redistribution of cholesterol to endolysosomes and ER, while C99‐defective in cholesterol binding showed no changes in these activities. Moreover, when the cholesterol‐interacting proteome of both conditions was compared, C99 caused a huge change/recruitment at MAM, especially of enzymes involved in lipid metabolism.ConclusionWe report that the lipid alterations caused by pathogenic C99 accumulation are a consequence of an exacerbated uptake of extracellular cholesterol and mobilization towards MAM. The increase content of cholesterol at MAM driven by C99 might be responsible of the persistent activation of MAM and a subsequent alteration of the lipid metabolism since a cholesterol‐binding deficient C99 fails to increase MAM activities and cholesterol trafficking.
Differential effects of confluent and non‐confluent white matter hyperintensities on functional connectivity in mild cognitive impairment
Authors: Kumar Dilip , Vipin Ashwati , Wong Benjamin , Ng Kok Pin , Kandiah Nagaendran 
Published: December 2020

AbstractBackgroundEmerging evidence suggests that confluent WMH results in greater cognitive impairment compared to non‐confluent WMH. However, the mechanism linking confluent WMH and early cognitive impairment is not clearly understood. We studied the effects of confluent and non‐confluent WMH on whole‐brain functional connectivity (FC) across 164 regions of interest (ROI) in subjects with Mild Cognitive Impairment (MCI).MethodSixty‐three MCI subjects with T1‐weighted MRI, T2‐weighted MRI, resting‐state functional MRI (rs‐fMRI) and neuropsychological data were studied. Subjects were classified as confluent WMH (C‐WMH) or non‐confluent WMH (NC‐WMH) using the Staal’s criteria on the Fazekas WMH scale. Group‐level ROI‐to‐ROI FC trends and differences at differential WMH subtypes were computed using standard rs‐fMRI analysis.ResultSubjects with C‐WMH exhibited increased inter‐regional FC in the fronto‐parietal, fronto‐occipital, parieto‐occipital, and temporo‐parietal regions of the salience, dorsal‐attention, default‐mode, and visual networks. Increased intra‐regional FC in the frontal lobe was also observed in C‐WMH. In contrast, only intra‐regional FC changes were seen in the frontal and temporal lobes in NC‐WMH. Performance on the Montreal Cognitive Assessment correlated positively with increased inter‐regional FC only in the C‐WMH group, suggesting that increased connectivity was associated with better global cognition in MCI subjects with C‐WMH.ConclusionC‐WMH in subjects with MCI is associated with widespread increased inter‐regional FC changes which correlates with better performance in global cognition. These findings provide novel insights into divergent functional alterations related to the confluence of WMH in MCI.
The association of depression with structural brain markers and cognitive impairment: The Maastricht study
Authors: Geraets Anouk F.J. , Schram Miranda T. , Jansen Jacobus F.A. , Koster Annemarie , Dagnelie Pieter C , Greevenbroek Marleen M.J. , Stehouwer Coen D.A. , Verhey Frans R.J. , Koehler Sebastian 
Published: December 2020

AbstractBackgroundThe risk of dementia is doubled in depression. However, the underlying etiology remains unclear. Clinical studies suggest that depression is related to brain atrophy and cerebral small vessel disease (cSVD), which are themselves related to cognition. We studied the associations between depression, structural brain markers and cognition in a general population aged between the 40 and 75 years.MethodWe used cross‐sectional data from the Maastricht Study (n=7,066; mean age 59.6±8.7 years, 50.1% women), which, by design, oversampled participants with type 2 diabetes (T2D). Major depressive disorder (MDD, n=236) was assessed by the Mini‐International Neuropsychiatric Interview. From a comprehensive neuropsychological battery, we derived standardized sum scores on tests for memory, information processing speed, and executive functioning and attention. Presence of significant overall cognitive impairment was defined as a score <‐.1.5 SD below norms scores for age, gender and education. Volumes of cerebral spinal fluid (CSF), white matter (WM), grey matter (GM) and white matter hyperintensities (WMH), and presence of lacunar infarcts, cerebral microbleeds and total cSVD burden were assessed by 3 Tesla MRI. Multiple linear and logistic regression analyses tested the associations between MDD, brain markers and cognitive functioning, adjusted for a range of demographic, cardiovascular, and lifestyle risk factors.ResultIn fully adjusted models, MDD was associated with lower scores in memory (B=‐0.11(‐0.22;0.00)), information processing speed (B=‐0.24(‐0.32;‐0.15)), executive functioning and attention (B=‐0.23(‐0.32;‐0.14)), and with presence of significant cognitive impairment (OR=2.37(1.77;3.17)). In those with available MRI data (n=4,734), MDD was associated with a lower GM volume only in older participants (p‐interaction=0.023), and with total WMH (B=0.17(0.01;0.34)), periventricular WMH (B=0.18(0.01;0.35)), and total cSVD burden (OR=1.70(1.09;2.65)) in participants without T2D (OR=1.70(1.09;2.65)).ConclusionThis study shows that MDD is associated with cognitive impairment, including worse memory, information processing speed, and executive functioning and attention, independent of major demographical, cardiovascular and lifestyle risk factors. In older participants, MDD is related to a lower GM volume, while in the wider general population without T2D, MDD is related to markers of cSVD burden. Longitudinal studies are needed to examine the role of structural brain damage in the development of cognitive impairment and dementia in depression.
Polypharmacy in long‐term care residents: Prevalence and relationships with age and dementia
Authors: Zhang Er Dong , Kelly Ronald , Arvan Tara , Chinda Betty Nhuoma , Low Hilary , Song Xiaowei 
Published: December 2020

AbstractBackgroundPolypharmacy is a significant problem of growing interest in healthcare for older adults with the current increase in drug consumption. Inappropriate polypharmacy is a risk factor for numerous adverse health outcomes and creates a growing financial burden to society. Yet, evaluations of objective measures of polypharmacy and their applications in older adults are not well studied. Here, we investigate the medication use in long‐term care residents and their relationships with age and cognition.MethodMedical records including medication consumption of 350 residents in long‐term care facilities (mean age: 81.1 ± 10.9 years; range: 52–104; female: 63.7%) diagnosed with or without dementia (203:147) were reviewed, using PointClickCare and the InterRAI‐MDS2.0. Four scores assessing medication use were generated at two time points (at baseline and at 12 months or at time of discharge). The drug scores included the counts of 1) total medications, 2) prescription drugs, 3) Beers Criteria drugs, and 4) over the counter medications and supplements. Distributions of each the drug scores were examined and their relationships with age and cognition scores (MMSE) were tested using correlation and regression analyses. Group mean scores were compared for dementia status.ResultThe average number of total drugs, prescription drugs, and beer’s drugs taken were 8.6±4.7 (range: 0‐24), 3.29±5.2 (0‐19), and 1.2±1.2 (0‐6) respectively, and differed by dementia status (p‐value<0.050). Each of the drug scores was related with age (r’s> 0.0685, p‐values<0.050).ConclusionPolypharmacy is prevalent in older adults with long‐term care. Residents with dementia have a distinguished profile with medication consumption. Ongoing research in better understanding polypharmacy profiles in relation to frailty and cognition status can further benefit medication optimization of older adults in residential care.
The LUCINDA trial: Leuprolide + cholinesterase inhibition to reduce neurologic decline in Alzheimer's
Authors: Butler Tracy , Atwood Craig S. , Galvin James E. , Maloney Thomas , Glodzik Lidia , de Leon Mony J. , Goldberg Judith D. 
Published: December 2020

AbstractBackgroundLeuprolide Acetate has been used for decades to treat hormone‐sensitive conditions such as prostate cancer and endometriosis. In animal models of AD, leuprolide preserves cognition and decreases amyloid deposition and tau phosphorylation by decreasing levels of Luteinizing Hormone. A subgroup analysis of a prior human trial (Bowen, 2016) showed that leuprolide benefited cognition and function in women who were also taking donepezil. Here we describe an ongoing clinical trial of leuprolide to confirm and extend these results.MethodA three‐site, double‐blind, randomized trial of Leuprolide Acetate (22.5 mg/12 weeks) compared with placebo to evaluate the changes over 48 weeks in cognition, function, brain MRI measures (volume, hippocampal blood flow) and blood biomarkers of inflammation in women (n=150) with mild‐moderate AD who are also taking a stable dose of donepezil. This trial is enrolling at three US sites: Weill Cornell in NYC, University of Miami in Southern FL and University of Wisconsin, Madison.ResultResults are expected in 2025.ConclusionBy re‐purposing an existing medication, in combination with a current AD treatment, we will be able to build upon extensive previous research and development efforts, reducing the time frame and costs of making this promising therapy available to patients with AD. Re‐purposing an existing drug likely represents the only realistic option for meeting the HHS goal to “Prevent and Effectively Treat Alzheimer's Disease and Related Dementias by 2025."
The biomarker roadmap for the validation for Alzheimer’s biomarkers: Methodological update for biomarkers of tauopathy
Authors: Boccardi Marina , Dodich Alessandra , Albanese Emiliano , Gayet‐Ageron Angèle , Walter Martin , Rabinovici Gil D. , Carrillo Maria C. , Drzezga Alexander , Hansson Oskar , Nordberg Agneta K , Ossenkoppele Rik , Villemagne Victor L.L. , Teipel Stefan J. , Winblad Bengt , Garibotto Valentina , Frisoni Giovanni B. 
Published: December 2020

AbstractBackgroundThe 2017 Alzheimer’s disease (AD) Biomarker Roadmap structures the validation of AD diagnostic biomarkers into a systematic sequence of 5 Phases, each encompassing primary and secondary aims assessing analytical validity (Phases 1‐2), clinical validity (Phases 3‐4) and clinical utility (Phase 5). This framework allows us to assess current evidence and identify requirements, gaps, and research priorities towards Phase‐5 validity. While using this methodology to assess the validation status of biomarkers of tau pathology we revised this methodology consistently with progresses in AD research.MethodFirst, we critically appraised the adequacy of the 2017 Biomarker Roadmap to assess tau biomarkers and relative to the current biomedical perspective of AD (e.g., A/T/N framework). Second, we proposed and discussed the adaptations at a workshop (Geneva, November 11‐12, 2019) convening the Alzheimer’s Association and 8 leading AD biomarker research groups, tasked with assessing the validity of CSF‐, plasma‐ and imaging‐tau biomarkers for AD according to the updated Biomarker Roadmap framework.ResultThe 2019 updates apply to tau as well as other biomarkers and include: Phase 3: a greater variety of study designs (e.g., cross‐sectional in addition to longitudinal) and reference standards (e.g., AD biomarker confirmation in addition to clinical progression) deemed appropriate to appraise the evidence on tau biomarkers; Phases 1‐5:evidence appraisal examining quality of evidence in addition to target results. Most urgent research priorities for both tau and other biomarkers are to: Define specific clinically‐ and patient‐relevant outcomes with all pertinent stakeholders (patients, caregivers, clinicians, regulators), to prepare proper studies on clinical utility and implementation; Produce/adapt specific reporting guidelines facilitating methodological compliance, reporting and assessment of the produced evidence.ConclusionWe have revised the Biomarker Roadmap accommodating biomarkers of tau pathology. This revision improves the methodology also for the other AD biomarkers. To further boost their validation up to Phase‐5 studies, the available evidence should be assessed by methodologists not directly involved in the assessed studies, possibly through dynamic data sharing on accessible platforms. Compliance with this methodology is essential to implement tau biomarkers efficiently in clinical research and diagnostics.
The MEMOWAVE project: A phase I/II clinical trial targeting treatment of mild cognitive impairment through sound stimulation during slow‐wave sleep
Authors: Cacciamani Federica , Arnulf Isabelle , Van Quyen Michel Le , Oudiette Delphine , Herreño David Leonardo Henao , Valderrama Mario , Volle Emmanuelle , Epelbaum Stéphane 
Published: December 2020

AbstractBackgroundMild Cognitive Impairment (MCI) is a highly prevalent syndrome especially among the elderly, but its treatment remains challenging. The MEMOWAVE project is a phase I/II randomized, double blind and cross‐over clinical trial. The first objective is to validate the safety and tolerance of a device consisting of a small microphone, also equipped with electroencephalographic electrodes, inserted in the external ear canals. The device produces pink noises during slow‐wave sleep based on real‐time EEG acquisition. The second objective is to investigate the effectiveness of this device in amplifying cerebral slow waves during sleep through sound emission. The third objective is to study the effect of this stimulation on memory consolidation, attention, executive functions, insight, creativity and mood in patients with MCI. Indeed, there is converging evidence that deep slow‐wave sleep plays a major role in these aspects. This process has already shown improvements in memory performance in healthy subjects and during normal aging.MethodTwenty‐four patients between 40 and 85 years of age will spend three nights in a Center for sleep disorders. Their cognitive functions, insight, creativity abilities and mood will be tested before and after a night of slow wave stimulation or placebo (device in place without stimulation), in a randomized and crossover fashion.ResultWe expect that this device will represent a simple therapeutic approach, easily tolerable by the patient, and able, if successful, of being offered quickly to a larger population of patients with MCI.ConclusionWe are proposing a new innovative methodology for the treatment of MCI which we are going to test for safety and efficacy.
Therapeutic implications of bio‐algorithm in Alzheimer's disease: Evaluation study
Authors: Mitrasinovic Olivera 
Published: December 2020

AbstractBackgroundUnderstanding Alzheimer's Disease (AD) at the molecular level is prerequisite for successful Diagnostics as well as testing experimental Therapies. Requirements for what are costly materials for many global laboratories have created, in the last two decades, interest in exploring potential of computer technologies, popular Artificial Intelligence (AI) as assisted discovery tool. Despite significant progress, theoretical search for new therapeutics remains under scrutiny. Our study objective was sought to add in the evaluation of its applicability.MethodIn a computer supervised undisclosed‐to‐user study, algorithmic learning task based on modified MatLab platform has been given input data for which experimental laboratory results were known, and program produced output files were subjected to comparative analysis in order to validate their accuracy.ResultsWe demonstrate protocol for AI modeling IL‐1α—>IL‐1αR—>MyD88—>TRAF—>IKK—>NFκB signaling pathway that is among main inducers of pro‐inflammation in AD. Rationale for how we introduce standards for normalization iis given. Comparative analysis with experimental laboratory results has showed complete accuracy overlap in mapping signal transducing sequence among interacting factors. Moreover, new protein interactions are identified. Kinetic assay of the IL‐1α/IL‐1αR extracellular binding, as [IL‐1] dose dependent, or over the time course, is feasible for monitoring.ConclusionOur results demonstrate collaborative potential of AI‐based methodology as cost‐effective for studies aimed to elucidate mechanism of AD, also early detection screenings and validation tests, while identifying signaling changes among interacting factors may be helpful in predicting clinical outcomes. Ability of the program to monitor kinetic changes is particularly useful for Cytotoxicity assays. Accuracy of AI methodology, dependent on quality of the available data used as input, represents the limitation at the present time. Acknowledgment: Alzheimer's Association, in part.