bluuebunny/crossref_metadata_2025_split huggingface dataset:
Brain‐targeted intranasal formulation of Centella asiatica: A potential strategy for treating Alzheimer’s disease
Authors: Haroon Hajira Banu B , Mukherjee Dhrubojyoti , Jayaraman Anbu 
Published: December 2021

AbstractBackgroundA major drawback associated with the conventional AD therapy is the inability of drugs to cross Blood Brain Barrier (BBB). Although, many drugs show potential to dissolve amyloid protein in vitro, only few mimics this action in vivo due to hindrance by BBB. One such drug is Centella asiatica containing asiaticoside that is proven to dissolves amyloid protein in vitro but lacks in vivo effects.MethodThe study was designed to develop a nasal formulation of an herbal drug (Centella asiatica) using brain targeted polymers to bypass the BBB to enhance the penetration of Centella in the brain.The extract of C. asiatica was first encapsulated into β‐ cyclodextrin by acid‐base precipitation method. These particles were nanonised and encapsulated into thiolated eudragit (TE) by ionic gelation method. The nanoparticles were characterized by FTIR, XRD, DLS, SEM, AFM and Ex ‐ vivo permeation studies. MTT assay was performed using Human Umbilical cord Vein Endothelial Cells (HUVECs) mimicking Blood‐Brain‐Barrier (BBB) to establish the safety and permeability of NPs. Further, the targeting efficacy was confirmed by molecular docking studies against receptors Sphingosine‐1‐Phosphate receptor 1 and Low‐density lipoprotein Receptor‐related Protein associated with BBB.ResultFTIR and XRD studies confirmed encapsulation of Centella into beta cyclodextrin and TE. Nanoparticle characterization confirmed the size and stability of the particles with zeta potential of −10.43 mV and Pdi of 0.260. NPs showed no signs of nasal ciliotoxicity and had good permeation of 88.44 ± 2.65 % (Mean ± SD, n=3) at 8h across nasal mucosa. MTT assay showed that the nanocomposite had lesser toxicity and better permeability compared to free drug (IC50 of Centella – 269.1 μg/mL and IC50 of nanoformulation – 310.625 μg/mL). The affinity of polymer to the receptors associated to BBB was proved by docking studies proves the ability of polymer‐based NPs to concentrate in brain post nasal administration.ConclusionThe study successfully showed that the NPs containing Centella had better permeability across BBB that could be beneficial in treating AD when administered intranasally.
A polygenic risk score for the prediction of Alzheimer's disease in rural‐dwelling older adults in China
Authors: Hou Tingting , Liu Keke , Liu Cuicui , Cong Lin , Wang Yongxiang , Du Yifeng , Qiu Chengxuan 
Published: December 2021

AbstractBackgroundPolygenic risk score (PRS), a weighted sum of the risk alleles of single nucleotide polymorphisms (SNPs), has been developed to predict Alzheimer’s disease (AD) among different ethnic populations. However, such a PRS is not available among the Chinese elderly population. We sought to develop a PRS for AD and further evaluate its predictive ability among rural‐dwelling older adults.MethodThis population‐based study included 4691 participants (age ≥65 years; 57.3% women) who were examined in 2018;of these, 2089 had been previously examined and diagnosed as free of dementia in 2014‐2015.We performed multiplex PCR assay to detect 58SNPs. AD was diagnosed following the NIA‐AA criteria. We applied logistic models to the 2018 data for the cross‐sectional SNPs‐AD associations, and identified candidate risk SNPs potentially associated with AD risk (p<0.30). The area under the ROC curve (AUC) was calculated to evaluate its discriminative ability. Cox models were employed to examine the longitudinal PRS‐AD association using the follow‐up data. We used C‐index to assess the predictive ability of the model. Finally, we conducted the internal validation of the model using bootstrap methods.ResultIn the cross‐sectional analysis (n=4691, 181 AD cases), 17 risk SNPs were identified for the PRS. A high PRS (>75th vs. <25th percentile) was associated with an age‐ and sex‐adjusted odds ratio of 2.62 for AD (95% CI: 1.65‐4.25); The AUC of PRS alone to discriminate AD was 0.597 (0.554‐0.638); when adding age and sex, AUC increased to 0.80 (0.763‐0.837). Of the 2089 baseline dementia‐free participants, 85 developed AD during the 4‐year follow‐up period. A high PRS (>75th vs. <25th percentile) was associated with a2.07‐fold risk of AD (1.12‐3.81) after adjusting for age and sex; The C‐statistic for AD prediction was improved from 0.783 to 0.826 when adding the PRS to the base model of age, sex, and education. Calibration plots showed good performance of the model for predicting the 3‐year risk of AD.ConclusionPolygenic risk score that incorporates common genetic variants is associated with an increased AD risk in Chinese elderly population. The PRS may help identify individuals at risk for AD.
Development of a healthy lifestyle index within a multidomain intervention aimed at prevention of cognitive impairment and dementia, and its association with cognition: Results from the FINGER trial
Authors: Barbera Mariagnese , Lehtisalo Jenni , Rissanen Heta , Hannukkala Roosamari , Ngandu Tiia , Solomon Alina , Laatikainen Tiina , Strandberg Timo , Antikainen Riitta L , Tuomilehto Jaakko , Hänninen Tuomo , Soininen Hilkka , Kivipelto Miia 
Published: December 2021

AbstractBackgroundGiven the complex and multi‐factorial aetiology of dementia, preventive interventions targeting several risk‐factors simultaneously and tailored on specific risk‐profiles are likely to be most beneficial. To date, trials testing lifestyle‐ and vascular‐based multidomain interventions for dementia and cognitive decline prevention have shown inconsistent results. In particular, achieving sufficient level of intervention intensity, accurately assessing adherence, and identifying the optimal target population have been highlighted among the key challenges. Within FINGER, the first large trial showing the efficacy of a multidomain intervention in preventing cognitive decline, we aimed to develop a Healthy Lifestyle Index (HLI) as a potential easy‐access indicator of adherence, and to assess its association with cognition.MethodThe HLI (score 0‐24) was developed based on a brief set of self‐reported questions collected at baseline, 12, and 24 months within the FINGER trial (N=1260) and across four lifestyle components: physical activity, diet, smoking and alcohol, and social and cognitive activity. The FINGER cognitive outcomes were the overall z‐score from a Neuropsychological Test Battery (NTB, 14 tests, primary outcome) and the z‐scores of the NTB cognitive domains (secondary outcomes). Linear mixed‐models repeated‐measures with maximum likelihood estimation were used to assess the effect of the intervention on change in the HLI and associations between HLI and cognition over the 2‐year study period.ResultThe intervention led to an increase in HLI (P<0.001). At baseline, the HLI was directly associated with the overall NTB z‐score (b=0.024; 95% CI: 0.014‐0.033; P<0.001) and individual cognitive domains. Baseline HLI was significantly associated with 2‐year changes in the NTB z‐score (0.006; 95% CI: 0.003‐0.010; P<0.001), as well as the memory domain. Changes in HLI were not significantly associated with 2‐year changes in cognitive outcomes.ConclusionThe FINGER HLI may potentially help measure and monitor adherence to multidomain interventions aimed at prevention of cognitive decline. Being developed as an easy‐access tool, its application could be especially relevant for those settings where more complex assessments are not feasible, such as implementation trials in clinical practice, and primary care in particular. More evidence is needed to determine its efficacy in predicting response to such interventions.
Effectiveness of home‐based telerehabilitation in mild to moderate Alzheimer’s disease: A randomised controlled study
Authors: Menengiç Kübra Nur , Yeldan İpek , Cınar Nilgun , Şahiner Türker AH 
Published: December 2021

AbstractBackgroundThe COVID‐19 pandemic has made it necessity that rehabilitation services are provided remotely to patients. These process required a transformation in healthcare. The aim of this study was investigate the effectiveness of the home‐based online supervised exercise program in Alzheimer’s disease (AD). To our knowledge, this is the first study to report the results of real‐time supervised physical exercise telerehabilitation program in AD.MethodEighteen subjects with early‐middle stage of AD were randomised into 2 group as telerehabilitation group (TG; mean age: 77.7 ± 5.29 years; 7 Female, 3 Male) and control group (CG; mean age: 78.5 ± 7.07 years; 5 Female, 3 Male). Our primary outcome was Mini‐Mental State Examination (MMSE), seconder outcomes were Timed Up&Go (TUG), One‐leg Balance Test (OLBT), Functional Independence Measure (FIM), Geriatric Depression Scale‐Short Form (GDS). The 6‐week motor‐cognitive dual‐task exercise training was performed online and under the supervision of physiotherapist through videoconference. No physical or cognitive intervention was applied to the control group for 6 weeks. Subjects were assessed before and after the treatment. In statistical analysis, the change in the outcome scores was calculated (∆ = last measurement‐first measurement), the difference between the groups was performed with the Mann Whitney‐U Test in SPSS 22.0. Trial’s protocol is registered with Clinicaltrials.gov under number NCT04606251.ResultThere was a significant difference between TG and CG in favor of TG in MMSE, TUG, FIM and GDS (p<0,05); There was no significant difference between groups in OLBT (p>0,05). Statistical results have been showed in Table 1. No safety problem was observed during the treatment. All subjects were completed the study, there was a high adherence to treatment.ConclusionPhysical exercise treatment with telerehabilitation was feasible, safe and well‐accepted by people with early‐middle stage of AD. Online‐supervised exercise program can improve cognitive function, functional mobility, independence and reduce depressive symptoms.
Evaluating the importance of historical address histories in an air pollution and dementia study
Authors: Leary Cindy S , Hajat Anjum , Fitzpatrick Annette L , Park Christina , Ilango Sindana , Adam Claire , Kaufman Joel D , Semmens Erin 
Published: December 2021

AbstractBackgroundEvidence linking long‐term air pollutant exposures with dementia‐related risks is increasing. Changes in the brain may occur decades before diagnosis, and studies assessing the effects of air pollution on dementia should account for participant residential history to reduce exposure misclassification. Using the Ginkgo Evaluation of Memory Study (GEMS), we evaluated cumulative PM2.5 and NO2 exposure on dementia risk both with and without historical residential addresses.MethodGEMS was a randomized trial of 3,069 participants in Hagerstown MD, Pittsburgh PA, Sacramento CA, and Winston‐Salem NC from 2000‐2008. Residential historical addresses were obtained through LexisNexis, a company constructing address histories from public databases. PM2.5 (1980‐1999) and NO2 (1990‐1999) cumulative exposures were calculated for each participant from a spatio‐temporal model in two ways: 1) using residential address histories reconstructed from LexisNexis addresses from 1980‐1999 (Figure 1), and 2) assuming participants lived from 1980‐1999 at the address documented during the GEMS baseline visit (2000‐2002). Hazard ratios from Cox models of all‐cause dementia, Alzheimer’s disease (AD), and mixed vascular dementia (VaD/AD) were compared across both sets of cumulative PM2.5 and NO2 estimates. Models were adjusted for age, study site, randomization year, gender, treatment group, neighborhood deprivation index (NDI), education, smoking status, smoking pack years, passive smoking exposure and apolipoprotein E4 (APOE4) status.ResultHazard ratios based on the LexisNexis historical addresses were generally larger than those from analyses without residential histories (Figure 2). The largest attenuation in effect after eliminating address history was for participants with vascular dementia either with or without AD (VaD/AD). An approximate interquartile range (IQR; 3 µg/m3) increase in 10 year mean NO2 exposure was associated with a 39% (95% CI: 7%, 81%) greater risk of mixed VaD/AD, but this decreased to 25% (95% CI: ‐7%, 66%) without histories. Similarly, an IQR (2 µg/m3) increase in 20 year PM2.5 was associated with a 19% (95% CI: 4%, 36%) greater risk of all cause dementia compared to 14% (95% CI:‐1%, 31%) without the historical addresses.ConclusionFor epidemiological studies aiming to quantify long term place‐based exposures related to dementia risk, utilizing residential address databases may reduce misclassification in exposure assignments.
Quantified analysis of Aβ plaques and microglia from in vivo cohort of patients with idiopathic normal pressure hydrocephalus
Authors: Luikku Antti J. , Rauramaa Tuomas , Nerg Ossi , Koivisto Anne M. , Junkkari Antti , Martiskainen Henna , Soininen Hilkka , Hiltunen Mikko , Leinonen Ville 
Published: December 2021

AbstractBackgroundAlzheimer’s pathologic change is frequently observed among patients with idiopathic normal pressure hydrocephalus (iNPH). Amyloid‐beta (Aβ) plaques and pathologic tau deposits in vivo are the hallmarks of neuropathologically verified AD, but correlation of Aβ plaque amount to cognitive decline remains controversial. The microglia reaction related with the brain Aβ pathology is under intense research and may modulate the toxicity of Aβ accumulation. Our aim is to characterize Aβ pathology and load in detail and evaluate microglia reaction related with the plaques and their correlation with clinical outcome.Method51 patients were shunted for iNPH between 9/2010 and end of 2017 with frontal cortical biopsy positive for Aβ. Aiforia create‐machine learning (ML) software was used on whole slide images (WSI) of ionized calcium binding adaptor molecule 1 (Iba1)/Aβ stained biopsies. ML was used to recognize Aβ area and Iba1 stained microglia somas. Clinical Dementia Rating global score (CDR‐GS) and Alzheimer’s clinical syndrome (ACS) were evaluated retrospectively at the end of the median follow‐up of 7.6 years (range 4.1‐ 14) during which 40 patients died.ResultDuring the follow‐up 19 patients were diagnosed with Alzheimer’s clinical syndrome. Trained image analysis yielded recognition precision for tissue, Aβ and microglia somas with 0.99, 0.98, and 0.96, respectively. Percentage of Aβ area, microglia soma density and reactive microglia within 25 µm of Aβ plaques were acquired. In univariate analysis, preoperative MMSE was significant predictor of CDR‐GS (p < .001) and ACS (p < .01). In multivariate analysis, high preoperative MMSE predicted lower CDR‐GS on follow‐up (OR 0.74 [0.63‐0.85]) and lesser development of ACS (OR 0.86 [0.75‐0.99]). Among demented subjects, there was a trend of higher Aβ area density (median 2.4 % for CDR‐GS 0.5 and 10.1 % for CDR‐GS 3), and reactive microglia (median 84 for CDR‐GS 0.5 and 178 for CDR‐GS 3).ConclusionHigher Aβ load and reactive microglia might predict worse cognitive outcome and dementia. As additional patients will be analyzed during spring 2021, we will expect this trend to turn significant. Good baseline cognitive performance seems to protect from later development of Alzheimer’s clinical syndrome and dementia among iNPH patients.
Higher levels of the astrocytic marker CSF YKL40 are associated with better memory performance only in amyloid‐positive individuals with subjective cognitive decline
Authors: Sánchez‐Benavides Gonzalo , Milà‐Alomà Marta , Suarez‐Calvet Marc , Brugulat‐Serrat Anna , Grau‐Rivera Oriol , Arenaza‐Urquijo Eider M , González‐de‐Echávarri José Maria , Minguillón Carolina , Fauria Karine , Salvadó Gemma , Shekari Mahnaz , Operto Greg , Cacciaglia Raffaele , Falcon Carles , Kollmorgen Gwendlyn , Suridjan Ivonne , Molinuevo Jose , Zetterberg Henrik , Blennow Kaj , Gispert Juan Domingo ,   ALFA Study
Published: December 2021

AbstractBackgroundIt is not clear whether neuroinflammation is a detrimental or a compensatory mechanism in Alzheimer’s disease (AD). Recent evidence suggests that increased levels of YKL40 are related to better memory performance in cognitively unimpaired older individuals with memory complaints. In this study, we aimed i) at replicating these previous findings and ii) extending to other markers by exploring the relationship between cognitive performance and cerebrospinal fluid (CSF) biomarkers of astrocytic (YKL40, GFAP and S100) and microglial (sTREM2) neuroinflammation‐related activation, and to explore whether this association is further modulated by amyloid status and presence of subjective cognitive decline (SCD) in a middle‐aged cohort of cognitively unimpaired individuals.MethodWe included data from 392 individuals from the ALFA+ cohort (mean age 61 years). CSF measures of amyloid pathology (Aβ42/40) pathology and YKL‐40, GFAP, S100 and sTREM2, were analyzed with the exploratory Roche NeuroToolKit assays, a panel of automated robust prototype immunoassays. Individuals were classified as amyloid positive (A+) or negative (A‐) using the Aβ42/40=0.071 cut‐off and as SCD or non‐SCD using the SCD‐Questionnaire. Memory and Executive cognitive composites were used as dependent variables in linear models using CSF biomarkers with covariates (age, sex, education) as predictors. Interaction terms with biomarker*Amyloid status*SCD status were also modeled.ResultOne hundred and thirty‐five individuals (34.4%) were A+ and 107 (27.3%) displayed SCD (Table 1). For Memory composite we found significant interactions for YKL40*Amyloid*SCD (p=0.04) and sTREM2* Amyloid *SCD (p=0.03). In stratified analyses by Aβ and SCD we observed that Memory performance was positively associated with YKL40 in Aβ+ that also display SCD (n=39, p=0.019, Figure 1). No significant associations were found in stratified analysis with sTREM2 (neither by Amyloid nor by SCD status). For GFAP and S100, no associations were observed nor for any analysis with the Executive composite.ConclusionAstrocytic (YKL40), but not microglial (sTREM2), activation was associated with better memory performance in those cognitively unimpaired individuals with evidence of Alzheimer’s pathophysiological changes and subjective cognitive decline. Thus, some specific neuroinflammation may be beneficial at the end of the AD preclinical stage, in which subjective SCD arise.
The association between diet in mid‐life and dementia incidence over a 20‐year period
Authors: Glans Isabelle , Sonestedt Emily , Nägga Katarina , Gustavsson Anna‐Märta , Stomrud Erik , Melander Olle , Nilsson Peter , Palmqvist Sebastian , Hansson Oskar 
Published: December 2021

AbstractBackgroundModifiable risk factors account for 40% of worldwide dementias. A potential modifiable risk factor for dementia and cognitive impairment is diet. However, there are conflicting results and methodological weaknesses in previous studies. The aim of this study was to investigate whether midlife diet quality is associated with subsequent risk of developing all‐cause dementia, Alzheimer’s disease (AD) or vascular dementia (VaD). In addition, the association between diet quality and future accumulation of β‐amyloid (Aβ) in cerebrospinal fluid (CSF) was examined.MethodBaseline examination within the Swedish population‐based Malmö Diet and Cancer Study (MDCS) took place between 1991‐1996 on 30,447 middle‐aged individuals. Participants from the MDCS with complete baseline dietary examination were included in this study (n=28,027) and the follow‐up for incident dementia took place until December 31, 2014. Diagnoses were collected from the Swedish National Patient Register and validated by Memory Clinic physicians. CSF Aβ42 was available in a sub‐population (n=777). Information on dietary habits was gathered through a 7‐day food diary, a detailed food frequency questionnaire and a one‐hour interview. A diet quality index was calculated from adherence to nutrition recommendations of intake of dietary fibre, added sugar, fish and shellfish, fruit and vegetables and red and processed meat (0‐5 points, poor to good). Cox proportional hazard models were used to examine associations between diet and risk of developing dementia adjusted for age, sex, education, total caloric intake and season.ResultDuring a median of 19.8 years of follow‐up, 1,943 (6.9%) participants were diagnosed with dementia. Individuals adhering to diet recommendations did not lower the risk of developing all cause dementia (HR 0.98, 95% CI 0.95‐1.02), AD (HR 0.99, 95% CI 0.95‐1.04) or VaD (HR 0.98, 95% CI 0.91‐1.06). No significant association was found between diet score and abnormal Aβ accumulation measured with CSF Aβ42 (OR 1.10, 95% CI 0.66‐1.84),Conclusion: In this long‐term prospective cohort study, adherence to dietary recommendations for fibre, sugar, fish, fruit and vegetables and red and processed meat was not significantly associated with subsequent reduced risk for developing all‐cause dementia, AD or VaD.
Age‐dependency of total tau in the cerebrospinal fluid is corrected by amyloid‐beta 1‐40: A correlational study in healthy adults
Authors: Zebhauser Paul Theo , Berthele Achim , Franz Marie‐Sophie , Goldhardt Oliver , Diehl‐Schmid Janine , Priller Josef , Ortner Marion , Grimmer Timo 
Published: December 2021

AbstractBackgroundTau‐proteins are established biomarkers of neuroaxonal damage in a wide range of neurodegenerative conditions. Although measurement of total‐Tau (t‐Tau) in the cerebrospinal fluid (CSF) is widely used in research and clinical settings, the relationship of age and t‐Tau in the CSF is not yet fully understood. While a small number of studies reported a correlation between age and t‐Tau in the CSF of healthy adults, in clinical practice the same cut‐off‐value is used independently of patient’s age.MethodTo further explore the relationship between age and t‐Tau in the CSF and to disentangle neurodegenerative from drainage‐dependent effects in normal aging, we analyzed CSF‐samples of 83 carefully selected cognitively healthy adults and included amyloid‐beta 1‐40 (Aβ40) as a putative marker of drainage from the brain’s interstitial system in our analyses.ResultWe found a significant correlation of t‐Tau and age, which was no longer present when correcting t‐Tau‐ for Aβ40‐concentrations.ConclusionThese findings were replicated under varied inclusion criteria and call into question the reported association of age and t‐Tau in the CSF. Furthermore, they suggest diagnostic utility of Aβ40 as a possible proxy for drainage‐mechanisms of peptides into the CSF when interpreting biomarker concentrations in the context of neurodegenerative disease.