bluuebunny/crossref_metadata_2025_split huggingface dataset:
Correlations of plasma kynurenines with CSF levels, and their relation to markers of Alzheimer’s disease pathology, diagnostic phases and cognitive performance
Authors: Bakker Lieke , Koehler Sebastian , Choe Kyonghwan , van den Hove Daniel L.A. , Kenis Gunter , Eussen Simone J.P.M. , Ueland Per M. , Verhey Frans R.J. , Ramakers Inez H.G.B. 
Published: December 2020

AbstractBackgroundFinding novel biomarkers for Alzheimer’s disease (AD) for prediction, diagnosis or disease monitoring is a key research area. The kynurenine pathway(KP) consists of different metabolites of the essential amino acid tryptophan that have putative neurotoxic and ‐protective properties such as NMDA‐receptor agonism or potent antioxidation. Small clinical studies have shown altered levels in blood plasma and cerebrospinal fluid(CSF) in AD and other neurodegenerative diseases. However, whether peripheral kynurenine concentrations in plasma resemble those found in CSF is still largely unknown. The present study aims to investigate whether kynurenine concentrations in plasma correlate with those measured in CSF, and to study the role of kynurenines as biomarkers for AD.MethodThis study uses baseline data from 800 participants obtained in the Biobank Alzheimer Centrum Limburg(BBACL) study, an ongoing prospective cohort study in patients of the memory clinic of the Maastricht University Medical Center, the Netherlands. Blood plasma and CSF concentrations (CSF available for 151 participants) of tryptophan, kynurenine, kynurenic acid, 3‐hydroxykynurenine, xanthurenic acid, anthranilic acid, 3‐hydroxy anthranilic acid, quinolinic acid and picolinic acid were determined by means of liquid chromatography‐tandem mass spectrometry. Additionally, Ab1‐42, total‐tau and phosphorylated tau in CSF were determined using commercially available single‐parameter ELISA methods. Correlational and multiple linear regression analyses studied associations between plasma and CSF kynurenine levels, associations of CSF kynurenine concentrations with AD pathological markers, differences in plasma and CSF kynurenine levels in different diagnostic phases (subjective cognitive decline, mild cognitive impairment, dementia) and their associations with cognitive performance.ResultPlasma concentrations of tryptophan (r = .43, p <0.001) and KP metabolites kynurenine (r = .42, p <0.001), 3‐hydroxykynurenine (r = .37, p <0.001), kynurenic acid (r = .32, p <0.001), anthranilic acid (r = .59, p <0.001), quinolinic acid (r = .67, p <0.001) and picolinic acid (r = .76, p <0.001) significantly correlated moderately to high with their corresponding CSF concentrations. Associations with Ab1‐42, t‐tau and p‐tau, disease stages and neuropsychological test scores are currently being analyzed and will be presented.ConclusionFrom a diagnostic viewpoint these results are promising, as the collection of plasma samples is less invasive compared to CSF.
Agreement between FDG‐PET and CSF biomarkers for AD
Authors: Rodrigo‐Herrero Silvia , Garcia‐Solis David , Sanchez‐Arjona Maria Bernal , Franco‐Macías Emilio 
Published: December 2020

AbstractBackgroundNICE 2018 guidelines recommend additional tests for the diagnosis of Alzheimer's disease (AD): FDG‐PET, or CSF biomarkers (T‐tau, P‐tau, Abeta42, Abeta40). If we cannot establish the diagnosis after one of the two tests, we should consider the other one. The objective is to study the agreement between FDG‐PET and CSF for diagnosing AD pathology in Mild Cognitive Impairment (MCI) or Mild Dementia stage (Global Dementia Scale 3‐4).MethodWe conducted a retrospective analysis of patients from July 2017 to May 2019 at the University Hospital Virgen del Rocio (Southern area of Spain, Andalusia). All patients were diagnosed with MCI (GDS‐3) or Mild Dementia (GDS‐4). We performed a CSF study ( Abeta42, T‐tau, P‐tau, and ratios; ELISA or automated method‐Elecsys‐) and FDG‐PET (blind to CSF results). We reviewed CSF trough the Biobank database ("Alzheimer's and other dementias") and FDG‐PET results from clinical database Histories. We classified CSF results as "positive CSF‐AD," or "negative CSF‐AD," following recommended cut‐off points. The classification of FDG‐PET was as well positive or negative, according to the presence or absence of typical AD hypometabolism. We studied the agreement between CSF and FDG‐PET with contingency tables and the Kappa index.ResultWe included 58 cases in the analysis. The mean age was 65.93 ± 8.38 years (range 51‐82); 31 (53.4%) females, 27 (46.6%) males. The average score in MMSE was 21.36 ± 4.68. The agreement was high‐grade (Kappa index = 0.60). 35 out of 39 cases with "positive CSF AD" had "positive FDG‐PET." 13 out of 19 cases with "negative CSF AD" had "negative FDG‐PET." There was disagreement in 10 cases, possibly due to false‐negative CSF, false‐positive FDG‐PET, or false‐negative FDG PET.ConclusionDespite not being a biomarker of the pathophysiology of AD, PET FDG has a diagnostic recommendation (NICE Guidelines 2018; Andriuta et al. J Alzheimers Dis. 2016). In this study, concordance with biomarkers in CSF was high‐rated, as shown in previous studies (Rubi S. et al. Rev Esp Med Nucl Imagen 2018). However, in 10 of the 58 cases, we had disagreements, supporting the recommendation to perform both CSF and FDG‐PET in doubt diagnoses.
Pharmacokinetic, pharmacodynamic and transcriptomic analyses of verubecestat treatment in 5XFAD mice
Authors: Territo Paul R. , Quinney Sara K. , Biesdorf Carla , Masters Andrea R. , Onos Kristen , Haynes Leslie , Keezer Kelly , Cope Zackery A. , Meyer Jill A. , Peters Jonathan , Persohn Scott C. , Figueiredo Lucas , Bedwell Amanda A. , Eldridge Kierra , Speedy Rachael , Sasner Michael , Howell Gareth , Carter Gregory W. , Oblak Adrian L. , Lamb Bruce T. , Rizzo Stacey J. Sukoff 
Published: December 2020

AbstractBackgroundThe Preclinical Testing Core (PTC) of the Model Organism Development for Late Onset Alzheimer’s Disease (MODEL‐AD) consortium established a preclinical strategy with go/no‐go decision points that permits unbiased assessments of potential therapeutic agents. In models at disease‐relevant ages, this strategy includes: 1) drug formulation, stability, and in vivo pharmacokinetics (PK); and 2) pharmacodynamics (PD) readouts of target engagement and disease modifying activity via non‐invasive PET/MRI, behavior, and transcriptomics. As part of the pipeline validation, verubecestat (VER), a BACE1 inhibitor, was selected for testing in 5XFAD mice.MethodsPK analysis was performed in 6 month aged 5XFAD mice of both sexes, for both oral gavage (PO) and drug milled into diet (10‐100 mg/kg) with blood and brain concentrations analyzed via LC/MS. PK/PD modeling determined dosing regimen for chronic treatments started at 3 months. All PD endpoints (n = 10‐15/sex/genotype/treatment) were measured at 6‐7 months of age, and included: 18‐FDG PET/MR, 18F‐AV45 PET/MR, autoradiography, immunohistochemistry, and behavioral assessments. Post treatment gene expression profiling was conducted using the nanoString and aligned to AMP‐AD consensus clusters.ResultsInitial PK analysis revealed rapid clearance of VER following PO dosing, thus all PD experiments were performed via chronic exposure to drug formulated in diet (10, 30, and 100 mg/kg/day). Prophylactic treatment with VER produced robust coat color changes consistent with hair color changes reported in the clinic. Moreover, VER resulted in dose‐dependent reductions in amyloid deposition via 18F‐AV45 PET, but did not alter glucose uptake via 18F‐FDG PET. VER failed to improve cognition in 5XFAD mice. Transcriptomics revealed dose depended genes expression that mapped to AMP‐AD consensus clusters for immune response, DNA repair, and RNA metabolism.ConclusionsThe effects of VER dosing on PD endpoints revealed the expected results consistent with clinical findings. Moreover, VER failed to improve cognitive behavior in 5XFAD mice, in line with the lack of cognitive improvement in patients. Together these data positive support for pipeline validation of the MODEL‐AD PTC, and highlight the importance for post‐treatment transcriptomics to align model systems with drug mechanism of actions.
Reliability of fractional anisotropy in diffusion tensor imaging of healthy subjects in the ADNI database
Authors: Chen Qianyun , Abrigo Jill , Chu Winnie C.W. 
Published: December 2020

AbstractBackgroundDiffusion tensor imaging (DTI) detects white matter microstructural changes in early Alzheimer’s Disease (AD), and can potentially serve as a sensitive biomarker in longitudinal scans. In this study we determined the reliability of DTI‐derived fractional anisotropy (FA) in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset, which to our knowledge has not been reported.MethodWe selected 21 healthy subjects (12 women and 9 men; age range, 60‐89 years) from the ADNI2 with two sets of DTI performed within 3 months serving as surrogate test‐retest datasets. The subjects’ cognitive status remained stable within one year. The MRI was performed on the same 3.0 T GE scanner following ADNI standard protocol for DTI acquisition (2.7×2.7×2.7 mm3, b=1000 s/mm2, 5 b0 and 41 diffusion weighted volumes). FMRIB Software Library (FSL) was used to process the DTI data to derive the FA scalar map. The two FA maps of the same subject were first co‐registered and then aligned to the JHU DTI atlas by using both linear and non‐linear registration method. A pre‐defined white matter region‐of‐interest (ROI) on the atlas was applied to the registered FA map to derive the value. The ROI related to AD were selected for analysis and included the corpus callosum (body, genu, splenium), corticospinal tract, superior longitudinal fasciculus, fronto‐occipital fasciculus and cingulum (cingulate gyrus, hippocampus). Reliability was assessed using intraclass correlation coefficient (ICC) and coefficient of variation (CoV) of the mean value within the ROI.ResultMean ICC of the paired FA values for all ROIs were 0.97(range: 0.93‐0.99). The CoVs for selected ROIs were all within 8% and the median was all below 2%. The greatest variation was found in the right cingulum hippocampus with CoV of 2.03%, while smallest variation 0.89% was present in the left superior longitudinal fasciculus. No significant correlation was found between ICC and CoV.ConclusionUsing short interval longitudinal scans of healthy subjects in the ADNI dataset as surrogate test‐retest datasets, we found FA values of DTI exhibited good reliability. Our results lay the foundation for our future analysis of longitudinal DTI datasets in the ADNI database.
Cognitive impairment and lower education predict physical frailty in an eight‐year longitudinal study in Brazil
Authors: Yassuda Monica Sanches , Borim Flavia Arbex , Cipolli Gabriela Cabett , Aprahamian Ivan , Neri Anita Liberalesso 
Published: December 2020

AbstractBackgroundThe cross‐talk between cognitive and physical systems is little understood. The present study aimed to verify whether physical frailty and cognitive impairment were related, in an eight‐year longitudinal analysis.MethodThe sample comprised 494 older adults who completed the Cardiovascular Health Study measures for the frailty phenotype and the Mini Mental State Examination at baseline and follow‐up. Participants included in the analyses were robust or pre‐frail at baseline. Logistic regression analyses were used to identify baseline characteristics associated with becoming frail 8 years later. The independent variables included in the model were sex, age, schooling and cognitive status at baseline.ResultAt follow‐up, 22.9% participants were classified as frail. Frail participants were significantly older (73.00±5.36 frail vs. 71.87±5.11 non‐frail) and among them there was a higher percentage of participants with cognitive deficits (35.5% versus 20.6%) at baseline. Results indicated that lower education (OR=0.94, z=‐2.06, p=0.040, CI 0.88 – 0.99) and cognitive impairment (OR=2.08, z=2.68, p=0.007, CI= 1.22 – 3.55) at baseline were predictive of frail status at follow up.ConclusionOlder adults with cognitive impairment need to be seen as ideal target participants for interventions to delay frailty.
Cognitive leisure activities in later older adulthood may protect against accelerated rates of memory decline
Authors: Hyun Jinshil , Katz Mindy J. , Hall Charles B , Sliwinski Martin J. , Lipton Richard B. 
Published: December 2020

AbstractBackgroundThe effects of mental activities in early and midlife (e.g., educational attainment, occupational complexity) may be associated with delayed onset and faster rates of cognitive decline afterwards, as predicted by the cognitive reserve hypothesis (Stern, 2002, 2009). Importantly, continued mental activities in later life may help protect cognitive abilities from further decline (Use it or lose it hypothesis). The aim of the current study is to examine the effects of late‐life cognitive leisure activity on rates of cognitive decline over and above the effects of education and occupational complexity.MethodThe sample consisted of 687 individuals (mean age=78.5, mean follow‐up=2.9 years; 66.3% female; 59.2% Whites, 31.5% African Americans) enrolled in the Einstein Aging Study. Information on years of education, midlife occupation information, and participation in late life cognitive leisure activities (in the previous month prior to the clinic visit) were collected at baseline. Using mixed models, we assessed the influence of education, occupation, and late‐life leisure activities on levels and rates of decline in three cognitive domains: memory, executive function, and processing speed.ResultMore years of education, higher occupational complexity, and more frequent participation in late‐life cognitive leisure were associated with higher levels of cognition in most cognitive domains (Table 1). Education was associated with faster rates of cognitive decline in all three domains of cognition (ps<.05). Late‐life cognitive leisure activity was associated with slower cognitive decline in memory domain (p<.001). To rule out the possibility of reverse causation (i.e., cognitive impairment results in less frequent participation in cognitive leisure activity), we removed individuals who developed mild cognitive impairment within the first two consecutive annual clinic visits, and the findings did not change.ConclusionThe results suggest that mental activities may protect against late‐life cognitive impairment in varying ways. Although the effects of distal mental activity (e.g., education) may be accumulated decades ago and delay the onset of cognitive impairment in late life, the effects of proximal mental activity (e.g., late‐life cognitive leisure) may have continuing benefits in buffering rapid memory decline.
Cross‐cultural acceptability of interventions at the end of life in dementia: Video vignette study design and pilot evaluation (ERC CONT‐END WP1)
Authors: van der Steen Jenny T , Azizi Bahar , Nakanishi Miharu , Shinan‐Altman Shiri , Mehr David R , Radbruch Lukas , Gaertner Jan , Werner Perla , Achterberg Wilco P , Tilburgs Bram , Smaling Hanneke JA 
Published: December 2020

AbstractBackgroundIn dementia, gradual cognitive and physical decline imply that control over life is typically lost. Interventions such as advance care planning (ACP), technology, or‐more extreme‐euthanasia can increase control over the end of life. So far, little is known about acceptability of these interventions from the perspective of persons with dementia and others involved. This study examines the cross‐cultural acceptability of four end‐of‐life interventions in dementia which contain an element of striving for control. We describe the development and pilot‐testing of video vignettes that explain interventions in a standardized manner.MethodThe CONT‐END study Work Package 1 (NTR 7985) employs a cross‐sectional mixed‐methods design to assess acceptability of two types of ACP, technology use at the end of life and euthanasia, in three groups (persons with dementia, their family caregivers and physicians) in six countries (Netherlands, Japan, Israel, USA, Germany, Switzerland). Participants (150 per country) are interviewed about acceptability of the interventions. We will examine different acceptability by group and country and explore potentially associated factors such as coping style. We are pilot testing the acceptability, feasibility and burden of four video vignettes in persons with dementia and their family caregivers in the Netherlands.ResultWe will demonstrate the video vignettes to explain the interventions. The first interviews indicate that persons with dementia and their family caregivers find the scripts of the video vignettes understandable, acceptable, feasible and not burdensome. They additionally commented on the subject matter in that they felt a current need for ACP on, for example, hospitalization, but would prefer to discuss need for technology and euthanasia later. We will present the pilot results and discuss hypotheses about acceptability of the four interventions in the three groups and six countries.ConclusionThe CONT‐END study will provide insight into cross‐cultural acceptability of interventions in dementia care from the perspective of persons with dementia, their family caregivers and physicians. This can help to better align interventions with preferences. The study will also result in a more fundamental understanding as to how and when having control at the end of life in dementia is perceived as beneficial or perhaps harmful.
Dependence clusters in Alzheimer’s disease and Medicare expenditures: A longitudinal analysis from the Predictors Study
Authors: Zhu Carolyn W , Lee Seonjoo , Ornstein Katherine , Cosentino Stephanie , Gu Yian , Andrews Howard , Stern Yaakov 
Published: December 2020

AbstractBackgroundDependence has been proposed as a holistic, transparent, and meaningful representation of dementia disease severity to quantify and stage disease progression. Modeling clusters in dependence trajectories can help understand changes over time in the course of dementia and related cost of care.Method199 initially community‐living patients with probable AD in early stages of the disease were recruited to the Predictors 2 Study from three academic medical centers in the US. Patients were followed for up to 10 years and had at least two Dependence Scale (DS) recorded. Non‐parametric K‐means cluster analysis for longitudinal data (KmL) was used to identify dependence clusters. Medicare expenditures (1999‐2010) were compared between clusters at 6‐month intervals and cumulatively over 5 years.ResultKmL identified two distinct DS clusters: (A) high initial dependence, faster decline, and (B) low initial dependence, slower decline. At baseline, DS score in cluster A was on average 2.25 points higher than in cluster B (p<0.0001). DS scores in both clusters steadily worsened (cluster A by 0.74±0.038 points, cluster B by 0.42±0.038 points every 6 month, both p<0.001), with significant between‐cluster differential rate of change over time (p<0.0001). At baseline, patients in cluster A were older, more likely to be female, have worse functioning and cognition, and more likely to have psychiatric symptoms than those in cluster B. Average per person Medicare expenditures in a 6‐month interval was higher in cluster A than B ($5,456 vs. $2,715). Adjusting for patient characteristics, cluster A was associated with an average of $1,554 higher Medicare expenditures every 6 months cluster B. By year 5, differences in expenditures between clusters accumulated to $54,557 per person in cluster A, twice as high as $27,153 for cluster B.ConclusionDistinct DS clusters with subtle differences at baseline and rates of decline over time were associated with widening difference in expenditures over time. Dependence is a useful measure to capture long‐term costs associated with dementia. Better characterization of dependence clusters has significant implications for understanding disease progression, trial design and care planning.
Palmar creases in Alzheimer’s disease: An observational study
Authors: Ramdane Said 
Published: December 2020

AbstractBackgroundThe pattern of palmar creases is determined by the interactions of environmental and genetic factors. Numerous studies have indicated associations of aberrant patterns of palmar creases with different disease conditions. Deviations in the configurations of palmar creases in Alzheimer’s disease (AD) could be indicative of insults during early intrauterine development. The aim of the present study was to analyze the pattern of palmar flexion creases in Alzheimer’s disease patients compared to healthy non‐demented elderly subjects.MethodWe have analyzed palmar creases patterns in an elderly population comprising a group of 120 consecutive patients with probable Alzheimer’s disease (Mean age: 73.7±7.8; range: 55‐85 years; 64 females) (DSM‐IV, NINCDS‐ADRDA criteria) and a group of 198 consecutive non demented healthy controls (Mean age: 73.2±8.3; range: 63‐89 years; 112 females). Study subjects were recruited from a community elderly in Skikda‐Algeria, (2018‐2019).ResultThe palmar creases of the healthy elderly subjects showed the normal palmar creases to be the most prevalent (85.35%), followed by Suwon crease (7.07%), Simian crease (5.05%) and Sidney crease (2.52%). In AD patients the normal crease was 67.50%, followed by Simian (15.83%), Suwon (12.50%) and Sydney (4.16%) creases. AD patients had significant higher frequency of aberrant palmar creases compared to controls: 32.50% vs. 14.64%, p= 0.0001. By gender, the difference between cases and controls was significant both in men: 33.92% vs. 15.11% respectively, p= 0.009; and in women: 31.25% vs. 14.28% respectively, p= 0.007. Simian crease was found to be significantly more frequent in the AD group than in control, both in males: 17.85% vs 5.81%, p= 0.022; and in females: 14.06 vs 4.46%, p= 0.023. Bilateral occurrence of Simian crease showed no significant difference between the two groups. No significant difference was found between the two groups in Suwon or Sydney creases frequencies.ConclusionThese results show simian crease was found to be twice as common in Alzheimer’s disease patients compared to controls. In addition to revealing the status of palmar creases, present study indicates that palmar creases configurations may give clues for an early and noninvasive method of diagnosis. Further large sample population studies are warranted.