bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predicting progression of Mild Cognitive Impairment patients through four distinctive groups obtained by a dimensionality reduction algorithm
Authors: Silva‐Spínola Anuschka , Leitão Maria João , Lima Marisa , Bernardes Catarina , Duro Diana , Regueira Patrícia , Tábuas‐Pereira Miguel , Durães João , Baldeiras Inês , Arrais Joel P , Santana Isabel 
Published: December 2023

AbstractBackgroundThe application of machine learning (ML) algorithms can help improve diagnosis and predict progression/conversion to Alzheimer’s disease (AD) at prodromal stages (Mild Cognitive Impairment – MCI)1. Due to the heterogeneity of the population at early stages and the large amount of data available, the use of unsupervised learning techniques can show distinctive patterns and help move towards personalized medicine2,3. In this work, we implemented a dimension reduction algorithm with the intent of characterizing MCI patients and develop a multistate model of progression to AD.MethodWe processed 57 variables including demographic, clinical, neuroimaging, fluid biomarkers, and genetic information from a mixed population of 1041 MCI patients (544 followed at the Dementia clinic of Centro Hospitalar Universitário de Coimbra (CHUC) and 497 obtained by ADNI). Data was normalized and scaled. Afterward, we applied a dimensionality reduction algorithm (UMAP) in Python. Missing data was handled accordingly. From those with longitudinal measures (n = 351), we generated transition probability estimates by Non‐Markov Multi‐State modelling, based on the change in the status of diagnosis through time by the MMSE z‐score at each visit.ResultWe obtained 4 clusters associated to: 1) increased cognitive reserve; 2) AD signature; 3) behavioral/mood alterations; and 4) mixed presentation with cardiovascular risk factors. We obtained theoretical progression rates (from faster to slower) in MCI individuals categorized in groups 2, 4, 1 and 3. After the onset of symptoms, initial decline within MCI is expected to occur in the 1st to 3rd year (in order: groups 2, 1, 4 and 3) with 60‐83% probability, and from MCI to AD from those more advanced as early as 5 (group 2) to 66 months for those in an initial phase with slower decline (group 3).ConclusionOur results show added value for the application of ML techniques in processing data with the intent to improve the characterization and follow‐up of MCI patients. We suggest that these four groups should be targeted and considered for monitoring patient care.1. Silva‐Spínola A, et al. Biomedicines 2022; 2.Chun MY, et al. Front Aging Neurosc. 2022; 3.Tam A, et al. J Prev Alz Dis. 2022.
Effects of pre‐analytical sample handling on the performance of plasma phospho‐tau217
Authors: Bali Divya , Hansson Oskar , Janelidze Shorena 
Published: December 2023

AbstractBackgroundPre‐analytical variables can greatly influence biomarkers concentration. Till now, only two studies have examined the effects of pre‐analytical factors on plasma concentrations of phosphorylated tau (p‐tau)1,2. Hence, in this study we investigated how pre‐analytical factors affect the performance of one of the most promising plasma biomarkers of Alzheimer´s Disease, p‐tau217.MethodWe included 50 β‐amyloid positive (Aβ+) and 50 Aβ− participants from the Swedish BioFINDER‐1 cohort. Plasma samples were either thawed at room temperature (RT) or on ice, centrifuged or not centrifuged and freeze‐thawed once, twice or three times. Plasma and CSF p‐tau217 were measured using immunoassay developed by Lilly Research Laboratories. Aβ‐status was determined by CSF the Aβ42/Aβ40 ratio.ResultIn the whole cohort, we found significant correlations between plasma p‐tau217 and CSF Aβ42/Aβ40 and p‐tau217 for all tested conditions (Table 1). Correlations between plasma p‐tau217 and CSF p‐tau217 were also significant for all conditions in the Aβ+ group (Table 1). However, in this group, correlations with CSF Aβ42/Aβ40 were only significant in the centrifuged samples (thawed at RT, Rs = ‐0.394, p = 0.005; thawed on ice, Rs = ‐0.406; p = 0.003). In Aβ− participants, significant correlations between plasma p‐tau217 and CSF p‐tau217 were found again only in the centrifuged samples (thawed at RT, Rs = 0.394, p = 0.005; thawed on ice, Rs = 0.334; p = 0.018, Table 1), with no significant correlations between plasma p‐tau217 and CSF Aβ42/Aβ40 for any of the conditions. Even though the accuracy to identify individuals with abnormal CSF Aβ42/Aβ40 or CSF p‐tau217 status was high for all conditions, the AUCs of samples that were thawed at RT without centrifugation were numerically lower than AUCs of other conditions (CSF Aβ42/Aβ40: 0.845 vs 0.872‐0.884; CSF p‐tau217: 0.866 vs 0.908‐0.924, Table 2). Furthermore, no differences were found in plasma p‐tau217 concentration between the samples that were freeze‐thawed once, twice or three times.ConclusionWe found that while centrifugation improved the performance of plasma p‐tau217, but thawing temperatures and upto three freeze‐thaw cycles did not have significant impact. These results might be of importance for future development of standard protocols for pre‐analytical blood sample handling.
Genetic analyses of the plasma proteome and metabolome in the same cohort from participants with African and European ancestry identify ancestry‐specific AD risk associated molecular traits
Authors: Yang Chengran , Gorijala Priyanka , Timsina Jigyasha , Wang Lihua , Wang Ciyang , Liu Ellen , Morris John C , Sung Yun Ju , Cruchaga Carlos 
Published: December 2023

AbstractBackgroundAlzheimer disease (AD) has different prevalence across different ancestries. However, the genetic factors underlying AD pathogenesis between diverse populations are largely unknown. The recent AD genome‐wide association study (GWAS) (Bellenguez et al 2022) reported 75 significant genetic loci in European ancestry, while the latest African‐based AD GWAS (Kunkle et al 2021) only reported two loci. It will be important to map these genetic loci into the functional molecular traits, e.g. RNA expression, protein abundance, metabolite levels. Multiple studies integrated such molecular traits with AD risk and termed them as TWAS, PWAS, and MWAS. However, few studies reported more than one molecular trait and in multiple ancestries.MethodWe first identified the plasma proteomic (SomaScan 7K) and metabolomic (Metabolon HD4) QTLs (quantitative trait loci) from participants with African (AFR, N = 400) and European (EUR, N = 2,300) ancestry, respectively. We next associated the genetic variants with the AD risk GWAS (EUR‐Bellenguez‐2022 & AFR‐Kunkle‐2021) using the protein or metabolite as the intermediate molecular trait. We extended the TWAS framework to test the disease association with the genetically predicted levels of proteins (PWAS) and metabolites (MWAS).ResultWe identified over 3,000 pQTLs and 400 mQTLs. Out of these findings, approximately 40% were novel QTLs compared to the previous studies. We found ancestry‐specific proteins and metabolites associated with AD risk. For example, proteins BIN1, TREM2, APOE, were only significant in EUR‐PWAS results but not AFR‐PWAS using the ancestry‐matched disease associations. Conversely, Spondin‐1 and RNF24 were only nominally significant in AFR‐PWAS. Similarly, metabolites glucuronide and sphingosine were only significant in EUR‐MWAS, whereas ethylmalonate was only nominally significant in AFR‐MWAS. There were 146 and 10 proteins associated with AD‐risk in EUR and AFR, respectively. 55 proteins can be used as drug targets. 119 proteins were not nominated by previous AD risk GWAS. Three and one metabolites were associated with AD‐risk in EUR and AFR, respectively. One metabolite can be used as drug target.ConclusionWe uncovered ancestry‐specific genetic architectures for proteomics and metabolomics. Our study serves as the first multi‐omic genetic study on multi‐ancestries for AD and can help guide the future ancestry‐specific therapy.
Identifying Individualized Neurophysiological Causal Features for Working Memory Performance: Implications for Non‐Invasive Brain Stimulation
Authors: Mirjalili Mina , Zomorrodi Reza , Daskalakis Zafiris J. , Blumberger Daniel M. , Hill Sean , Rajji Tarek K. 
Published: December 2023

AbstractBackgroundNon‐invasive brain stimulation (NIBS) has been extensively used to target specific neural oscillations with the aim of improving working memory performance. However, current NIBS paradigms have two main limitations: first, lack of personalization and second, a need for a randomized controlled trial (RCT) to infer causality between targets of NIBS and subsequent performance. RCT is a powerful measure to infer causality, but its implementation is expensive, time consuming, and sometimes simply not possible. Therefore, our aim was to use computational models and observational data to discover causal relations between neural oscillations and working memory performance to identify potential targets and stimulation parameters for personalized NIBS paradigms.MethodWe used electroencephalography (EEG) data of 66 young healthy participants collected while performing a 3‐back working memory task. Using graphical causal modeling, we extracted individualized causal brain oscillations of 3‐back performance and compared the causal features between two groups: high and low performers.ResultTotal number of causal features in high performers was higher than low performers. Among the causal features, right temporal gamma oscillation was ∼5 times (z‐score = 3.87, p = 0.003) more frequently a causal feature among high performers than low performers. However, the power of causal temporal gamma oscillation was not different between the two groups.ConclusionOur findings suggest that a potential approach to improve working memory performance using NIBS is to induce more causal gamma oscillations by, for example, generating more local gamma entrainment over the right temporal cortex and not necessarily by increasing gamma power.
Hippocampal subregion‐specific proteomic differences between Alzheimer disease (AD) and primary age‐related tauopathy (PART)
Authors: Walker Jamie M. , Orr Miranda E. , Orr Timothy C. , Crary John F. , Woodoff‐Leith Emma , Teixeira‐Yokoda Raquel , Gupta Meenakshi , Daoud Elena , Kautz Tiffany F , Richardson Timothy E. 
Published: December 2023

AbstractBackgroundAlthough Alzheimer disease (AD) and primary age‐related tauopathy (PART) both harbor 3R/4R‐tau immunopositive Alzheimer‐type neurofibrillary degeneration, they differ in the spatial development of neurofibrillary tangles (NFTs) in the hippocampus. PART displays an early predilection for neurofibrillary degeneration in the CA2 subregion of the hippocampus, whereas AD typically develops NFTs in the entorhinal cortex and CA1 subregion initially (Figures 1‐2).MethodUsing Nanostring’s GeoMx™ Digital Spatial Profiling (DSP), we compared hippocampal subregion protein expression differences between AD and PART. The DSP panel allows for spatial analysis of the level of expression of 73 different proteins in multiple regions of interest (ROIs) on formalin‐fixed paraffin embedded sections. Our ROIs were NFT‐bearing neurons and non‐NFT‐bearing neurons in the entorhinal cortex, CA1 and CA2 hippocampal subregions, as well as the neuronal microenvironments in these regions.ResultAnalyses identified several proteins displaying differential expression in tangle‐bearing neurons when comparing AD to PART. These included higher levels of synaptic and neuronal markers in PART, such as Synaptophysin, MAP2, Calbindin and NRGN, as well as higher levels of proteins involved in degradation pathways, such as CTSD, GPNMB, Park7 and FUS. PART also displayed higher levels of Neprilysin in CA2, and higher IDE in CA1, which are proteins that help degrade β‐amyloid (Figure 3). Many of these proteins were also differentially expressed in the non‐tangle bearing neurons. In addition, AD demonstrated higher levels of p‐tau T231, S214, S199, and S396 in non‐tangle bearing neurons of CA1, as well as higher expression of Aβ1‐40. In the microenvironment, NEFL, NRGN, CLEC7a, GPNMB, and CTSD were higher in PART, while p‐tau S396 and BACE1 were higher in AD.ConclusionIn conclusion, PART cases displayed higher levels of neuronal and synaptic markers, suggesting better maintenance of neuronal and synaptic integrity than AD, as well as higher levels of proteins important for degradation of detrimental proteins. AD cases expressed higher levels of certain p‐tau epitopes, especially in and around CA1 non‐tangle bearing neurons. In addition, AD displayed higher levels of BACE1, whereas PART displayed higher levels of CTSD, Neprilysin and IDE, which could explain the differences in β‐amyloid deposition in these cases.
Sleep Phenotypes predict self‐reported measures of cognition and mild cognitive impairment in diverse Hispanics/Latinos
Authors: Ramos Alberto R , Tarraf Wassim , Gonzalez Kevin A , Gallo Linda C , Wallace Douglas M , Redline Susan , Mossavar‐Rahmani Yasmin , Pike James R. , Zeng Donglin , González Hector M , Decarli Charles 
Published: December 2023

AbstractBackgroundThe Hispanic Community Health Study/Study of Latinos (HCHS/SOL) showed that self‐reported cognitive decline (SCD) is associated with objectively assessed cognition. In HCHS/SOL, sleep phenotypes using empirically derived latent class/cluster analyses are associated with brain vascular outcomes. Since these measures may predict cognitive decline and dementia, we examined the associations between sleep phenotypes, SCD and mild cognitive impairment (MCI) among a diverse sample of Hispanics/Latinos living in the United States.MethodHCHS/SOL is prospective cohort study designed using a multisite (Bronx, NY, Chicago, IL, Miami, FL, San Diego, CA) multistage probability sample. SCD was measured as part of SOL‐INCA, an HCHS/SOL ancillary study. SOL‐INCA obtained repeated cognitive tests, seven‐years apart and the Everyday Cognition Short Form (ECog‐12). The ECog‐12 is a self‐rated questionnaire of current multiple cognitively relevant functional abilities compared to 10‐years ago administered to 5,563 SOL‐INCA participants aged ≥ 50 years. We used latent class analysis using 15 common sleep related symptoms, home sleep apnea test and four comorbidities to derive three sleep phenotypes: (1) Minimally Symptomatic group (49.6%), (2) Disturbed Sleep group (17.1%), and (3) Daytime Sleepiness group (33.3%). We used survey regression to evaluate associations between visit‐1 sleep phenotypes and the ECog‐12 (linear) cognitive domains (memory, language, executive function, and global) and MCI (logistic) using the minimally symptomatic sleep group as the reference. Models were adjusted for age, education, sex, background, field center, insurance, body mass index, cigarette use, alcohol use, cardiovascular disease, language preference, and respiratory event index.ResultAverage age was 64.34±8.25 years and 55% were female. In fully adjusted models, participants with disturbed sleep had worse global cognition β = 0.18 [0.14;0.22], memory β = 0.21 [0.16;0.26], language β = 0.23 [0.17;0.29], and executive function β = 0.16 [0.12;0.21]. Compared to the reference, we observed stronger associations in participants with daytime sleepiness; global cognition β = 0.22 [0.16;0.27], memory β = 0.26 [0.19;0.32], language β = 0.26 [0.19;0.34], and executive function β = 0.20 [0.15;0.26]. Adults with disturbed sleep, OR = 1.44 [1.08;1.93], and daytime sleepiness OR = 1.67 [1.16;2.40] had higher odds of MCI.ConclusionEmpirically derived sleep phenotypes capturing disturbed sleep and sleepiness had associations with self‐reported cognitive function and MCI in this sample of U.S. Hispanic/Latino adults.
The Cingulate Island Sign in a Mixed Memory Population: Prevalence and Diagnostic Accuracy
Authors: Feng Linda Ruohua , Waldemar Gunhild , Hasselbalch Steen G. , Vogel Asmus , Henriksen Otto Mølby , Law Ian , Frederiksen Kristian Steen 
Published: December 2023

AbstractBackgroundVisual rating of the cingulate island sign (CIS) on [18F]fluorodeoxyglucose ([18F]FDG) position emission tomography (PET) has a high specificity for dementia with Lewy bodies (DLB) in selected populations such as DLB versus Alzheimer’s disease (AD). This study aims to uncover the prevalence of CIS in an unselected memory clinic population, diagnostic accuracy to detect DLB, and the relationship between CIS and disease severity.MethodWe assessed the CIS on [18F]FDG‐PET with the visual CIS rating scale (CISRs) in 1000 consecutive patients with a syndrome diagnosis of dementia or mild cognitive impairment (MCI) with no restrictions in terms of etiological diagnosis.ResultPossible (CISRs score 1‐2) or definite CIS (CISRs score 3‐4) was found in 24.3% of the cohort and 7.8% had definite CIS. The prevalence of definite or possible CIS was highest in DLB (n = 57 (74.0%)) followed by AD/AD + vascular dementia (AD/AD + VaD) (n = 158, (26.0%)) and other non‐neurodegenerative diseases (n = 6 (9.5%)). The prevalence of CIS across disease severities showed no statistically significant difference (p = 0.23). To differentiate DLB from non‐DLB with MCI or mild dementia the cut‐off which yielded the highest balanced accuracy was at CISRs score ≥ 1 (balanced accuracy = 77.1%) and in moderate or severe dementia a cut‐off at CISRs score ≥ 2 yielded the highest balanced accuracy (80.6%). The positive predictive value of definite CIS for DLB was 48.5% in MCI or mild dementia and 31.3% in moderate or severe dementia.ConclusionCIS on [18F]FDG‐PET is most prevalent in DLB followed by AD/AD + VaD. The prevalence of CIS across disease severities showed no significant difference. CISRs is useful in differentiating DLB from a variety of other diagnosis in a mixed memory cohort, and the diagnostic accuracy was comparable at early and late stages of dementia.
Impaired Astrocytic Synaptic Function by Peripheral Cholesterol Metabolite 27‐Hydroxycholesterol
Authors: Loera‐Valencia Raúl 
Published: December 2023

AbstractBackgroundAstrocytes represent the most abundant cell type in the brain, where they play critical roles in synaptic transmission, cognition, and behavior. Recent discoveries show astrocytes involved in synaptic dysfunction during Alzheimer´s disease (AD). AD patients have imbalanced cholesterol metabolism shown by high levels of a side‐chain oxidized cholesterol known as 27‐hydroxycholesterol (27‐OH). Evidence from our laboratory has shown that elevated 27‐OH can abolish synaptic connectivity during neuromaturation, but its effect on astrocyte function is currently unclear.MethodOur results suggest that elevated 27‐OH decrease the astrocyte function in vivo in one model of brain cholesterol imbalance. To study the relationship between astrocytes and neurons we have developed a 3D co‐culture system (3D‐NAMs) that allows all of the cell types from mice embryos differentiate together in vitro.ResultWe have validated our 3D‐NAMs and show that it reproduces effects of 27‐OH observed in 2D and in vitro. Moreover, we found novel degenerative effects in astrocytes that do not appear in 2D cultures but are present in 27‐OH overproducing mice. We uncover a mechanism of GLT‐1 dysfunction that leads to astrocyte activation, neuronal hyperexcitability and synaptic dysfunction based on the effects of 27‐OH on astrocytes.ConclusionWe propose 3D‐NAMs as tools that can give information about mechanisms of disease and will help elucidate the effectiveness and safety of drug interventions and report a new simple mechanism based on GLT‐1 downregulation in the presence of elevated 27‐OH as the culprit of hyperexcitability in neurons under hypercholesterolemia metabolic conditions.
Interaction of genetic and cardiovascular risk factors identifies pathways involved in Alzheimer’s Disease
Authors: Lee Annie J , Raghavan Neha S , Bhattarai Prabesh , Reyes‐Dumeyer Dolly , De Jager Philip L , Bennett David A. A , Schneider Julie A , Menon Vilas , Wang Yanling , Lantigua Rafael A , Medrano Martin , Mejia Diones Rivera , Jiménez‐Velázquez Ivonne Z. , Kukull Walter A. , Brickman Adam M. , Manly Jennifer J. , Tosto Giuseppe , Mayeux Richard , Kizil Caghan , Vardarajan Badri N 
Published: December 2023

AbstractBackgroundCardio and cerebrovascular diseases co‐exist in up to a third of the Alzheimer’s disease (AD) patients, and the presence of cardiovascular/cerebrovascular risk factors (CVRFs) are associated with the risk of AD in middle age and later. The relationship between CVRFs such as hypertension, body mass index, diabetes and coronary heart disease, and AD is well known, but there has been limited mechanistic evidence directly linking these vascular risk factors in AD to the presence of ischemic microvascular pathology. Each of these vascular factors has the capacity to impair the blood‐brain barrier and glio‐vascular units. Arterial pulses and flow are required for glymphatic clearance of molecules including amyloid β. Few studies have directly linked genetic variation related to the risk factors and the molecular mechanisms underlying the interplay of CVRF and genetics in AD. APOE plays a role in the metabolism of cholesterol and other lipids in the brain. Other genetic variants that have been found to interact with cardio and cerebrovascular risk factors include the CLU, PICALM, CR1, BIN1, ACE, AGT, and ALDH2.MethodsWe analyzed several large multi‐ethnic AD cohorts to understand the role of cardiovascular risk in the disease. We created a CVRF score comprised of hypertension, diabetes, heart disease and body‐mass‐index and tested the interaction of the score with genetic variants in conferring risk of AD.ResultsWe found that genetic variants in FMNL2, BRINP1, RFC2, and IGFN1 interact with enhanced risk score for CVRFs, to modify the risk of developing AD. FMNL2 and BRINP1 brain expression is increased in patients that have pathological hallmark of AD and have chronic infarcts. Causal mediation analysis found that both amyloid and tau pathology increased FMNL2 expression which in turn resulted in higher risk of AD, suggesting that AD brains enhance the activity of this gene.ConclusionsWe propose that that FMNL2 is part of a larger set of genetic and molecular network that underlies the interaction between CVRF and AD. Clinical studies and basic science with animal models could be harmonized to discover new disease mechanisms, which could open new clinical directions and drug development efforts.