bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of ergothioneine with neurodegeneration and cerebrovascular disease in cognitive impairment and dementia
Authors: Wu Liu‐Yun , Cheah Irwin K. , Chong Joyce R. , Chai Yuek Ling , Hilal Saima , Chen Christopher , Halliwell Barry , Lai Mitchell Kim Peng 
Published: December 2021

AbstractBackgroundErgothioneine (ET) is a dietary amino‐thione with strong antioxidant properties and therapeutic potential for neurodegenerative and vascular diseases (Halliwell et al., 2018; Smith et al., 2020). Decreased blood concentrations of ET have been found in patients with mild cognitive impairment (Cheah et al., 2016), but its status in neurodegenerative and vascular dementias are currently unclear. We thus investigated the association of plasma ET levels with (1) cognitive impairment and dementia, (2) cerebrovascular disease (CeVD), namely white matter hyperintensities (WMH), cortical infarcts and lacunes and (3) brain atrophy.MethodA cross‐sectional study was conducted in a total of 496 participants in an ongoing longitudinal study, including 88 subjects with no cognitive impairment (NCI), 201 subjects with cognitive impairment but no dementia (CIND), 207 dementia patients of whom 160 had Alzheimer’s Disease and 47 vascular dementia (VaD). All subjects underwent collection of blood samples, neuropsychological assessment, and neuroimaging. Plasma ET levels were measured with a high sensitivity liquid chromatography tandem‐mass spectrometry (LC‐MS/MS) method.ResultPlasma ET concentrations were lowest in dementia (p<0.001 vs. NCI and CIND), with intermediate levels in CIND (p<0.001 vs. NCI). In multivariate analyses, lower levels of ET were significantly associated with CIND (OR, 0.20; 95% CI, 0.07–0.56; p<0.01) and dementia (OR, 0.06; 95% CI, 0.02–0.20; p<0.001) after adjustment for demographics and risk factors. There was a positive correlation between plasma ET and MMSE scores (r=0.341, p<0.001). Lower ET levels were also strongly associated with WMH (OR, 0.44; 95% CI, 0.123–0.85); p<0.01) and brain atrophy markers (cortical atrophy: OR, 0.42; 95% CI, 0.20–0.92; central atrophy: OR, 0.46; 95% CI, 0.22–0.93; medial temporal atrophy: OR, 0.45; 95% CI, 0.24–0.99, p<0.05 for all).ConclusionThe incremental decreases in ET levels along the clinical continuum suggest that ET may be associated with disease severity and is a potential biomarker for early detection of cognitive impairment. Deficiency of ET may contribute towards neurodegeneration‐ and CeVD‐associated cognitive impairments by exacerbating the deleterious effects of oxidative stress in these conditions.
Person‐centred dementia care in an acute hospital: Experiences from nurses working in a specialized dementia unit
Authors: Cheong Chin Yee , TAY Felicia Hui En , Yap Philip Lin Kiat 
Published: December 2021

AbstractObjectivesPerson‐centred care (PCC) is synonymous with best practice in the care of persons with dementia (PWD). However, the focus has been in long‐term care settings with less attention in acute hospitals. We aimed to study the implementation of PCC in an acute hospital dementia unit (Care for Acute Mentally Infirm Elders [CAMIE]) from the perspectives and experiences of nurses working with PWD.MethodThis was an exploratory qualitative study involving individual, face‐to‐face, semi‐structured in‐depth interviews. A purposive sample of ten nurses participated in the interview. We employed an inductive thematic analysis approach to analyze the qualitative result.ResultsThe findings highlighted the challenges e.g. managing challenging behaviour and the positive experiences e.g. meaningful connection with patients in providing PCC. The initial challenges were due to a lack of prior knowledge and experience. Through formal and informal learning, the nurses built confidence and competence, and also provided support to each other. They emphasized the importance of teamwork and camaraderie in the CAMIE team but raised concerns about the negative perceptions of non‐CAMIE nurses on the value of their work.ConclusionDespite the challenges, with adequate knowledge and robust organizational level support to embrace PCC as the care ethos, implementing of PCC is feasible among nurses in the acute care setting.
Inflammation biomarkers for future development of all‐cause dementia, Alzheimer's disease, and vascular dementia
Authors: Trares Kira , Schöttker Ben 
Published: December 2021

AbstractBackgroundInflammation is one of the key mechanisms involved in the development and progression of dementia. However, not all details on the association between inflammation and dementia have been explored yet. Inflammatory biomarkers can be measured at an early stage of dementia and thus can contribute to an early diagnosis. Besides, these biomarkers could contribute to drug development or therapeutic strategies.MethodBiomarkers from the Olink Proseek® Inflammation panel were analyzed in blood samples of a longitudinal German, population‐based cohort including 1782 older adults. Logistic regression models were used to identify associations of these biomarkers with all‐cause dementia, Alzheimer's disease (AD), and vascular dementia (VD) incidence. Strongly associated biomarkers were further analyzed in subgroup and sensitivity analyses for dementia risk factors like age, diabetes, and APOE ε4 polymorphism. Moreover, clusters including highly correlated biomarkers (r > 0.5) were built based on these biomarkers.ResultDuring 17 years of follow‐up, 504 participants were diagnosed with dementia, including 163 AD and 195 VD cases. A total number of 56 biomarkers showed a significant association with all‐cause dementia, 22 biomarkers were significantly associated with AD, and 33 with VD incidence, even after correction for multiple testing. The strongest, independent associations were found for the biomarkers CX3CL1 (OR [95% CI] per 1 standard deviation (SD): 1.41 [1.24‐1.60]) and EN‐RAGE (1.41 [1.25‐1.60]) with all‐cause dementia incidence, EN‐RAGE (1.51 [1.25‐1.83]) and LAP TGF‐beta‐1 (1.46 [1.21‐1.76]) with AD incidence, and VEGF‐A (1.43 [1.20‐1.70]) with VD incidence.ConclusionThis study was the first to assess the associations of blood‐based biomarkers from the Olink Proseek® Inflammation panel with all‐cause dementia, AD, and VD incidence in a large, prospective, population‐based cohort study. The biomarkers CX3CL1, EN‐RAGE, LAP TGF‐beta‐1, and VEGF‐A, were independently associated with different forms of dementia and have great potential as predictive biomarkers.
Development of 1,2,3,4‐tetrahydrocarbazole derivatives as dual binding cholinestarse inhibitors
Authors: Singh Manjinder , Sharma Pratibha , Arora Sandeep 
Published: December 2021

AbstractBackgroundAcetylcholinesterase (AChE) is one of the most promising targets for treatment of Alzheimer’s disease. The 1,2,3,4‐tetrahydrocarbazole compounds have been reported to inhibit AChE, reduce plaque formation in AD. Hence our focus is on the synthesis and biological assesment of 1,2,3,4‐tetrahydrocarbazole derivative to manage Alzheimer’s disease.MethodA total of 16, 1,2,3,4‐tetrahydrocarbazole derivatives were synthesized and assesed for AChE and BuChE (butyrylcholinesterase) inhibitory effect. After that, the protein‐ligand interactions and pharmacokinetic of most active derivatives were determined using in silico approaches.ResultThe in vitro assays showed that all 1,2,3,4‐tetrahydrocarbazole derivatives inhibited AChE and BuChE. Additionally, the in silico investigations exhibited that the designed derivatives have capability to intearct with both PAS (peripheral anionic) and CAS (catalytic active) sites of chomiesterase enzyme. The pharmacokinetic parameters prediction disclosed that all synthesized compounds have drug like properties.ConclusionThe study revealed that the newly synthesized 1,2,3,4‐tetrahydrocarbazole ligands could be developed as cognitive enhancers and may be employed in cognitive disorders including Alzheimer’s disease. Thus, 1,2,3,4‐tetrahydrocarbazoles might be taken as lead for the management of Alzheimer’s disease.
Prognostic value of amyloid/tau/neurodegeneration (ATN) classification based on diagnostic cerebrospinal fluid samples for Alzheimer’s disease
Authors: Schaeverbeke Jolien , Delmotte Koen , Vandenberghe Rik , Poesen Koen 
Published: December 2021

AbstractBackgroundAs first objective, we examined in a clinical, real‐life setting, the prognostic value of cerebrospinal fluid (CSF) based Amyloid Tau Neurodegeneration (ATN) classification for subsequent cognitive decline during the three years following a lumbar puncture. The secondary objective was to investigate the prognostic value of CSF biomarkers as continuous variables.MethodRetrospective data from an academic memory clinic sample of 228 patients (median age 67 (47‐85) years) were retrieved. CSF data (Innotest assays) were available in all patients and used for ATN classification: the cut‐off values were 798 pg/mL for amyloid‐beta 1‐42 (Aβ42) (A), 87 pg/mL for hyperphosphorylated tau (p181‐tau) (T), and 465 pg/mL for total tau (t‐tau) (N). A secondary analysis with ATN based on lower tau cut‐offs (p181‐tau: 58.9 pg/ml; t‐tau: 354 pg/ml) was also applied. Cognitive performance was evaluated by Mini Mental State Examination (MMSE) every 6 months over a period up to 36 months following the lumbar puncture. Linear mixed‐effects modelling was performed on non‐imputed data (minimum 3 MMSE scores) as well as on imputed data using the R packages ‘nlme’ and ‘mice’.ResultIn the current sample, classification showed 32.02% A‐/T‐/N‐, 33.33% A+/T‐/N‐, 17.11% A+/T+/N+, 11.84% A+/T‐/N+, 4.39% A‐/T‐/N+ and 1.32% A‐/T+/N+ (3 cases), with the A‐/T+/N‐ and A+/T+/N‐ class being absent. Hence the latter 3 classes were excluded from further analyses. The change of MMSE relative to A‐/T‐/N‐ over a 36 months period was significant in all four ATN classes: A+/T+/N+ = ‐4.78 points on the MMSE; A‐/T‐/N+ = ‐4.76; A+/T‐/N+ = ‐2.83; A+/T‐/N‐ = ‐1.96. The earliest significant difference in slope was seen in the A+/T+/N+ class at 12 months after baseline (Figure 1A). The effect of ATN class on future cognitive decline was confirmed for a different set of CSF thresholds (Figure 1B). All individual baseline CSF biomarkers including the Aβ42/t‐tau ratio showed a significant correlation with subsequent cognitive decline, with the highest correlation seen for Aβ42/t‐tau.ConclusionATN classification based on CSF biomarkers has a statistically significant and clinically relevant prognostic value for the course of cognitive decline in a 3‐year period in a clinical practice setting.
Health conditions that predict Alzheimer’s disease and vascular dementia: A phenome‐disease association study
Authors: Beason‐Held Lori L , Kerley Cailey I , Chaganti Shikha , Moghekar Abhay , Thambisetty Madhav , Resnick Susan M , Landman Bennett A 
Published: December 2021

AbstractBackgroundPoor health increases the risk of cognitive decline and dementia. Here, we examined medical records to determine health conditions that were most predictive of dementia at intervals prior to dementia diagnosis. This phenome‐disease association study (PheDAS) used ICD‐9 health code medical record data from participants in the Baltimore Longitudinal Study of Aging (BLSA).MethodsData were available for 347 Alzheimer’s disease (AD), 76 vascular dementia (VD), and 811 non‐demented control participants. Logistic regressions were performed associating ICD‐9 health codes with dementia status at 5 and 1 year(s) prior to dementia diagnosis and at the year of diagnosis, controlling for maximum age, sex and follow‐up length of medical record.ResultsIn AD, the earliest and most consistent predictors across all time points included depression, erectile dysfunction, gait abnormalities, hearing loss, and nervous and musculoskeletal symptoms. Cardiomegaly, disorders of esophageal motility and non‐epithelial skin cancer were not significant until 1 year before dementia diagnosis. In VD, the earliest and most consistent predictors across all time points included abnormal EKG, cardiac dysrhythmias, cerebrovascular disease, non‐epithelial skin cancer, depression, and hearing loss. Atrial fibrillation, occlusion of cerebral arteries, and abnormal reflexes were not significant until 1 year before dementia diagnosis.ConclusionsThese findings suggest that some health predictors of future dementia begin at least 5 years before dementia diagnosis and are consistently seen over time, while others only reach significance closer to the date of diagnosis. These results also show that there are both shared and distinctive health predictors for AD and VD. Together, this study reinforces the need for proper care and treatment of modifiable health risk factors throughout the lifespan. This work was supported by the Intramural Research Program of the NIH, National Institute on Aging.
Occupational complexity and neuroimaging measures of structural MRI and PET‐amyloid in a randomized controlled trial: FINGER
Authors: Rydström Anders , Stephen Ruth , Kåreholt Ingemar , Darin‐Mattsson Alexander , Liu Yawu , Ngandu Tiia , Rinne Juha O , Kemppainen Nina , Antikainen Riitta L , Bäckman Lars , Sindi Shireen , Soininen Hilkka , Strandberg Timo , Tuomilehto Jaakko , Kivipelto Miia , Solomon Alina , Mangialasche Francesca 
Published: December 2021

AbstractBackgroundHigher occupational complexity has been associated with better cognition in late life, but associations with brain changes remain unclear. We assessedwhether occupational complexity was associated with baseline brain structural MRI measures and PIB‐PET amyloid burden in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER).MethodFINGER is a two‐year, population‐based, multicenter, multidomain randomized controlled trial. Inclusion criteria included age 60‐77 years; Cardiovascular Risk Factors, Aging and Dementia Risk Score of at least 6; cognition at a mean level or slightly lower than expected for age. Participants (n=1260) were randomly assigned in a 1:1 ratio to a multidomain intervention group (diet, exercise, cognitive training, vascular risk management) or a group receiving general health advice. Primary outcome was change in cognition (Neuropsychological Test Battery). Occupational complexity with data, people, and substantive complexity were classified through the Dictionary of Occupational Titles. The MRI analyses included a subgroup of 126 participants from three different FINGER study sites and the PiB‐PET measures included 42 participants from one study site. MRI regional cortical thickness and volumes were measured using the Freesurfer image analysis suite (version 5.0.3). Linear, logistic, and ordinal logistic regression models were used to assess the association between occupational complexity and neuroimaging measures, adjusting for age, sex, education, intracranial volume, and study site. Neuroimaging assessments included hippocampal and total gray matter volume, Alzheimer´s disease signature thickness, visually rated medial temporal atrophy (MTA), and amyloid accumulation.ResultThere was no association between occupational complexity and brain cortical thickness, volume measures, or PiB‐PET measures.ConclusionNo association between occupational complexity and brain structure and amyloid burden was found in older adults at increased risk of dementia. These findings should be verified in larger cohorts.
Association between sleep, depressive symptoms, and pain with physical activity and physical functioning in the oldest old: CAIDE 85+ study
Authors: Kekkonen Eija , Hall Anette , Kulmala Jenni , Lisko Inna , Ngandu Tiia , Barbera Mariagnese , Hallikainen Merja , Soininen Hilkka , Kivipelto Miia , Solomon Alina 
Published: December 2021

AbstractBackgroundThe aim was to investigate 1) the associations of sleep, depressive symptoms, and pain with physical activity and physical functioning in the oldest old age group (85 years and older); 2) the effects of Covid‐19 related restrictions on physical activity in the oldest old.MethodThe data is from Cardiovascular Risk Factors, Aging and Dementia (CAIDE 85+) longitudinal cohort study in Eastern Finland. From the original cohort, participants were invited to follow‐up visit during 2019‐2020. Self‐reported measures were physical activity (active: ≥2 times a week/inactive: <2 times a week), sleep duration (hours/night). We also assessed depressive symptoms (BDI‐21 scale), sleep quality (PSQI), pain (RAND‐36), physical functioning (Short Physical Performance Battery (SPPB)) and Clinical Dementia Rating (CDR). Cross‐sectional associations of sleep quality and duration, depressive symptoms, and pain with physical activity and physical functioning were assessed using logistic regression, adjusted for age, sex, education and CDR.ResultAltogether 194 individuals participated in the CAIDE 85+ study. The mean age was 88 (SD 4.5) years, and 90% (n=170) were community‐dwellers, and 66% (n=124) were physically active. Participants with long sleep duration (<8 hours/night) were less likely to be physically active (OR 0.10, 95% CI 0.03–0.40) compared to participants with normal sleep duration (6‐8 hours/night). Also, participants with pronounced pain (3rd tertile of RAND‐36 pain score) were also less likely to be physically active (OR 0.33, 95% CI 0.12–0.90) compared to the group with lowest level of pain. Participants with elevated depressive symptoms (BDI‐21 score ≥10) were more likely to have lower level of physical functioning (SPPB score ≤6), (OR 0.32 95% CI 0.12–0.84), compared to participants with no depressive symptoms. The results were similar when participants with CDR score ≥1 were not included in the analysis. Furthermore, of the 96 participants who answered questions about Covid‐19 related restrictions, 47% (n=38) reported no effects on physical activity, and 36% (n=29) reported physical activity level was decreased.ConclusionThese preliminary results suggest that long sleep duration and pronounced pain are associated with physical inactivity. However, only elevated depressive symptoms are associated with low levels of physical functioning in the oldest old.
The role of biomarkers in cell counting with U‐Net CNN
Authors: Miramontes Silvia , Piergies Antonia M. H. , Grinberg Lea T. , Ushizima Daniela 
Published: December 2021

AbstractBackgroundImaging methods that are non‐destructive preserve tissue integrity and lead to improved topography analysis for the study of neurodegenerative diseases like Alzheimer’s Disease (AD). Immunofluorescence (IF) staining methods facilitate such investigations by addressing a gradient of intensity variations relevant for in situ cell detection [1] and morphology quantification. This paper reports on the colocalization of proteins and cell structures from human post‐mortem tissue by evaluating IF expression by means of TBR1 and NeuN biomarkers. We compare different U‐Net‐based models by exploring image representations obtained by combining image channels with different biomarkers.MethodFrom an image dataset with 21 full‐size IF micrographs, we augment it by creating a cropping mechanism resulting in 40 to 60 image crops from each micrograph, each crop with 128x128 pixels. Later, we enhance the resulting 1,200 cropped images, and construct 3‐channel (x,y,z) image inputs of dimensions 128x128x3 for the U‐Net model in a two‐fold process: (I) stack all 3 channels with single‐channel IF cropped images corresponding to NeuN biomarkers (NeuN, NeuN, NeuN); (II) stack the single channel images of TBR1, NeuN, and a single image representing the maximum pixel intensities from TBR1 and NeuN images (TBR1, NeuN, max (TBR1, NeuN)). With a test‐train split of 70% ‐ 30%, and parameter tuning, we compare the two models via metrics such as neuron areas, counts, accuracy and recall.ResultThe model trained with channel stacking (II) outperforms the model trained with (I) with an accuracy and recall of 0.96 and 0.5, as opposed to 0.95 and 0.4. We also found a great variation in neuron area and counts as depicted in the images below.ConclusionWhile this is the first step in accelerating the quantification of neurons for the pathophysiology studies necessary for drug development, there is a need in establishing protocols for the generation of datasets with manual segmentation to further train our models. The inclusion of prior information about the expected neuron morphology increases the performance of our networks, and successfully deploy a foreseen automated pipeline. Reference: [1] Ehrenberg et al. A manual multiplex immunofluorescence method for investigating neurodegenerative diseases. Journal of Neuroscience Methods, June, 2020.
Midlife measures of lipid fractions and fasting glucose are associated with late‐onset Alzheimer disease
Authors: Zhang Xiaoling , Tong Tong , Chang Andrew , Ang Ting Fang Alvin , Tao Qiushan , Auerbach Sandford H. , Devine Sherral , Qiu Wendy , Mez Jesse , Massaro Joseph , Lunetta Kathryn L. , Au Rhoda , Farrer Lindsay A. 
Published: December 2021

AbstractBackgroundMeasures of cardiovascular and metabolic disease are well‐established risk factors for late‐onset Alzheimer disease (AD). However, it is poorly understood whether exposure to these risk factors in early adulthood is associated with AD in late‐life.MethodAssociation of incident AD occurring after age 60 with measures of lipid fractions, hypertension, diabetes, blood glucose, BMI and smoking obtained prospectively across nine quadrennial examinations was evaluated in the Framingham Heart Study (FHS) Offspring cohort (n=5,124) using Cox proportional hazard models. Age‐ and sex‐adjusted models were tested for each risk factor measured at each exam and within three age groups (early adulthood=35‐50, middle adulthood=51‐60, late adulthood=61‐70). Additional models included covariates for risk factor‐specific treatment and APOE ε4 carrier status.ResultDuring a mean follow‐up period of 31.7±6.7 years, a diagnosis of incident AD was established for 271 participants. A 15 mg/dL increase in high‐density lipoprotein cholesterol (HDL‐C) measured during early adulthood and middle adulthood was associated with a 19.1% decreased risk of AD in each group (HR=0.81 [95%CI 0.70, 0.96], P=0.011 and HR=0.81 [0.67, 0.97], P=0.019, respectively). An increased risk of AD was also associated with 15 mg/dL increases of triglyceride (TG) (HR=1.05 [1.002, 1.10], P=0.023) and low‐density lipoprotein cholesterol (LDL‐C) (HR=1.06 [1.003, 1.12], P=0.041) measured in early adulthood. A 15 mg/dL increase in fasting blood glucose (FBG) measured during middle adulthood was associated with a 11.0% increased risk of AD (HR=1.11 [1.03, 1.20], P=0.0039). These findings remained significant after adjusting for treatment. Survival analysis showed that AD risk was significantly higher and occurred earlier among individuals with FBG in the pre‐diabetic (100‐126 mg/dL) and diabetic (>126 mg/dL) ranges compared to those with normal FBG (<100 mg/dL) in middle adulthood (P=0.038), but not in late adulthood.ConclusionHDL‐C, LDL‐C, TG and FBG levels measured in cognitively normal individuals between ages 35 and 60 years are significantly associated with incident AD several decades later. Our findings suggest that careful management of cholesterol and glucose levels beginning in early adulthood can lower AD risk in later life including among APOE ε4 carriers, in addition to the benefits of promoting cardiovascular and metabolic health.