bluuebunny/crossref_metadata_2025_split huggingface dataset:
AD Biological Domains—an evolving computational resource for big data classification in AD from the TREAT‐AD Consortium
Authors: Wiley Jesse C , Cary Gregory A. , Ganesh Sruthi , Levey Allan I. , Carter Gregory W , Greenwood Anna K 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is a highly heterogenous disease with a multitude of subtypes and interacting biological systems emerging in a complex pattern of pathology, neurodegeneration and cognitive decline. In order to help organize large scale data analysis in AD in an unbiased manner, we developed a computational model of endophenotypes associated with AD. We call these models the AD Biological Domains.MethodThe Common Alzheimer’s Disease Research Ontology (CADRO) was leveraged in association with literature mining to identify 19 parent endophenotypes that are largely sufficient to cover AD related pathology. These endophenotypes are instantiated as large sets of manually curated gene ontology (GO) terms and linked genes. This framework enables researchers to unambiguously move from an identified gene to a larger disease‐associated biological phenotype.ResultWe defined 19 biological domains in terms of constitutive sets of GO terms. A gene‐set enrichment analysis has confirmed that these 19 biological domains cover almost all AD‐enriched GO terms, barring those that fall outside the reach of the biological domains due to lack of specificity in biological implication. The size of the biological domains ranges from over a thousand GO terms for ‘Proteostasis’ and ‘Synapse’, and just over a dozen for the terms ‘APP Metabolism’ and ‘Tau homeostasis’. There is a low level of cross‐domain utilization of common GO terms, as the biological domains are effectively siloed in their definition, however, at the level of gene annotation we see high levels of promiscuity across domains, potentially providing a molecular trail to find interdependencies between domains. These biological domains are currently being used across several NIA‐funded consortia, including TREAT‐AD, AMP‐AD, MODEL‐AD, and have been adopted by partnered resources such as the AD‐Atlas and Agora. The full list of biological domains and associated GO terms and genes are openly accessible through the AD Knowledge Portal.ConclusionThe biological domains are an open resource designed to provide a community driven definition of discrete areas of AD biology, allowing AD investigators to utilize a standard set of computationally accessible resources to define emerging transcriptomic and proteomic datasets in a unified manner, making cross study comparisons more informative.
Memory dysfunction in mild cognitive impairment (MCI) and early Alzheimer disease (AD) dementia is closely associated with synapse loss, and shows significant correlation with pathological tau in synapses and inflammatory glial cell responses in postmortem human brain
Authors: Taddei Raquel N , Perbet Romain , Wiedmer Anne E , Connors Theresa , Gaona Angelica , Melloni Alexandra N , Duff Karen E , Gomez‐Isla Teresa 
Published: December 2023

AbstractBackgroundSynapse density loss is among the strongest histopathological correlates of dementia in AD. Prodromal stages of AD, comprising amnestic MCI and mild AD dementia, represent the most promising timepoints for interventions aimed at attaining efficacious neurobiological and clinical effects. Yet, the understanding of other contributing neuropathologic changes in these prodromal disease stages and their impact on early cognitive dysfunction remains limited.MethodsWe studied the visual cortex of 28 demented and non‐demented human brains who had died at Braak III‐IV stages of NFT pathology, and who showed a comparable β‐amyloid plaque burden and absence of NFT deposits in the studied brain region, and a group of age‐matched healthy controls. We used immunohistochemical analyses with artificial intelligence quantifications, expansion microscopy, synaptosome extractions, and Western blotting, to assess associations between antemortem MMSE scores and synapse densities, glial cell phenotypes, and pathological tau.ResultsWe found a significant loss of presynapses (Synapsin 1+), excitatory postsynapses (PSD95+), and colocalized synapses (Synapsin1‐PSD95+) in the brains of demented compared to non‐demented and controls. Moreover, we observed an association between excitatory synapse loss and memory dysfunction (MMSE score) as well as rate of disease progression (MMSE loss/time). MMSE scores were further associated with increase in tau oligomers (TOC1+) and phospho‐tau (AT270+) in synaptosomes, but not with 4G8+ β‐amyloid burden. Additionally, disease severity and rate of progression were significantly correlated with inflammatory glial changes.ConclusionsOur data suggest that excitatory synapse loss could serve as an early and robust neuropathologic correlate of disease severity and rate of progression from MCI stages of the disease, and be a closer and better determinant of cognitive decline than β‐amyloid and tau deposits. Moreover, early increases in soluble tau in synapses together with local inflammatory glial cell responses could drive development of incipient changes in memory function and serve as potential early biomarkers. Our results point to the importance of early detection and interventions aimed at synapse preservation from prodromal stages of AD, and suggest soluble tau and inflammatory glial cell changes as key targets in the early AD phases.
Assessment of brain oxygen extraction fraction between normal cognition and mild cognitive impairment in an elderly cohort using quantitative BOLD
Authors: Le Linh N. N. , Wheeler Gregory J. , Fletcher Evan , Blockley Nicholas P. , Fan Audrey 
Published: December 2023

AbstractBackgroundThis study is to quantify oxygen extraction fraction (OEF), an important physiological biomarker for brain hemodynamic impairment, in the elderly cohort using non‐invasive quantitative BOLD (qBOLD) modeling, which is an MRI method for assessment of hemodynamic and metabolic properties.Methods56 participants (75.4±7.0yo, 37F), including 46 cognitively normal (CN) individuals (75.2±7.3yo, 29F) and 10 mild‐cognitive‐impairment (MCI) patients (76.0±6.1yo, 7F), were recruited from UC Davis Alzheimer’s Disease Research Center cohort. MRI scans were acquired on a 3T scanner (Siemens Tim Trio) with a 32‐channel head coil, including an Asymmetric Spin Echo (ASE) scan (TR/TE, 2800/66ms; 2.3×2.3.x1.3mm3 resolution; FOV, 224mm; 13 values of the spin echo displacement time, from 0 to 52ms) and a T1‐weighted MPRAGE. T1‐weighted images were segmented into regions of interest (ROI), including gray matter (GM), white matter (WM), and cortical lobes (frontal, parietal, occipital, temporal) using FSL FAST. ASE signal curves were preprocessed and fit to two‐compartment qBOLD model with Variational Bayesian framework to estimate deoxygenated blood volume (DBV) and transverse relaxation rate (R2
’), which are used to quantify OEF with known physiological constants (Cherukara et al., NeuroImage 2019). Average OEF values were calculated and compared for each ROI between CN and MCI groups using pairwise t‐tests with Bonferroni correction. The correlation between OEF and age were assessed using a linear mixed effects model that accounted for subject clustering.ResultsCompared to CN, reduced DBV and increased OEF were observed throughout most of the brain on the group average level in MCI (Figure 1). In regional analysis, we observed a trend of increased OEF in MCI compared to CN in several ROIs, which was significant in the occipital lobe (p = 0.007) (Figure 2). In Figure 3, OEF was inversely correlated with age in the parietal lobe for CN (p = 0.026). In contrast, there was a positive trend of association between OEF and age for MCI across all regions.ConclusionThis study showed that age has an association with brain oxygen extraction that are differently affected by normal aging and MCI. Higher brain OEF in MCI individuals may reflect changes in oxygen metabolism because of underlying pathology, including vascular injury and compensation for hypoperfusion.
Florbetapir PET Measurements of Amyloid Plaque Deposition are More Closely Correlated with Cross‐Sectional and Longitudinal Cognitive and Clinical Measurements Using a White Matter Reference Region of Interest
Authors: Bhargava Vedanshi , Wang Michele S , Chen Yinghua , Luo Ji , Weiner Michael S. W. , Landau Susan M. , Su Yi , Reiman Eric M. , Chen Kewei 
Published: December 2023

AbstractBackgroundWe previously reported stronger associations of FDG‐PET measured glucose hypometabolism with florbetapir PET measured Aβ deposition quantified using Standard Uptake Value Ratio (SUVR) with a cerebral white matter reference region (SUVRwm) compared to the commonly used SUVR with cerebellar reference region (SUVRcrblm) both cross‐sectionally and longitudinally (Wang et al., AAIC 2021). This study compared cross‐sectional and longitudinal associations of SUVRwm and SUVRcrblm with various cognitive/clinical measuresMethodOur study population consisted of 1133 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) including 206 participants clinically diagnosed with AD dementia, 563 with Mild Cognitive Impairment (MCI), and 364 cognitively unimpaired individuals (CU). We computed partial correlation of SUVRwm or SUVRcrblm, covarying out baseline age and years of education, with Mini Mental State Exam (MMSE); Clinical Dementia Rating Scale Sum Boxes and Global (CDR‐SB and CDGlobal); Alzheimer’s Disease Assessment Scale (ADAS11, ADAS13); Auditory Verbal Learning Test – Short Term Memory, Long Term Memory, and Total (AVLT STM, AVLT LTM, and AVLT Total respectively). Steiger’s Z‐test was used to compare SUVRwm and SUVRcrblm correlation coefficient differences with each of these cognitive/clinical measures at uncorrected p = 0.05 significance. Analyses were carried out over all subjects and within each diagnostic group, first for baseline data and then longitudinally.ResultCross sectionally, correlations were significantly stronger with SUVRwm than with SUVRcrblm for all subjects in all cognitive/clinical measures (all p<1.314E‐04) with the strongest correlation of SUVRwmRef with MMSE (r = ‐0.4717 for SUVRwm and r = ‐0.3463 for SUVRcrblm; p = 1.93E‐13). The strongest correlation within AD subjects was found between SUVRwm and MMSE (r = ‐0.1432 for SUVRwm and r = 0.0459 for SUVRcrblm; p = 9.7063E‐04).Longitudinally, stronger SUVRwm correlations than SUVRcrblm with each of these cognitive measures were also observed over all subjects (p<0.05), and significance with CDR‐SB and AVLT Total in AD; with MMSE, ADAS11, ADAS13, CDGlobal, CDR‐SB, AVLT Total in MCI; and with CDGlobal in CU.ConclusionThe use of cerebral white matter reference region for florbetapir PET SUVR quantification demonstrated stronger associations between amyloid deposition and cognitive measures than cerebellar reference region.
Assessing the associations between plasma C reactive protein, Ab 42/40 ratio, global amyloid and entorhinal tau PET
Authors: Wheeler Koral V , Tennant Victoria R , Lee Noelle , Tubi Meral A , Matsiyevskiy Elizabeth , Terner Jamie , Hall Brandon J , Davison Marylan , Toga Arthur W. , O'Bryant Sid E. , Yaffe Kristine , Braskie Meredith N 
Published: December 2023

AbstractBackgroundLower plasma ratio of amyloid beta (Ab42/Ab40) has been associated with brain amyloid, however, the mechanistic link is unclear. Systemic inflammation may contribute to plasma Ab levels and promote or reduce the accumulation of Alzheimer’s disease (AD) neuropathology. C reactive protein (CRP) is an inflammatory marker implicated in amyloidosis. Using a cross sectional analysis, we evaluated the relationship between blood levels of CRP and Ab ratio, global amyloid positron emission tomography (PET), and tau PET in the entorhinal cortex where tau accumulates early. We hypothesized that Ab positivity would modify the relationship between CRP and AD pathology.MethodIn 969 cognitively normal participants (age: 50‐87, 781 Ab‐/188 Ab+) (Table 1) from the Health and Aging Brain Study‐ Health Disparities (HABS‐HD), we acquired 18F‐PI‐2620 tau‐PET, florbetaben amyloid PET scans, and plasma measures of Ab 42/40 and CRP. Subjects were categorized by Ab + or Ab ‐ by a global amyloid PET standardized uptake value ratio (SUVR) cutoff of 1.08. Within Ab groups, we performed multiple regressions to evaluate associations between 1) global amyloid and entorhinal tau‐PET SUVRs and 2) plasma markers of Ab ratio and CRP. We covaried for age, gender, education, APOE4, and scanner and used false discovery rate (FDR) for multiple comparison corrections.ResultIn Ab+ participants, higher amyloid (b = ‐0.31, p = 0.0005) and tau PET (b = ‐0.36, p = 0.004) were significantly associated with low Ab ratio, but not in Ab‐ for amyloid or tau, with significant interactions by Ab positivity for amyloid (b = ‐0.45, p = 2.65×10−6) and tau (b = ‐0.77, p = 0.0002) (Figure 1). In Ab+ participants, higher CRP was associated with higher Ab ratio (b = 0.21, p = 0.04) and a trend toward lower amyloid (b = ‐0.15, p = 0.084) and tau PET (b = ‐0.22, p = 0.084), but not in Ab‐ participants, with a significant interaction by Ab positivity for Ab ratio (b = 0.46, p = 0.011) (Figure 2) and amyloid (b = ‐0.11, p = 0.0006) and tau PET (b = ‐0.17, p = 0.016).ConclusionIn cognitively intact Ab+ but not Ab‐ adults, higher plasma Ab ratio was associated with lower global amyloid and entorhinal tau PET. In Ab+ participants, higher CRP was associated with blood and brain amyloid and tau levels consistent with less AD pathology.
Peripheral insulin resistance and creatinine levels are associated with plasma phosphorylated tau
Authors: Yang Kao Lee , Ennis Gilda E. , Jonaitis Erin M. , Johnson Sterling C , Ashton Nicholas J. , Blennow Kaj , Zetterberg Henrik , Bendlin Barbara B 
Published: December 2023

AbstractBackgroundType 2 diabetes (T2D) and insulin resistance (IR) are associated with increased dementia risk, but their association with plasma AD biomarkers e.g., plasma phosphorylated tau (pTau) is unknown. Here, we tested the relationship between diabetes, IR, and pTau, as well as considering the influence of comorbid conditions (obesity and kidney disease) on plasma biomarker measurements.Method425 participants from the Wisconsin Registry for Alzheimer’s Prevention were included based on availability of plasma assays. Plasma pTau181 and pTau231 were measured using a single molecule array (Simoa) assay on Quanterix. Diabetes status at baseline visit was determined using fasting blood glucose and medication usage. IR was measured using the homeostatic model assessment of IR (HOMA2‐IR) and z‐scored. Obesity was indicated through body mass index (BMI) and kidney function was determined by blood creatinine levels. We used Welch’s t‐test to examine differences in pTau levels based on diabetes status. Pearson correlations tested the linear relationships between longitudinal pTau181 and pTau231 with baseline HOMA2‐IR, BMI, and creatinine. Two linear mixed effects models were fitted; one for each of the pTau markers. Each model included random intercepts and age‐related slopes with fixed effects of baseline z‐scored HOMA2‐IR, BMI, and creatinine. Results were considered significant at p<.05unadjusted.ResultSample characteristics are in the Table. Baseline HOMA2‐IR correlated with pTau181 (r = 0.066, p = 0.021), but not pTau 231. Baseline creatinine associated with both pTau181 and pTau231 (Figure 1). Creatinine was also longitudinally associated with pTau231 (β = 4.82, p = 0.004; Figure 2). When accounting for BMI and creatinine, HOMA2‐IR was no longer associated with longitudinal pTau181 or pTau231. Age was robustly associated with pTau181 (β = 0.04, p = 6.06×10−7) and pTau231 (β = 0.15, p = 5.21×10−7) change. Plasma pTau did not differ based on diabetes status.ConclusionIR associated with pTau181 but this relationship did not hold when adjusting for obesity and kidney function. Creatinine levels were associated with longitudinal changes in pTau231 levels. Age was strongly associated with pTau181 and pTau231 change, such that older age was associated with increasing pTau181 and pTau231 levels. Though this study was completed in a largely healthy cohort, the results suggest comorbid conditions are important considerations when utilizing plasma pTau biomarkers as primary outcomes.
A systematic review of drug interventions to enhance cognition in patients with primary central nervous system infections
Authors: Rizvi Syeda Taliya , Shah Jhankhana , Shaaya Sarah , Mollayeva Tatyana 
Published: December 2023

AbstractBackgroundAlthough drug therapy is part of the clinical routine for individuals with central nervous system (CNS) infections, its efficacy with respect to cognitive impairments has not been systematically studied. We aimed to synthesize the evidence for optimal treatment decisions.MethodWe searched for experimental studies published in English prior to October 2021 in MEDLINE, Embase and Cochrane databases. We selected non‐randomized studies (NRS) and randomized control trials (RCT) of a drug efficacy versus placebo, another drug, or a combination of drugs. The certainty of the evidence was rated according to GRADE guidelines.ResultWe included eight RCTs and one NRS, involving a total of 805 patients (50.77% male patients; mean age 42.67±10.58; duration (in years) of primary CNS infections 4.69±3.16) with Lyme disease (LD), herpes simplex virus type 1 (HSV‐1), or Creutzfeldt–Jakob disease (CJD) studying the efficacy of antibiotics, antiviral, and non‐opioid analgesic drugs, respectively. The duration of the interventions varied, depending on the type of CNS infection and class of drug, with a range between four weeks in patients with LD treated with antibiotics and 18 weeks in patients with HSV‐1 treated with an antiviral drug. In patients with LD, antibiotics alone or in combination with other drugs enhanced certain cognitive domains relative to placebo. In patients with HSV‐1, the results were inconsistent. In patients with CJD, flupirtine maleate enhanced baseline cognitive scores. Of the available evidence, only one study had “low” risk of bias. An important limitation of the included studies was the lack of consistent reporting of adverse effects and safety parameters, which must be addressed in future work.ConclusionThere is not enough existing evidence of sufficient quality to support the use of antimicrobials and non‐opioid analgesics in combatting cognitive deficits in patients with LD, HSV‐1, or CJD. Future clinical trials enrolling participants at earlier stages of primary CNS infections, at the time of greatest inflammation, and which address the elements of biases found in the existing clinical trials, are warranted.
Evaluation of HIVEP3 polymorphic variants and gene expression in Alzheimer’s disease
Authors: Dauar Marina Tedeschi , Picard Cynthia , Labonte Anne , Poirier Judes 
Published: December 2023

AbstractBackgroundIt has been increasingly recognized that neuroinflammation plays an important role in the pathophysiology of Alzheimer’s disease (AD). The HIVEP3 gene encodes a transcription factor that regulates inflammatory response, and variants in this gene have been associated with increased risk for Parkinson’s disease. HIVEP3 gene expression is transiently decreased following nerve damage, consistent with a role during neuronal remodeling . In the present work, we investigate genetic variants in the HIVEP3 gene as risk factors for AD, and study HIVEP3 gene expression in human cerebral cortex.MethodWe have used three different cohorts to assess the association of HIVEP3 polymorphisms with the risk of developing AD: the International Genomics of Alzheimer’s Project (IGAP), the Quebec Founder Population Cohort (QFP) and Kunkle et al. stage 1 GWAS dataset. In the QFP cohort, we measured HIVEP3 protein levels (using ELISA) and mRNA levels (using RT‐PCR) in the frontal cortex of autopsied‐confirmed AD and control subjects.ResultWe have found that the rs10493098 C variant is associated with increased risk of AD in IGAP 2009 (p = 0.018, OR = 1.04), QFP (p< 5 × 10−8, OR = 1.37) and Kunkle et al. 2019 stage 1 IGAP GWAS (p = 0.006). In the IGAP cohort, this variant is associated with increased risk of AD only in APOE4 negative participants (p = 0.0009). Cortical HIVEP3 protein levels are increased in subjects with AD compared to controls (p = 0.029) and in subjects with at least one copy of the rs10493098 C variant compared to non‐carriers (p = 0.03). There are no changes in mRNA levels as a function of disease status or presence of the rs10493098 C variant. There is no correlation between HIVEP3 protein or mRNA levels and senile plaques or neurofibrillary tangles densities.ConclusionWe have identified a new genetic variant associated with increased risk for AD. The HIVEP3 rs10493098 C variant is associated with increased risk of AD, particularly in APOE4 negative participants. HIVEP3 proteins levels are increased in the frontal cortex of AD subjects compared to controls and in rs10493098 C carriers.
Charting the genetic architecture of Alzheimer’s disease across APOE*4 and sex
Authors: Belloy Michael E , García‐González Pablo , Castillo Atahualpa , Guen Yann Le , Kasireddy Nandita , Stewart Ilaria , Eger Sarah J , Young Christina B. , Mormino Elizabeth C. , Napolioni Valerio , He Zihuai , Altmann Andre , Greicius Michael D ,   Members of the GR@ACE/DEGESCO, GERAD, and EADB groups
Published: December 2023

AbstractBackgroundAPOE*4 status and sex (and their interaction) are among the strongest risk factors for late‐onset Alzheimer’s disease (AD). We thus sought to perform large‐scale, stratified genome‐wide association study (GWAS) of AD to chart the role of common genetic variation in AD sexual dimorphism and heterogeneity of APOE*4‐related AD risk.MethodThe study overview and GWAS models are shown in Figure.1A. SNP‐array AD GWAS datasets primarily composing the ADGC, together with whole‐genome sequencing (WGS) from ADSP (NG00067.v7), provided case‐control diagnoses for phase‐1. The UK Biobank provided subjects with ICD codes and family history of AD status for phase‐2. Subjects were of European ancestry. Linear mixed model regressions were performed (LMM‐BOLT v.2.3.4) on AD outcome measures, adjusting for sex, APOE*4/APOE*2 dosage, genetic principal components, and array/batch/center. GWAS hits (P<5e‐*8) were evaluated for interactions effects (meta‐regression for phase1+2 meta‐analyses) and assessed in functional follow‐up analyses. The effect of stratification on genetic risk scores (GRS) predictive performance on AD risk was also evaluated.ResultStratified AD GWAS identified 28 loci/variants, including 5 known lead variants in known AD loci, 6 novel independent variants in known AD loci, and 17 novel loci (Figure.1B). 13 out of 17 novel loci showed varying degrees of functional support, with 4 also showing evidence for QTL colocalization (Figure.2). Many implicated genes showed prior support or effects relevant to AD: MARCHF10 was recently implicated as a risk gene for all‐cause dementia; EMP2 is a regulator of cell membrane composition, cell‐matrix adhesion, and blood vessel endothelial cell migration; SLIT2 binds APP, and EYA4 and TBC1D9 have respectively been implicated in brain tau deposition and MAPT haplotype‐stratified GWAS. Nonetheless, most novel hits were low/uncommon frequency variants and QTL colocalization evidence was limited. Further, there appeared to be no predictive benefit for stratified GRS analyses (Figure.3).ConclusionWe identified novel loci/variants differentially associated with AD risk across APOE*4 and/or sex. Yet, we inferred relatively limited evidence for stratified effects (propensity for low frequency hits and no benefit for stratified GRS). Overall, our findings contribute to our understanding of the genetic etiology of AD, which in turn contributes to advance personalized genetic medicine.