bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of an SGLT2 inhibitor on cognition in diabetes involving amelioration of deep cortical cerebral blood flow autoregulation and pericyte function
Authors: Wang Shaoxun , Liu Yedan , Zhang Huawei , Guo Ya , Li Man , Gao Wenjun , Fang Xing , Shaffery James P. , Hosler Jonathan P. , Roman Richard J. , Fan Fan 
Published: December 2020

AbstractBackgroundDiabetes mellitus (DM) is a leading risk factor for aging‐related dementia. We previously demonstrated that an SGLT2 inhibitor (SGLT2i) reversed the impaired myogenic response (MR) of the middle cerebral artery (MCA) and cerebral blood flow (CBF) autoregulation on the surface cortex, and improved cognition with an eight‐arm water maze in 18‐month old diabetic rats. The present study aims to investigate whether normalizing plasma glucose by inhibition of SGLT2 also ameliorate MR of parenchymal arteriole (PA) and CBF autoregulation in the deep cortex, and the role of pericyte in the regulation of CBF autoregulation and cognitive function in DM.MethodDeep cortical CBF autoregulation was studied using laser Doppler flowmetry coupled with an implanted fiber‐optic probe. MR of PA was investigated using a pressure myography. The novel object recognition and open field tests were used to evaluate cognition. Mitochondrial‐derived superoxide production was detected by MitoSOX, and mitochondrial function was evaluated using Seahorse XFe24. Cell contraction was detected by a collagen gel‐based kit.ResultDeep cortical CBF rose by 223.34 ± 28.11, 49.03 ± 12.62, 50.12 ± 0.89%, respectively, in diabetic, SGLT2i treated diabetic and non‐diabetic rats when blood pressure was increased from 100 to 180 mmHg. PA constricted in response to elevated transmural pressure in SGLT2i treated diabetic and non‐diabetic rats, whereas dilated in diabetic rats. The percentage of time spent in the novel object was 43.32 ± 8.04%, 71.94 ± 8.48%, 75.68 ± 3.33% respectively in diabetic, SGLT2i treated diabetic, and non‐diabetic rats. No significant differences in total travel distance and resting time were found between these rats. High glucose‐treated pericytes displayed elevated mitochondrial ROS, and decreased ATP production, and lower their contractile capabilities.ConclusionThese results indicate that the SGLT2 Inhibitor reversed the impaired MR of the PA, CBF autoregulation in the deep cortex, and cognitive impairments in old DM, which may involve amelioration of hyperglycemia‐induced mitochondrial ROS production and ATP depletion in pericytes.
Targeting the BDNF/TrkB pathway for the treatment of amyloid beta 1‐40‒induced neurodegeneration: Focus on ocular manifestations of Alzheimer’s disease
Authors: Lazaldin Mohd Aizuddin Mohd , Iezhitsa Igor , Agarwal Renu , Agarwal Puneet , Bakar Nor Salmah , Ismail Nafeeza Mohd 
Published: December 2020

AbstractBackgroundAmyloidosis‐related alterations, similar to those seen in the brain of patients with AD, occur in the retina of glaucoma patients. Decreasing level of brain‐derived neurotrophic factor (BDNF) is believed to be associated with neurotoxic effect of Aβ peptide. Hence, in this study we investigated (1) the effect of BDNF on retinal damage induced by Aβ1‐40 and (2) involvement of BDNF‐TrkB signalling in neuroprotection by BDNF against beta 1‐40‐induced retinal damage in Sprague Dawley rats.MethodRats were divided into 3 groups: group 1 received PBS via intravitreal injection, group 2 received intravitreal Aβ1‐40 (5 nmol) while group 3 received BDNF (1 µg) as co‐treatment with Aβ1‐40 via intravitreal injection. Fourteen days after injections, rats were euthanized and eyes were enucleated, fixed and processed for histopathological examination of retinal and optic nerve morphology using H&E and toluidine blue staining, while retinal cells apoptosis were detected using TUNEL assay immunostaining. Estimation of GSH, SOD, catalase and BDNF level in retina was done through ELISA method. Additionally, retinal target proteins (caspase‐3, TrkB and ERK) and their gene expression level were assessed by Western blot analysis and real‐time PCR, respectively.ResultBDNF showed protective effect against Aβ1‐40‐induced retinal and optic nerve injury by preserving retinal and optic nerve morphology, lowering number of apoptotic cells, improving oxidative status and restoring BDNF level. Neuroprotective effect of BDNF correlated with number of survived retinal ganglion cells after Aβ1‐40 exposure. Assessment of visual function of rats using visual object recognition tests showed that BDNF improved difficulties for rats to recognise the visual cues after Aβ1‐40 exposure thus showing that visual function of rats was relatively preserved by treatment with BDNF. It was observed that treatment with BDNF abolishes Aβ1‐40‐induced increase in retinal expression of caspase‐3 and upregulates TrkB and ERK levels as it was shown by western blot analysis. BDNF also suppresses Aβ1‐40‐induced transcriptional activity of caspase‐3 and increases TrkB and ERK transcriptional activity in the regulation of apoptosis.ConclusionTreatment with BDNF prevents Aβ1‐40 induced retinal injury by inhibiting Aβ1‐40‐induced neuronal apoptosis via downregulation of caspase 3 and upregulation TrkB and ERK levels.
Causal pathway to analyze racial disparities in ADRD
Authors: Kim Yejin , Jiang Xiaoqian 
Published: December 2020

AbstractBackgroundHealth disparities in prevalence of Alzheimer’s disease and related dementia (ADRD) across different racial groups are mostly due to variations in socioeconomic status and comorbidity such as cardiovascular disease, diabetes, and obesity. We aim to investigate multifactorial influence of comorbidity to the ADRD risk for African Americans compared to Caucasian.MethodFrom 106 million patients’ electronic medical records in Cerner Health Facts, we built paired and comparable cohorts of each racial group by matching age, observation window, cardiovascular diseases, diabetes, obesity, and head injury. We then derived causal graphs respectively using PC algorithms.ResultWe found that the two causal graphs from African‐American and its paired Caucasian show very different clinical pathway to ADRD, even though the two cohorts follow similar distribution except race. For African‐American, we found three inflammatory pathways and one cardiology pathway, whereas for paired Caucasian, we found a pathway from polyneuropathy to septicemia, and dementia.ConclusionOur study identified the root and pathway of comorbidity risk factors, which hopefully will reveal more information about the differential weights of known risk factors to patients of different race.
CSF levels of the BACE1 substrate Neuregulin1 correlate with cognition and synaptic biomarkers in Alzheimer’s disease
Authors: Mouton‐Liger Francois , Dumurgier Julien , Cognat Emmanuel , Hourregue Claire , Zetterberg Henrik , Vanderstichele Hugo Marcel , Vanmechelen Eugeen , Blennow Kaj , Paquet Claire , Hugon Jacques 
Published: December 2020

AbstractBackgroundThe presynaptic protein Neuregulin1 (Nrg1) is cleaved by BACE 1 like amyloid precursor protein (APP), can activate post‐synaptic ErbB4 receptors and has been linked to schizophrenia. The couple Nrg1/ErbB4 is neuroprotective, can trigger synaptogenesis and plasticity and increases the expression of NMDA and GABA receptors. In addition this couple can also induce neuroinflammation and can reduce memory formation. In Alzheimer’s disease (AD) Nrg1 accumulates in neuritic plaques. It is therefore difficult to determine if Nrg1 has beneficial and/or detrimental effects in AD. BACE 1 levels are increased in AD brains and CSF, but no study has assessed CSF Nrg1 levels in AD and MCI‐ AD patients.MethodThis is a retrospective study, including 172 patients suffering from AD dementias (56), MCI‐ AD (21), non‐AD MCI (32), non‐AD dementias (36) and neurological controls (27). All patients had neurological exams, MRI and neuropsychological evaluations. After written informed consent and using the ELISA method, the CSFs of all patients were evaluated for Aβ1‐42, Aβ1‐40, tau, ptau, BACE1, neurogranin, SNAP25, SNAP25 aa40, synaptotagmin and Nrg1.ResultLevels of Nrg1 were significantly increased in the CSF of AD and MCI‐AD patients compared to non‐AD MCI, non‐AD dementias and neurological controls. In addition, Nrg1 levels positively correlated with tau, ptau, Aβ 1‐40, all synaptic biomarkers and BACE1 levels and negatively with MMSE and Frontal Battery ( BREF) scores.ConclusionAPP and Nrg1 are both cleaved by BACE 1 at synaptic levels. Aβ toxicity induces synaptic degradation with increased CSF levels of synaptic biomarkers and Nrg1. Reduced brain Nrg1 levels may reduce neuroptotection. Nrg1 is a new biomarker reflecting BACE1 activity and Aβ‐ induced neurodegeneration and can be correlated with the cognitive status in MCI‐AD and AD patients.
Utilizing a mobile clinical trials unit: Lessons learned from the first three years
Authors: Smith Amanda G. , Rodrigo Kelly , Lowe Patricia , Andrade Melissa , Burnett Elisabeth , Vasquez‐Ramos Myriam , Mba Ijeoma , Janavs Juris , Major Beth , Epstein Patricia , Wynne‐Phillips Heather , Flynn Myrna DeJesus , Morgan Dave 
Published: December 2020

AbstractBackgroundIt is well‐established that clinical trials for Alzheimer's Disease need faster enrollment. Transportation challenges can sometimes prevent potential subjects from participating in clinical trials. In Florida, many persons live more than 30 minutes from sites conducting clinical trials. Based on these facts, we created a mobile clinical trials unit that launched in the 2nd half of 2016.MethodWe created a mobile clinical trial unit on which all trial screening activity other than imaging could be performed. It is a 53' trailer with 400 square feet of space and allows for all aspects of study visits other than imaging to be conducted on it. We reflected upon the successes and failures of the last three years of experience with the unit with the team members who staff it. We also documented feedback from sponsors and participants.ResultWe have previously reported that the mobile unit increased the number of minorities participating in memory screening at Health Fairs (CTAD 2016) and doubled the number of participants we screened in prevention trials (AAIC 2018.) Additional positive findings include increased visibility in the community, feelings from subjects that we were making an effort to accommodate them, increased request for appointments in our clinic, increased enrollment in treatment trials compared to our main clinic alone, and national and international interest in expanding the concept. Challenges included cost of moving the unit and need to use a trucking company to do so, space requirements for parking, unexpected maintenance issues and associated costs, hesitancy of sponsors to adopt the concept, need for development of unit‐specific SOPs, staffing issues, and additional work & accountability transporting study materials such as drug, source documents, and labs.ConclusionThere are both pros and cons associated with the operation of a mobile clinical trials unit, especially when the unit itself is only semi‐mobile. Nevertheless, it has thus far ultimately been successful in expanding our pool of subjects across the spectrum of AD and increasing trial participation.
In silico modeling of pathogenic point mutations in APP, PSEN1 and PSEN2 in Asia
Authors: Nguyen Thuy Trang , Vo Tuong Kha , Vo Van Giau 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD), the most common form of senile dementia, is a genetically complex disorder. In most Asian countries, the population and the number of AD patients are growing rapidly, and the genetics of AD has been extensively studied. Amyloid protein precursor (APP), presenilin‐1 (PSEN1), and presenilin‐2 (PSEN2) mutations cause autosomal dominant forms of early‐onset Alzheimer disease (EOAD). Although these genes were identified in the last several decades, variant classification remains a challenge, highlighting the need to elucidate their role in neuropathologic features of autosomal dominant ADAD.MethodWe tested the performance of four prediction tools (Align‐GVGD, SIFT, PolyPhen‐2, MutationTaster2) using a set of 50 missense variants that had previously been reported. Finally, 3‐D modeling was also performed for all mutations.ResultWe summarized substitution mutations in the APP, PSEN1 and PSEN2 genes in Asia and attempted to identify pathogenic mutations using Align‐GVGD, SIFT, PolyPhen‐2, MutationTaster2, and 3‐D structure analysis techniques. Most of the mutations were confirmed as pathogenic mutations by these algorithms.ConclusionOur results contribute to a better understanding of the behavior of the mutations and their pathogenic nature process, which is necessary to understand AD pathogenesis. Following this work, some potential mutations would be chosen and further checked out their pathogenicity of in AD through cellular studies.
Anti‐amyloidogenic and cyclooxygenase inhibitory activity of Indigofera zollingeriana Miq
Authors: Vo Tuong Kha , Nguyen Thuy Trang , Vo Van Giau 
Published: December 2020

AbstractBackgroundAlzheimer's disease (AD) is a devastative neurodegenerative disorder which needs adequate studies on effective treatment options. The extracts of plants and their effect on the amelioration of AD symptoms have been extensively studied. Indigofera zollingeriana Miq is known in traditional folk medicine for treating cough, cold, sore throat, fever, wounds, epilepsy, and headaches.MethodTo discover the scientific pharmacological potential of Indigofera zollingeriana Miq, we explore its anti‐inflammatory, cytotoxicity, and inhibition of amyloid‐beta (Aβ) aggregation effects.ResultCyclooxygenase assay of the ethanol and aqueous extracts of Indigofera zollingeriana Miq are more selective to COX‐1 inhibition with a 50% inhibitory concentration (IC50) of 10.15 μg/mL for the both extracts. Neuroblastoma SH‐SY5Y inhibition and thioflavin T assay amyloid‐beta (Aβ) aggregate inhibition of the extracts significantly revealed their potential therapeutic effects against Alzheimer’s disease. The putative compounds from the LC‐MS analysis could be responsible for the observed activities.ConclusionThe results suggest that Indigofera zollingeriana Miq possesses anti‐inflammatory and anti‐neurodegenerative properties and a promising lead as a source of pharmacologically active compounds.
PET‐[18F]UCB‐H for assessing synaptic density in FTD
Authors: Salmon Eric , Bahri Mohamed Ali , Plenevaux Alain , Becker Guillaume , Seret Alain , Giacomelli Fabrice , Delhaye Emma , Degueldre Christian , Balteau Evelyne , Luxen André , Bastin Christine 
Published: December 2020

AbstractBackgroundThe behavioural variant of fronto‐temporal dementia (FTD) is characterized by clinical symptoms including behavioural and cognitive changes and by neurodegenerative involvement of the anterior part of the brain. The objective was to study the in vivo distribution of synaptic loss.Method12 patients with possible FTD and frontotemporal hypometabolism on FDG‐PET (mean disease duration of 4 years) were compared to 12 control participants and 12 patients with Alzheimer’s disease, matched for age, sex and education. Measures of verbal fluency, episodic memory and awareness of cognitive impairment did not differ between patients groups. We used [18F]UCBH‐PET to assess the regional loss of synaptic density. Total distribution volume was obtained with Logan method and carotid artery derived input function. SPM12 was used to analyze pve‐corrected PET and MRI images.ResultA significant decrease of [18F]UCBH uptake was observed in the right anterior parahippocampal gyrus of FTD patients, while atrophy was observed in the ventromedial prefrontal cortex. Loss of synaptic density was observed in the right hippocampus of AD participants, while atrophy extended from the right hippocampus to bilateral posterior associative cortices. AD patients showed lower [18F]UCBH uptake in the precuneus that FTD patients. Anosognosia for clinical symptoms was correlated with synaptic density in caudate nucleus and prefrontal cortex in FTD, and with synaptic density in posterior hippocampus in AD.ConclusionSynaptic loss was predominant in the anterior parahippocampal gyrus of our bvFTD patients. This region is part of the limbic network and the perceptive social brain. A validated measure of anosognosia (a characteristic but variable symptom in bvFTD) was related to synaptic density in two interconnected regions, caudate nucleus and anteromedial prefrontal cortex, the later being involved in self‐reference.
Optimizing Practices, Use, Care and Services‐Antipsychotics (OPUS‐AP): A phase 2 scale‐up to 129 long‐term care (LTC) centers in Quebec, Canada
Authors: Bruneau Marie‐Andrée , Couturier Yves , Gilbert Suzanne , Boyer Diane , Ricard Jacques , MacDonald Tanya , Arcand Marcel , Morin Michèle , Tousignant Marilyn , Rhéaume Andrée‐Anne , Turcotte Jean‐Philippe , Cossette Benoit 
Published: December 2020

AbstractBackgroundAntipsychotics are often used for the first‐line management of behavioral and psychological symptoms of dementia (BPSD) despite risks and side effects, and with disregard for guidelines recommendations to prioritize non‐pharmacological interventions. OPUS‐AP builds on Canadian Foundation for Healthcare Improvement, Appropriate Use of Antipsychotic initiatives and previous work by the 4 university‐affiliated research centers on an aging population in Quebec. The OPUS‐AP strategy is supported by an evidence‐based approach, involving provincial clinical guidelines developed by Québec’s health‐technology assessment agency, the Institut national d’excellence en santé et en services sociaux (INESSS). In phase 1 of OPUS‐AP, conducted in 24 long‐term care (LTC) centers in Quebec, Canada, antipsychotic deprescribing (cessation or dose decrease) was achieved in 85,5% of residents in whom it was attempted (Cossette et al. JAMDA, 2019).MethodPhase 2 of OPUS‐AP was conducted in 129 LTC centres in Quebec, Canada, from April to December 2019. OPUS‐AP aims at improving resident care through increased staff’s knowledge and competency, resident‐centered approaches, nonpharmacologic interventions, and antipsychotic deprescribing in inappropriate indications. OPUS‐AP is implemented through integrated knowledge translation and mobilization activities. Antipsychotic, benzodiazepine, antidepressant prescriptions and BPSD were evaluated every 3 months for 6 months.ResultAt baseline, 10,601 residents were admitted on OPUS‐AP participating wards from which 74% had a diagnosis of major neurocognitive disorder (MNCD) and 47% an antipsychotic prescription. The follow‐up cohort included 4,087 residents with both MNCD and antipsychotic prescription. Among the 1216 residents in whom antipsychotic deprescribing was attempted between baseline and 6 months and still included at 6 months, successful deprescribing was achieved in 85.6% (cessation 50.0% or dose decrease 35.6%). No increase in benzodiazepine or antidepressant prescriptions nor worsening of BPSD were observed.ConclusionPhase 2 of OPUS‐AP confirmed phase 1 results of successful antipsychotic deprescribing with scale‐up to 129 LTC centers. Phase 3 of OPUS‐AP is underway in 2020 in all of Quebec’s 341 public LTC centers.
A conceptual framework for future studies on subtypes of Alzheimer's disease
Authors: Ferreira Daniel 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is a heterogeneous disease. Recent neuropathology and neuroimaging studies have sought to formalize this heterogeneity by defining AD subtypes based on the distribution of tau neurofibrillary tangle pathology and regional brain atrophy. These studies consistently revealed the existence of four subtypes: typical, limbic‐predominant, hippocampal‐sparing, and minimal atrophy AD. We will give an overview on the current state‐of‐the‐art, leveraging on the first systematic review and meta‐analysis on subtype studies based on neuropathological and neuroimaging data, recently published by our group (Ferreira et al. 2020 Neurology). We will also present a conceptual framework to guide subtype studies in the future. Our ultimate goal was to advance our current understanding of mechanisms driving heterogeneity in AD dementia and its pre‐dementia stages.MethodThe EMBASE, PubMed and Web of Science databases were consulted for AD subtype studies based on neuropathological or neuroimaging data. We calculated meta‐analytical estimates on key demographic, clinical, and CSF biomarker measures. Prevalence values for the subtypes were also calculated. We summarized and integrated all the data on a hypothetical conceptual framework.ResultOur meta‐analytical analysis shows that typical AD displays tau neurofibrillary tangle pathology and atrophy both in hippocampus and association cortex, and has a pooled frequency of 55%. Limbic‐predominant, hippocampal‐sparing, and minimal atrophy AD had a pooled frequency of 21%, 17%, and 15%, respectively. Between‐subtype differences were found in age at onset, age at assessment, sex distribution, years of education, global cognitive status, disease duration, APOE ε4 genotype, and CSF biomarker levels.ConclusionWe identified two core dimensions of heterogeneity: “typicality” and “severity”. We propose that these two dimensions determine individuals’ belonging to one of the AD subtypes based on the combination of protective factors, risk factors, and comorbid non‐AD brain pathologies. This model is envisioned to aid with framing hypotheses, study design, results interpretation, and understanding mechanisms in future subtype studies. Unraveling the heterogeneity within AD is critical for implementing precision medicine approaches and for ultimately developing successful disease‐modifying drugs for AD.