bluuebunny/crossref_metadata_2025_split huggingface dataset:
Screening of new BACE‐1 inhibitors from marine animals: Molecular interaction and pharmacokinetic studies to find new drug prototypes
Authors: Romanek Thabatta Giuliani Monclus , De Blasio Paola , Sciani Juliana Mozer 
Published: December 2021

AbstractBackgroundOne cause of the Alzheimer's disease (AD) is the amyloid plaques accumulation, generated after an endoproteolytic cleavage of APP by secretases (WAKABAYASHI; STROOPER, 2008). Secretase inhibitors have been studied, but failed in clinical trials due to high toxicity and/or efficacy (HUNG; FU, 2017). So far, the main clinical treatment for AD is the administration of cholinesterase inhibitors that only increases the patient's survival in a few years (GAN et al., 2004). Molecules from natural products have been used as prototypes in the development of new drugs, and species from marine habitat have provided compounds of therapeutic interest, none of them applied to AD (MALVE, 2016). Thus, the objective of this work was to find new druggable β‐secretase (BACE1) inhibitors among molecules described from marine animals, aiming a new prototype for amyloid plaques decrease.MethodMolecules from marine animals were searched in scientific articles and prepared for docking, conducted by Swiss Dock server, to predict molecular interaction with BACE1 (PDB code 2VKM). Results were analyzed by UCSF Chimera, and molecules were selected if they were positioned in the enzyme active site, with distance lower than 3 Å and binding energy lower than ‐6 kcal/mol. Selected molecules were analyzed for their pharmacokinetics properties (PK) and druggability using the SwissADME server.ResultFrom 48 molecules, 3 were selected by molecular docking. Psammaplin A (PsA) is one of them, extracted from the poriferous Aplysin and known for its antibacterial and antitumor activities (SELEGHIM et al, 2007). It had favorable binding energy (−9.71 kcal/mol) and short distance between the ligand and the protein (1,923 and 2,615 Å2); however, its PK was not suitable for a drug. On the other hand, 1H‐Benzo[de][1,6]naphthyridine and Sebastianine A had lower binding energy as well (−6.76 and −6,98 kcal/mol, respectively) and favorable PK: logP ∼2.5, high gastrointestinal absorption, brain‐blood barrier permeant, low ability to inhibit liver enzymes and no violation of the Lipinski’s rules, characteristics to be druggable.ConclusionUsing molecular docking, 3 molecules were selected as potential inhibitors of BACE1, being two of them druggable and good prototypes for the treatment of AD.
Evaluating the relationship between vascular endothelial growth factor (VEGF) and cognitive improvements following exercised‐primed transcranial direct current stimulation (tDCS) in mild cognitive impairment (MCI) and Alzheimer’s disease (AD)
Authors: Song Bing Xin , Herrmann Nathan , Gallagher Damien , Rapoport Mark , Charles Jocelyn , Papneja Purti , Rajji Tarek K. , Andreazza Ana C. , Oh Paul I. , Marzolini Susan , Kiss Alex , Swardfager Walter , Liu Celina , Vieira Danielle , Kim Doyoung , Koo Grace KY , Lanctôt Krista L. 
Published: December 2021

AbstractBackgroundVEGF has been associated with memory decline in neurodegenerative diseases. As an angiogenesis biomarker, VEGF should be analyzed to better understand the variable treatment response from tDCS, a non‐invasive brain stimulation, and the priming effect of exercise on tDCS for memory improvements in MCI and AD. Using blinded data from an ongoing clinical trial (EXPRESS), we aimed to evaluate the ability of serum VEGF to predict improvements for recall memory in MCI and mild AD patients.MethodParticipants were enrolled in a five‐week, randomized, blinded tDCS clinical trial to receive either exercise and sham tDCS, exercise and tDCS, or exercise‐education only and tDCS intervention. Exercise groups included a three‐week ramp‐up period. Participants were diagnosed using the Diagnostic and Statistical Manual of Mental Disorders (DSM‐5) criteria for major or mild neurocognitive disorder due to AD or mixed AD/vascular disease (etiology). VEGF serum concentrations were measured from blood samples at screening. Recall memory was assessed using the Word Recall Task from the Alzheimer's Disease Assessment Scale‐Cog (ADAS‐Cog) at screening, baseline and endpoint (2 weeks from baseline). Analysis of variance (ANOVA) evaluated recall memory and VEGF concentrations at screening between the two etiology groups. Multiple linear regression analysis determined the association between VEGF concentrations (pg/mL) and recall memory score improvements over treatment period (Δrecall).ResultIn 17 participants (58.8% male, 70.6% MCI, mean(±SD) age 72.8±7.2, years of education 17.1±2.0, VEGF 332.4±157.5, Δrecall 0.5±0.9), six participants (35.3%) were diagnosed as AD etiology only and eleven participants (64.7%) were mixed vascular/AD etiology with no differences in recall memory [F(1,15)=0.019,p=0.893] or VEGF concentrations [F(1,15)=1.488,p=0.241] between these two groups at screening. The regression analysis found that VEGF and etiology predicted Δrecall [F(2,14)=7.103,p=0.007,R2=0.504]. Controlling for etiology, VEGF concentrations were associated with Δrecall [B(SE)=‐0.003(0.001),p=0.039]; Δrecall decreased 0.003 for each pg/mL of VEGF.ConclusionIn this pilot sample, lower serum VEGF concentrations at screening predicted greater recall memory improvements when controlling for etiology. After un‐blinding, longitudinal analysis and a larger sample size will allow further examination of VEGF’s predictive and monitoring capacity as a biomarker for recall memory and other cognitive responses to exercise‐primed tDCS.
Relationship between CDR Sum of Boxes and ADAS‐COG derived from historical clinical trials
Authors: Mitchell Emma , d'Amico Valeria , Geerts Hugo 
Published: December 2021

AbstractBackgroundAlzheimer’s Disease Assessment Scale, cognitive subscale (ADAS‐Cog) has traditionally been used for monitoring cognitive function in AD clinical trials, while Mini‐Mental Score Evaluation (MMSE) usually is determined at baseline. Recently however, Clinical Dementia Rating Sum of Boxes (CDR‐SOB) has become increasingly popular. We sought to define a relationship between these three clinical scales based on outcomes in clinical studies where these three scales have been used on the same patient groups.MethodWe used Certara’s CODEx (Clinical Outcomes Database Explorer) Alzheimer database, consisting now of summary endpoints in 240 clinical trials with 651 study arms (over 83300 patients) from 290 publications. 65 datasets were identified where patients were evaluated both with ADAS‐Cog and CDR‐SOB, 53 datasets for MMSE and CDR‐SOB and 167 datasets for MMSE and ADAS‐Cog.ResultStrong correlation (r2=0.8817) was observed for the relationship CDR‐SOB = 0.3105 ADAS‐Cog ‐1.1159 (p=2.2E‐16). Similarly, the relationship between ADAS‐Cog = ‐1.90881 MMSE + 62.27423 had a correlation coefficient of 0.801. Finally the linear relationship between CDR = ‐0.62806 MMSE + 18.50328 had a correlation coefficient of 0.839.ConclusionUse of the CODEx database enables to derive relationships between popular cognitive clinical scales. This would help historical clinical trials in perspective using ADAS‐Cog with more recent studies where CDR‐SOB is used as the primary outcome.
Prevalence of sporadic cerebral amyloid angiopathy: A systematic review and meta‐analysis
Authors: de Kort Anna M. , Jäkel Lieke , Klijn Catharina J.M. , Schreuder Floris H.B.M. , Verbeek Marcel M. 
Published: December 2021

AbstractBackgroundThere is large variation in estimates of the prevalence of cerebral amyloid angiopathy (CAA). CAA is associated with an increased risk of cognitive dysfunction and intracerebral hemorrhages, and it is tightly linked to immunotherapy‐related side‐effects in Alzheimer’s disease (AD). Thus, accurate estimates of the prevalence of CAA are important. CAA can be diagnosed neuropathologically (‘definite CAA’), or during life (‘probable CAA’) using the (modified) Boston criteria based on MRI markers.MethodWe performed a systematic literature search in PubMed and EMBASE for studies on CAA prevalence in cohorts of patients with AD, population‐based individuals, healthy elderly, patients with intracerebral hemorrhage (ICH), and patients with lobar ICH. Study inclusion criteria were: 1) a study population of at least 10 subjects, 2) a mean age of ≥ 55 years, 3) diagnostic criteria included use of neuropathology or MRI (T2* or SWI), 4) outcome measures included CAA prevalence according to neuropathological assessment or the (modified) Boston criteria, or the prevalence of the MRI markers used in the Boston criteria: strictly lobar microbleeds or cortical superficial siderosis.ResultWe included 170 studies including over 73,000 subjects. We found that in patients with AD, the estimated prevalence of CAA based on pathology (48%) is twice the prevalence based on the presence of strictly lobar microbleeds (22%). In the general population, this difference is threefold (23% vs 7%). However, both methods yield the same estimated prevalence of CAA in healthy elderly (5‐7%), in patients with ICH (19‐24%), and in patients with lobar ICH (50‐57%). In addition, we observed large heterogeneity in both neuropathology and MRI study protocols.ConclusionCAA is a very prevalent condition in AD and in the population. Since CAA is associated with the development of amyloid‐related imaging abnormalities in anti‐amyloid β immunotherapy, a faster decline of cognitive function in AD, and a growing spectrum of clinical symptoms, awareness of the high prevalence of CAA is important. In addition, we found that MRI markers seriously underestimate the prevalence of CAA in AD patients and population‐based individuals. Lastly, our results emphasize the need for standardized assessment and reporting of CAA in neuropathology and MRI studies.
Plasma biomarker profiles and the association with cognitive function across the clinical spectrum of Alzheimer's disease
Authors: Xiao Zhenxu , Wu Xue , Wu Wanqing , Liang Xiaoniu , Luo Jianfeng , Ding Saineng , Zheng Li , Zhao Qianhua , Xu Hong , Ding Ding 
Published: December 2021

AbstractBackgroundThe plasma biomarkers showed a promising value in the disease management of Alzheimer’s disease (AD). However, the profiles of the plasma biomarkers and the association with cognitive domains along the spectrum of AD have seldom been reported.MethodA total of 451 participants were recruited from a memory clinic cohort and a cohort with community‐dwellings. The global and domain‐specific neuropsychological tests were administrated in all participants. The Clinical Dementia Rating (CDR) was used to assess the severity of cognitive impairment. The diagnosis of mild cognitive impairment (MCI) and dementia were based on the Petersen’s criteria and DSM‐IV criteria. The AD was diagnosed according to the NINCDS‐ADRDA criteria. We described the continuum of AD based on the combination of CDR and the cognitive diagnosis: NC (CDR = 0), aMCI‐s (CDR = 0.5), aMCI‐m (CDR = 0.5), AD (CDR = 1), AD (CDR = 2), and AD (CDR = 3). The plasma Aβ 40, Aβ 42, Aβ 42/Aβ 40, t‐Tau, neurofilament protein light chain, and p‐Tau 181 were quantified using the Single molecule array platform. One‐way Analysis of Variance and Welch test were used for comparison among plasma markers. The association between domain z scores and log‐transformed plasma biomarker indexes were examined using partial Pearson correlation analysis with the adjustment for confounding variables.ResultThe concentration of plasma p‐Tau 181 basically increased along the clinical cognitive status, from normal cognition (CDR = 0) to AD (CDR = 3). There are varying degrees of correlation between six plasma biomarkers and different cognitive domains. Plasma p‐Tau 181 had the strongest correlation with MMSE (r = ‐0.494, P< 0.001), Memory (r = ‐0.417, P< 0.001), Attention (r = ‐0.388, P< 0.001), Visuospatial function (r = ‐0.328, P< 0.001), and Language (r = ‐0.123, P= 0.014). There was significant negative correlation between plasma p‐Tau 181 and four subgroups of cognitive domains, including MMSE in CDR >=1 group, Memory in CDR = 0.5 group & CDR >=1 group, and Attention in CDR >= 1 group.ConclusionPlasma p‐Tau 181 increased along the clinical continuum of AD, and had the strongest correlation with cognitive domains among all plasma biomarkers.
Cannabinoid agonist WIN 55,212‐2 improves memory consolidation in a rat model of basal forebrain cholinergic lesion
Authors: de Tena Iker Bengoetxea , Martínez‐Gardeazabal Jonatan , Moreno‐Rodríguez Marta , Pereira‐Castelo Gorka , Manuel Iván , Rodríguez‐Puertas Rafael 
Published: December 2021

AbstractBackgroundAlzheimer’s disease (AD) is associated with a selective vulnerability of basal forebrain cholinergic neurons (BFCN). The endocannabinoid (eCB) system modulates those BFCN pathways in AD. However, the effect of cannabinoid compounds on memory and learning remains controversial. Therefore, we evaluate the effect of cannabinoid agonists in recognition learning and memory in rats with a specific lesion of BFCN.MethodSprague‐Dawley male rats were infused bilaterally in the BFCN with 192IgG‐saporin toxin, (SAP group, n=10). Another group of SAP rats was treated with CB1 receptor agonist WIN 55,212‐2 for 5 days (SAP+WIN, n=10). Memory and learning were evaluated by Novel Object Recognition Task (NORT). The ability to identify new objects in the short term (3h after learning) and the long term (24h after learning), and other exploratory parameters, were measured.ResultIn the short term, control group and SAP group spent significantly more time exploring the new object than the old one (CON: 68.37% ± 4.05, p>0.01 and SAP: 60.72% ± 2.86, p>0.01), while SAP+WIN group did not (50.42% ± 5.73). In the long term, control group spent significantly more time exploring the new object than the old one (70.81% ± 2.42, p>0.001), but SAP group failed to do so (54.85% ± 3.93). Interestingly, SAP+WIN rats also spent more time exploring the new object than the old one (60.37% ± 6.36, p>0.05). Moreover, SAP group showed an increased exploratory behavior compared to control group, measured by the total exploration time in the long term (SAP: 49.76s ± 5.36 vs CON: 26.51s ± 4.45, p>0.05) and the number of rearings performed (SAP: 30.5 ± 2.4 vs CON: 21.3 ± 2.3, p>0.05). WIN 55,212‐2 treatment did not modify these latter parameters.ConclusionThese results suggest that degeneration of BFCN pathways does not impair learning in NORT test, but impairs memory consolidation. A sub‐chronic treatment with WIN 55,212‐2 was able to restore memory in rats with a BFCN lesion, even if it induces attention deficits at the short term. Thus, we suggest that cannabinoid agonists might be a plausible treatment for the typical contextual recognition problems derived from BFCN impairment in AD patients.
Midlife infarct burden and risk of dementia: The Atherosclerosis Risk in Communities Neurocognitive Study
Authors: Sullivan Kevin J , Ghelani Kunali , Rajesh Aishwarya , Shrestha Srishti , Gottesman Rebecca F , Knopman David S. , Mosley Thomas H , Griswold Michael E , Windham B Gwen 
Published: December 2021

AbstractBackgroundImaging‐based markers of cerebrovascular disease are associated with adverse health events, including incident dementia. However, only infarcts ≥3mm are typically considered in clinical and research settings. Recent evidence demonstrates that smaller infarcts in individuals during mid‐life, particularly when co‐occurring with larger infarcts, may be clinically relevant to cognitive decline, incident stroke, and stroke mortality. We aimed to determine if there was a similar compounding of risk for incident dementia among those with both smaller and larger infarcts at midlife.MethodThe ARIC study is a multi‐site longitudinal cohort study which began in 1987. At visit 3 (1993‐95), brain 1.5T MRI scans were completed in 1881 participants with self‐reported Black/White race and no history of stroke (Mean age=62.9±4.9, 40% Male, 50% Black). Infarcts were identified on T2 and proton density weighted images, with smaller infarcts defined as those <3mm and larger infarcts defined as ≥3mm. All participants were followed prospectively for incident dementia using a combination of medical record surveillance, telephone interviews, in‐person assessments, and expert adjudicated dementia status at three in‐person exams (2011‐2013, 2015‐17, 2018‐19). Cox regression was used to determine the association between infarct group [none(referent), smaller only, larger only, both] and incident dementia adjusted for age, sex, education, site‐race, APOE4, and competing risk of mortality.ResultAmong 1881 participants, 539 incident dementia cases were identified over 25 years of follow‐up. 1611 participants were infarct‐free, 50 participants had only smaller infarcts, 185 had only larger infarcts, and 35 participants had both. Compared to those with no infarcts, participants with both smaller and larger infarcts were over 2.5 times more likely to develop dementia [Hazard Ratio(HR)=2.61; 95% Confidence Interval(CI)=1.44, 4.72]. Associations were in similar directions but had wider and indeterminate confidence intervals when comparing the smaller infarcts only (HR=1.22; 95%CI=0.70, 2.13) or larger infarcts only (HR=1.27; 95%CI=0.92, 1.74) to the no infarct group. Of the 35 participants with both smaller and larger infarcts, all but two either died or developed dementia.ConclusionA midlife infarct burden including both smaller and larger lesions may represent a vulnerability to dementia beyond the risk conferred by either smaller or larger infarcts alone.
Are developmental learning disorders risk factors for late‐onset Alzheimer's disease?
Authors: Leiman Marina , Guinjoan Salvador Martín , Brusco Luis Ignacio , Villarreal Mirta Fabiana , Fiorentini Leticia 
Published: December 2021

AbstractBackgroundFactors associated with early life educational performance can be related to neurodevelopment, cognitive functioning and, consequently, the risk for dementia, but have received less attention than adult biomarkers.MethodA systematic review of the evidence available up to October 2020 in PubMed and Scopus was carried out. Original articles addressing both developmental learning disorders (LD) and late‐onset neurodegenerative diseases (NDD) were included.ResultA significant prevalence of LD was found in patients with atypical variants of Alzheimer's disease (AD). Furthermore, an association was found between primary progressive aphasia ‐ logopenic variant and language‐related LD, and also between posterior cortical atrophy and non‐language‐related LD. These results could be explained by the selective vulnerability hypothesis, which states that the vulnerability of a particular brain network or area could predispose both to developmental LD and late‐onset NDD.ConclusionDevelopmental LDs can be considered as risk factors for late‐onset NDD, especially for atypical AD variants. Given the scarcity of results and the limitations reported, a greater number of studies are required, with larger samples and, preferably, of longitudinal design in order to address this issue.
Target populations for behavioral and clinical interventions to protect cognitive function and brain structure: A two‐age, two‐cohort comparison
Authors: Zhang Xuan , Mbangdadji Djass , Gudnason Vilmundur , Launer Lenore J 
Published: December 2021

AbstractBackgroundMany multi‐modal lifestyle and cardiovascular risk reduction trials to lower the burden of Alzheimer’s Disease and Related Dementias (ADRD) are on‐going or planned. The optimal target populations for specific interventions are not established. We compared the association of behavioral and clinical risk factors to cognitive and brain MRI outcomes in two target groups from the same source population: an older [late age, LA] non‐demented participants in the Age, Gene/Environment Susceptibility – Reykjavik Study (AGES‐RS; n=4218, 76 yrs. old) and a middle‐aged (MA) cohort of Offspring, (n= 372, 63 yrs. old) to AGES‐RS AD cases.MethodOutcomes were the Digit Symbol Substitution Test (DSST) and total brain volume (TBV percent of intracranial volume). Protective factors were based on the American Heart Association (AHA) “simple 7”: moderate‐to‐vigorous physical activity (PA;>0 hours/week), no alcohol, no smoking, meeting socially≥1 time/week; low blood pressure (BP;<120/80mmHg), low cholesterol<200 mg/dl), and normal BMI<25kg/m2. Comparisons were made within and between two cohorts using age and sex‐adjusted logistic or linear regression. Between‐cohort effects were tested by an interaction term in the model. P‐values were Bonferroni corrected.ResultCompared to the LA, MA were significantly more likely to be physically active; among drinkers, consume more alcohol; more likely to smoke; but less likely to be social or have high BP. Cholesterol and BMI levels were similar. As expected, MA compared to LA cohort had a higher DSST and TBV. PA was significantly positively associated with the DSST and TBV (Table 1) in both cohorts; among the active MA, compared to LA, DSST was significantly higher (delta=3.7, p=0.02). In the MA, no smoking, social activity, and normal BMI were associated with better cognition but not to MRI. In the LA, no smoking, alcohol intake, and normal BMI were associated with better cognition and TBV. High cholesterol of MA was significantly associated with better cognition compared to LA (delta=2.9, p=0.02).ConclusionThe magnitude or directionality of associations varied between cohorts and outcomes, suggesting behavioral or clinical intervention needs to be tailored to specific target groups.
Self‐reported poor sleep accelerates hippocampal volume loss in cognitively normal healthy elderly
Authors: Alperin Noam 
Published: December 2021

AbstractBackgroundPoor sleep quality is a known risk factor for the development of Alzheimer’s disease (AD). However, minimal data is available on the rate of brain tissue volume loss related to self‐reported poor sleep. Our previous cross‐sectional study in cognitively normal elderly adults age 60 and over, demonstrated that poor sleepers exhibited significantly smaller volumes, approximately 7%, in the bilateral hippocampi, superior parietal lobules and left amygdala and smaller cortical thicknesses, over 3%, in the right superior frontal, medial orbitofrontal cortices and frontal pole, compared to normal sleepers (Alperin et al, 2019). Current study is a follow‐up longitudinal investigation comparing rates of tissue loss in these brain regions of interest (ROIs) between elderly good and poor sleepers with normal cognition.MethodForty‐eight cognitively normal elderly individuals age 60 to 92 years were classified into two groups: 23 normal sleepers with self‐reported Pittsburgh Sleep Quality Index (PSQI) < 5 and 25 poor sleepers with PSQI ≥ 5. The two groups were equivalent in terms of age, gender, years of education and white matter hyperintensity (WMH) load. The volumes and thickness of the ROIs were measured at baseline and at follow‐up scans to assess rates of tissue loss using FreeSurfer software. Rates of tissue loss over 2 years were compared between two groups.ResultNo significant association was found between sleep quality, WMH load and rates of thickness loss. Compared to normal sleepers, poor sleepers exhibited 2.8 times higher rates of volume loss in the hippocampus, and 3.3 times higher rate in the posterior cingulate. Global PSQI at baseline was significantly and negatively associated with rates of volume loss in the right hippocampus (rs=‐0.33) and right posterior cingulate cortex (rs=‐0.47). Scores in verbal memory was negatively associated with rates of volume loss in the right hippocampus (r≥0.388).ConclusionPoor sleep quality is associated with significantly accelerated volume loss in the hippocampus and the posterior cingulate cortex in cognitively normal elderly individuals. Intervention for improving sleep quality should be highly considered in cognitively normal elderly adults to delay onset of cognitive impairment and onset of AD.