bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cholesterol content in peripheral blood cells of patients with Alzheimer's disease
Authors: Montes Angel Martin , Recuero Maria , Sastre Isabel , Sanchez‐Caro Juan Maria , Frank‐García Ana , Bullido María J. 
Published: December 2020

AbstractBackgroundAlzheimer's disease (AD) is the most frequent degenerative dementia, with a prevalence expected to increase in coming years. Deposits of amyloid and hyperphosphorylated TAU protein constitute the characteristic pathological findings of the disease, although its etiology in sporadic cases is still unknown. Cholesterol metabolism has been related to AD through multiple evidences. Filipin is a macrolide that binds to cholesterol and allows its quantification. We consider assessing whether there are differences in cholesterol content determined by Filipin’s fluorescence (FF) in peripheral blood mononuclear cells (PBMCs) of patients with AD and healthy controls.MethodCross‐sectional study.Patients diagnosed with AD at different stages with support of biomarkers in cerebrospinal fluid (CSF) and cognitively healthy controls were included. PBMCs obtained from whole blood were co stained with Filipin and antibodies specific for several leucocyte subpopulations (CD8, CD4, CD11b, CD19, CD14 and CD16).FF was measured by flow cytometry in PBMCs and in different subpopulations.ResultsN=61 (51 AD,10 controls);When the whole PBMCs were compared, no significant differences in filipin fluorescence among diagnostic groups were observed (AD 1280, controls 1218.9; p=0.65). However, subpopulation analysis revealed significant decrease in cholesterol content in CD14+ cells of patients with AD (AD 2623.9, controls 4433.2; p = 0.007). Differences in cholesterol content in this CD14+ subpopulation were also significant in ApoE4 carriers (2427.1 in carriers, 3130.43 non‐carriers, p=0.017)ConclusionsCholesterol content of CD14+ peripheral blood mononuclear cells could be a neurodegeneration biomarker and it could be related with AD,which supports the involvement of cellular cholesterol homeostasis in the pathophysiology of the disease.
Initial exploration of a brain age score based on validated computerized cognitive assessments in Japanese individuals
Authors: Edgar Chris J. , Schembri Adrian , Maruff Paul T. , Gee Michelle , Iwatsubo Takeshi , Aisen Paul S. , Sperling Reisa A. , Irizarry Michael C. 
Published: December 2020

AbstractBackgroundDifferences between chronological age and biological age can be used to communicate health related information to the general population. For the brain, cognitive performance can be used to define biological age. We utilized data from performance on tests from the Cogstate Brief Battery (CBB) to develop a ‘Brain Age’ score for characterizing the presence of any cognitive impairment in Japanese older adults at risk of dementia.MethodsTo compute an Brain Age, data from the One Card Learning and One Back tests from the CBB was compared to age stratified normative data. Brain Age was computed as the difference in standardized score from age matched normative data. For every point better or worse than the normative mean (0), 0.5 years was added or subtracted from chronological age, to a maximum of 10 years (20 points, or 2 SD). For the current analysis, Brain Age scores were derived for 106 Japanese cognitively normal (CN) individuals from clinical trial screening data for the A4 study and 611 Japanese adults classified with a memory impairment during their screening for the elenbecestat MissionAD program (memory impaired). Differences between these groups were used to determine known groups validity.ResultsMean chronological age was equivalent in the CN (mean = 71.7, SD = 4.6) and memory impaired (mean =72.6, SD= 7.4) samples. Brain Age score was equivalent to chronological age in the CN sample (mean Brain Age = 72.4, SD = 7.45). However in the memory impaired group Brain Age was 6.3 years greater than chronological age (mean Brain Age = 78.9, SD = 8.2). Accordingly, Brain Age was significantly greater in the memory impaired than cognitively normal groups (p < 0.01; d = 0.81).ConclusionBrain Age score is a valid construct for defining biological age impairment in Japanese individuals at risk for dementia. The current data suggest the presence of a difference between chronological and biological age of approximately six years is a criterion that would warrant more detailed investigations. The Brain Age score may be a useful means for communicating brain health information, including the need to adopt a healthier lifestyle.
Fractional anisotropy in white matter hyperintensities is linked to associative memory performance
Authors: Haddad Seyyed Mohammad Hassan , Scott Christopher J.M. , Ozzoude Miracle , Holmes Melissa F. , Arnott Stephen R. , Nanayakkara Nuwan D. , Kwan Donna , Tan Brian , Casaubon Leanne , Mandzia Jennifer , Sahlas Demetrios J. , Saposnik Gustavo , Hassan Ayman , Black Sandra E. , Dowlatshahi Dar , Strother Stephen C. , Swartz Richard H. , Symons Sean , Montero‐Odasso Manuel , Bartha Robert 
Published: December 2020

AbstractBackgroundAlzheimer’s disease pathology commonly coexists with cerebrovascular anomalies, suggesting a strong association between cerebrovascular lesions and cognitive performance. While different types and locations of cerebrovascular lesions such as strokes and white matter hyperintensities (WMHs) may interfere with various cognitive domains, these associations are not thoroughly understood. The most common approach to characterize and evaluate cerebral lesions is with structural neuroimaging. However, diffusion tensor imaging (DTI) can assess the microstructural integrity of cerebral tissue lesions, which may directly impact neuronal communication and consequently cognitive function. This study examines the variation in DTI metrics within different cerebrovascular lesions and their association with cognition in people with cerebrovascular disease (CVD).MethodThe variation of DTI metrics in 10 different cerebral tissues and lesions was examined in 152 subjects (aged 55‐85 years, 32% female) with CVD, (evidenced by an ischemic stroke event documented by MRI or CT, with a modified Rankin score 0‐3) available from the Ontario Neurodegenerative Disease Research Initiative (ONDRI). Fractional anisotropy (FA) and mean diffusivity (MD) were measured using an established DTI processing pipeline from 3 Tesla DTI images (32 directions, b=1000 s/mm2). Cerebral tissue lesion masks were obtained by semi‐automated segmentation of the structural T1‐weighted images to calculate average DTI metrics in each region of interest (ROI). In addition, FA in normal appearing WM (NAWM) and WMHs were correlated with MoCA score (measure of gross cognition), Rey Auditory Verbal Learning Test Long‐Delayed Recall score (measure of episodic memory), Trail Making Test‐Part B in seconds (measure of executive function), and Face‐Name Associative Memory Test score (measure of associative memory).ResultFigure 1 shows a T1‐weighted anatomical image, corresponding tissue mask identifying vascular lesions, and corresponding MD and FA maps. Fig. 2 provides the average FA and MD in different cerebral tissues/lesions. FA within WMHs was found to be significantly correlated with Face Name Associative Memory Test score (p‐value<0.01, r=0.23, Fig. 3) after Bonferroni correction. No other significant associations were identified.ConclusionConsiderable heterogeneity in DTI metrics was observed between cerebral tissues and lesions. Importantly, the structural integrity within WMHs also associated with higher associative memory performance.
Circadian rhythms and misalignment in older adults and those ‘at risk’ for dementia: A study examining correlates of dim‐light melatonin onset
Authors: Schrire Zoe M. , Naismith Sharon L. , Pye Jonathon , Duffy Shantel L. , Gordon Christopher J. , Lewis Simon J.G. , Hoyos Camilla M 
Published: December 2020

AbstractBackgroundCircadian rhythms are altered with ageing, mild cognitive impairment and dementia and may be aetiologically linked to neurodegeneration. The gold standard measure of the circadian system is melatonin. This can be measured using Dim‐Light Melatonin Onset (DLMO), which measures the initial rise of melatonin signalling preceding sleep. However, DLMO collection is resource intensive, expensive and not feasible within the clinical environment. In older adults and those ‘at risk’ for dementia, the current study aims to determine 1) the best clinical and actigraphic associations of DLMO and 2) misalignment between melatonin onset and habitual sleep onset (phase angle of entrainment).MethodIndividuals who were healthy or ‘at risk’ (diagnosed with depression and/or mild cognitive impairment) had 14‐days of actigraphy followed by in‐lab measurement of salivary melatonin, from which DLMO and phase angle were computed. Standard nonparametric analyses were computed from actigraphy.Result21 healthy (age=66±9.6, MMSE =29.25±0.79) and 44 individuals ‘at risk’ (age=66±10.3, MMSE=28.34±1.73) completed the study. Across all participants, multiple linear regression showed BMI(β=0.20), age(β=‐0.02), sex(β=‐0.26) and sleep onset time(β=0.35) predicted DLMO(F(4,59) =4.70, p=0.002, R2=0.238), driven by the strong correlation between DLMO and sleep onset (r=0.41, p=0.001). An additional exploratory analysis revealed M10 onset, the start of the 10 hours with greatest activity, was significantly correlated with phase angle in individuals ‘at risk’ (r=0.36, p=0.02) and not controls (r=‐0.31, p=0.19), Fisher’s r‐to‐z p=0.02. No other variables differed between groups.ConclusionThe current study demonstrates that earlier habitual sleep onset is associated with advanced circadian rhythms in older adults, and that aside from demographic factors, BMI is a factor affecting circadian timing. Of significance, this study also shows that ‘at risk’ individuals who begin activity later in the day exhibit greater misalignment between their biological clock and external cues. This work highlights the potential use of actigraphy‐derived sleep onset as a circadian marker in ageing. Moreover, for those at risk for dementia, the timing of daytime activity may play a vital role in circadian misalignment. With growing evidence that circadian misalignment is involved in the pathogenesis of neurodegeneration, BMI and actigraphy markers could yield viable targets focusing on chronotherapeutic interventions.
Analysis of cell‐type specific exosomes isolated from cryopreserved human brain
Authors: Bilousova Tina , Melnik Mikhail , Cohn Whitaker , Huang Calvin , Teter Bruce , John Varghese , Gylys Karen H. 
Published: December 2020

AbstractBackgroundExosomes are small extracellular vesicles (EVs) originated from multivesicular endosomes which carry biochemical information about their cell‐of‐origin and signals for surrounding cells. EVs may also play a role in spread of proteopathic tau and amyloid beta seeds in Alzheimer’s disease (AD). Thus, brain exosomes may be a valuable therapeutic target for AD treatment. Ability of brain exosomes to cross the blood brain barrier make them a potential diagnostic and monitoring tool. Despite recent progress in development of EV isolation methods, our knowledge of human brain exosomal subpopulations and their roles in disease progression is very limited.MethodCryopreserved parietal cortex from 5 late stage AD (Braak V‐VI) and 3 control (NL) cases were used for the experiment. Brain exosomes/EVs were purified by sucrose density gradient ultracentrifugation after gentle enzymatic and mechanical dissociation of the brain tissue. Microglia‐derived EVs were isolated from the brain EV fraction by immunoprecipitation with anti‐CD11b antibodies. We performed analysis of miRNA transcriptome and proteome using NanoString and quantitative proteomics respectively.ResultWe identified 105 miRNAs which are present in more than 80% of analyzed human cases. The pathways controlled by five significantly upregulated miRNAs can be converged to control microglia activation (TGFβ, TLRs, and chemokine signaling pathways) and neuronal survival and function (LTD and LTP, NGF and neurotrophin signaling pathways). One of the upregulated exosomal miRNAs (miR‐188‐5p) is known to be downregulated in human AD brain and it can restore synaptic and cognitive deficits in 5xFAD mice. MiR‐381‐3p can promote recovery of spinal cord injury in rats. On the protein level we found a moderate increase (around 50%) in exosomal markers CD9 and CD81 and decrease in CHMP4B (ESCRT‐III) protein in the AD group. Levels of mitochondrial proteins and annexins were around 2 times higher in AD group compared to NL controls. ApoE protein was also significantly upregulated in AD microglial EVs.ConclusionOur data revealed the presence of anti‐inflammatory and neuroprotective miRNA signature in CD11b‐positive microglia‐derived exosomes. Proteomics data suggests upregulation of ESCRT‐independent pathway of exosome biogenesis in AD microglia. Increased association of microglial EVs with ApoE maybe related to amyloid packaging and release by exosome‐mediated mechanism.
Higher diastolic blood pressure aged 40‐44 is associated with declining cognition and increasing white matter lesions over 8‐12 year follow up.
Authors: Peters Ruth , Xu Ying , Cherbuin Nicolas , Sachdev Perminder S. , Anstey Kaarin J 
Published: December 2020

AbstractBackgroundBackground: High midlife blood pressure (BP) is an accepted risk factor for later life cognitive decline and dementia. However, the changing patterns of systolic and diastolic (DBP) blood pressure from our 40s to our 60s highlight the need for a more sophisticated understanding of the relationships between BP during the midlife period and cognition as well as brain measures, including white matter lesion (WHL) volume as a marker of small vessel disease.MethodThe Personality and total health (PATH) study is an Australian longitudinal population based cohort with four waves of follow‐up at approximately 4‐year intervals (W1‐4). Data was used from two PATH cohorts, one aged 40‐44 at W1 (40s) and the other aged 60‐64 at W1 (60s) and included the subset of participants with BP (W1), neuropsychological testing (W1, W4), imaging (MRI)(40s W2, W4, 60s W1, W4). Linear regression models with relevant adjustment, including antihypertensive use, were used to examine the relationship between baseline BP and change in imaging and cognition over time. P≤0.01 was taken as significant.ResultData were available for 492 participants,’40s’: 218 (53% female) ‘60s’: 274 (42%). Key findings were that higher DBP at ages 40‐44 was associated with a significant decline in performance over the subsequent 12 years on the symbol digit modalities test (slope‐0.7 (95% CI ‐1.2, ‐0.3) p=0.002) and to a lesser extent, trail making A (0.9 (0.2, 1.6)p=0.01) per 10mmHg increment. There were no associations for recall, digit span or dexterity tests. There were no associations for the 60s. Higher DBP aged 60‐64 was associated with a 31% (95% CI 13%, 51%) increase in WML over 12 years (p<0.001) per 10mmHg and a similar but less strong relationship (13% (3%, 24%) in the 40s over 8 years (p=0.008). There were no relationships between change in hippocampal or total brain volume. There were no significant relationships for SBP.ConclusionHigher DBP was associated with decline in processing speed in the 40s and growth of WML overall. The next step is to examine the relationship between change in BP and change in cognition and imaging measures.
The protective effect of physical activity on the alpha power is influenced by age and APOE genotype
Authors: de Frutos Jaisalmer , Cuesta Pablo , Toraño Federico Ramirez , Cuadrado‐Soto Esther , Peral‐Suarez Africa , Nebreda Alberto , Fernández Ricardo Bruña , Sanz David López , Marcos Silvia , Losada María Luisa Delgado , Sobaler Ana Maria Lopez , Rojo Inmaculada Concepción Rodríguez , Barabash Ana , Rodriguez Juan Manuel Serrano , Laws Simon M , Dolado Alberto Marcos , Higes Ramón López , Brown Belinda M , Maestú Fernando 
Published: December 2020

AbstractBackgroundPhysical activity (PA) has been identified as one of the most relevant modifiable lifestyle factors against Alzheimer's disease (AD). Magnetoencephalography has proven to be a useful tool to predict future risk of AD. In particular, decreased power in the alpha band has been associated with pathological aging. We had already reported how PA was significantly associated with higher alpha peak frequencies in older adults, especially among those at standard genetic risk for AD (APOE ε4 non‐carriers). Recent literature suggest that age could play an important role in the emergence of these relationships, a role that has not been explored yet.MethodWe used a sample of 112 cognitively normal individuals aging <50 who had worn an accelerometer for one week, divided into four carefully matched groups: younger adults at increased risk (age <60;APOE ε3ε4;n=20), older adults at increased risk (age >60;APOE ε3ε4;n=15), younger adults at standard risk (age <60;APOE ε3ε3;n=44) and older adults at standard risk (age>60;APOE ε3ε3;n=33). Each subject underwent four minutes of closed eyes resting state MEG recording. The aim was to detect any robust correlation between power values derived from clusters of nodes localized in certain brain regions and TPA, using network‐based statistics. Clusters consisted of several adjacent nodes, which systematically showed a significant partial correlation (with age as covariate) in at least 3 consecutive frequency steps between their corresponding power values and TPA (spearman correlation p‐value<0.01).ResultA significant cluster was found in the frequency interval 10.75–13Hz involving mainly posterior brain regions (rho=0.360;p=0.0001;see Figure 1/Table 1). This correlation remained significant for both ε3ε3 carriers (rho=0.326;p=0.004;n=77;) and ε3ε4 carriers (rho=0.442;p=0.007;n=35;see Figure 2). It also remained significant for younger adults (rho=0.456;p>0.001) but not for older adults (Figure 3). Interestingly, when looking at the four groups individually, only younger ε4 non‐carriers (rho=0.487;p>0.001) and older ε4 carriers (rho=0.603;p=0.013) show this association.ConclusionGreater PA seems to be associated with increased alpha power in posterior brain regions, a robust biomarker of brain health which is negatively affected in AD. However, the time window when this association can be observed seems to differ between ε4 carriers and non‐carriers.
Neuropsychiatric symptoms and cognition: An observational study in a Filipino memory clinic setting
Authors: Cano Jemellee , Uy Judy Grace Laurilla , Cruz Precy S. , Lorca Maria Leni Lat , Martinez Ma. Socorro , Dominguez Jacqueline C. 
Published: December 2020

AbstractBackgroundA growing body of evidence has described neuropsychiatric symptoms (NPS) as early markers of cognitive decline and may precede onset of measurable neurocognitive changes.1,2 NPS have been associated with accelerated cognitive decline and higher dementia conversion rates.3 The repeated observation that individuals with NPS are at increased risk of further cognitive decline delineates this group as high risk and suitable for early interventions to prevent cognitive and functional loss.4 The objectives are to determine the prevalence and compare the demographic and cognitive profiles of non‐demented individuals with NPS in a Filipino cohort.MethodA total of 435 patients with no cognitive impairment (NCI) and Mild Cognitive Impairment (MCI) from St. Luke’s Medical Center Memory Clinic were included. NPS were assessed by administration of the Neuropsychiatric Inventory Questionnaire (NPI‐Q) to a reliable caregiver. Participants were administered the Mini‐Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Alzheimer’s Disease Assessment Scale Cognitive Subscale (ADAS‐Cog).ResultCompared to patients without NPS, patients with NPS have more impaired cognition with lower MMSE (25 + 4 vs 27 + 3, p=0.001); MoCA (21 + 5 vs 23 + 5, p=0.002) and higher ADAS‐Cog scores (12.4.6 + 6 vs 10.6 + 6, p=0.01). A fully adjusted model showed NPS to be significantly associated with MMSE (‐0.8, 95% CI ‐1.6 to ‐0.02, p=0.04) and MoCA scores (‐1.2, 95% CI ‐2.3 to ‐0.2, p=0.02).ConclusionThis study shows that non‐demented individuals with NPS have more cognitive impairment suggesting the importance of NPS as a potential marker for early cognitive decline and a need for further trials that targets treatment for NPS even at an early stage to prevent cognitive impairment.
Integrative metabolomics‐genomics approach reveals that pathways related to the metabolism of acylcarnitines and amines are new potential targets of Alzheimer’s disease
Authors: Horgusluoglu‐Moloch Emrin , Wang Minghui , Arnold Matthias , Krumsiek Jan , Galindo‐Prieto Beatriz , Kastenmüller Gabi , Han Xianlin , Baillie Rebecca , Nho Kwangsik , Saykin Andrew J. , Kaddurah‐Daouk Rima F. , Zhang Bin 
Published: December 2020

AbstractBackgroundThe metabolic basis of Alzheimer’s Disease (AD) is poorly understood, and the relationships between systemic abnormalities in metabolism and AD pathogenesis remain elusive. In this study, we systematically interrogated metabolomics, genetics, proteomics, and clinical data from the matched subjects in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to identify key drivers and metabolic pathways associated with changes in metabolites with disease severity.Method140 Metabolites in fasting serum samples from the ADNI (362 controls, 94 significant memory concerns, 764 mild cognitive impairment, and 298 AD) were analyzed using the AbsoluteIDQ‐p180 kit. Values adjusted for age, gender, body mass index (BMI), education, cohort, and medication. A metabolite co‐expression network was constructed using Multiscale Embedded Gene co‐Expression Network Analysis (MEGENA). Co‐expressed metabolite modules were then prioritized for the strength of association with clinical/cognitive and pathology biomarker variables. Correlation analysis of the co‐metabolite modules and the matched gene/protein expression data was performed. The ROS/MAP cohort was used as a replication study of the co‐expression network. Six brain transcriptomic datasets from the Mount Sinai Brain Bank, ROS/MAP, and MAYO clinic cohorts were utilized to build up gene‐centered correlation networks to elucidate functions of upstream regulators of candidate metabolites.ResultModules comprised of short‐chain acylcarnitines/amino acids (M8, M3), and medium/long‐chain acylcarnitines (M6) were most associated with worse AD clinical outcomes, including episodic memory scores and disease severity (CDR‐SB) (Figure 1A‐C). CPT1A gene expression was highly correlated with an increased level of the medium/long‐chain acylcarnitines (corrected p‐value = 1.87 × 10‐6). Increased ABCA1 gene expression and adiponectin protein (a regulator of ABCA1) levels corresponded to decreased short‐chain acylcarnitines and amines in AD (corrected p‐value < 0.02) (Figure 2A‐C). In addition, CPT1A and ABCA1 were differently expressed in the brains of AD patients compared to controls (Table 1), and their subnetworks were enriched for AD, aging, and neuronal system‐related gene signatures/pathways (Figure 3A‐D). Eight out of eleven modules were highly preserved between the ADNI and ROS/MAP cohorts (Z summary preservation score > 5; corrected p‐value < 0.05).ConclusionIdentification of acylcarnitines enriched modules and their potential upstream genetic and transcriptional regulators paves the way for developing novel biomarkers and targets for AD.