bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigating phenotypic modifiers of Alzheimer’s disease utilizing cellular and transcriptomic signatures of PSEN1 mutation carriers
Authors: Pottier Cyril P , Lincoln Sarah J. , Boon Baayla D.C. , Wickland Daniel P. , Rothberg Darren M. , DeTure Michael , Ertekin‐Taner Nilufer , Graff‐Radford Neill R , Dickson Dennis W. , Murray Melissa E. 
Published: December 2023

AbstractBackgroundPSEN1 mutations are the most common genetic cause for autosomal dominant forms of Alzheimer’s disease patients with an age at onset below 65 years (ADAD). Even though all PSEN1 mutations lead to an increased Aβ processing and production, there is a large variability in phenotypic presentation even in individuals with the same mutation. Splicing isoforms in AD genes are reported to be associated with the disease, however little is known about correlation between splicing pattern and phenotypic presentation (e.g. variable age onset). We hypothesized that cellular and transcriptomic alterations differ amongst patients with different phenotypic presentation. In a group of 8 ADAD with the same PSEN1 p.G206A mutation, we investigate the association between brain cell type proportion, gene expression, and splicing isoforms with age at onset, Aβ plaque type and severity of AD neuropathologic change.MethodsEight Hispanic ADAD cases with PSEN1 p.G206A mutation were identified in the Mayo Clinic brain bank housed in Jacksonville, FL. Standard (immuno)histochemical stains, including H&E and thioflavin S, were performed to evaluate AD neuropathologic change. We focused on distinct Aβ plaque types in an association cortex (inferior parietal gyrus) and primary cortex (motor). We carried‐out single‐nuclei short and long read RNA sequencing on both brain regions. We will stratify our transcriptomic analyses based on neuropathology and phenotypic presentation.ResultsWe observed large variability in age at onset (median = 53 years; range: 42‐59 years). Furthermore, disease duration was reportedly variable (median = 10 years; range: 8‐17). All cases had a Braak tangle stage VI and Thal amyloid phase 5. Only 3 patients carried at least one APOE*ε4 risk allele, suggesting that its effect was minimal on ages at onset and death. Different plaque types were observed for short versus long survivors. In short survivors, plaques were predominantly fibrillar with an eosinophilic radial component, whereas in longer survivors predominantly cored plaques were observed.ConclusionLarge phenotypic variability within patients with the same mutation is observed suggesting the involvement of yet to be discovered genetic modifiers. Understanding cellular transcriptomic events in ADAD is essential to future development of therapeutic approaches and development of biomarkers.
Differentiation of clinically diagnosed patients with aMCI and dementia from cognitively unimpaired older adults using plasma and serum p‐tau 181 and NfL
Authors: Jurasova Vanesa , Veverova Katerina , Angelucci Francesco , Katonova Alzbeta , Vyhnalek Martin , Andel Ross , Hort Jakub 
Published: December 2023

AbstractBackgroundBlood‐based biomarkers give the possibility of having a less invasive, more acceptable to patients, and cost‐ and time‐efficient screening tool. Therefore, blood‐based biomarkers represent an ideal addition to cerebrospinal fluid (CSF) and neuroimaging biomarkers. Standard examination of neurocognitive disorders, such as lumbar punction or brain PET scan, cannot be performed within general practice. Given the high prevalence of these diseases, alternatives such as blood‐based biomarkers would represent a significant advance. The aim of this study was to investigate whether levels of p‐tau 181 and neurofilament light chain (NfL) in serum and plasma can differentiate cognitively unimpaired (CU) elderly individuals from individuals in the stage of aMCI and dementia.MethodA total of 75 biomarker‐defined individuals from the Czech Brain Aging Study were recruited for the study, including the CU, individuals in the aMCI stage, and individuals in the stage of dementia syndrome with various etiology (AD, FTLD or LBD). Commercial ELISA kits were used for the assessment of standard biomarkers from CSF (Aß42, Aß40, pTau, tTau). Plasma and serum samples were analyzed using a Quanterix SR‐X analyzer with Simoa technology. Receiver operating characteristic analyses of the concentrations of p‐tau 181 and NfL in plasma and serum were performed using the R statistical software and GraphPad Prism.ResultPlasma NfL, AUC 0.9861 (95% CI, 0.9439 to 1.000), and serum NfL with AUC 0.9583 (95% CI, 0.8774 to 1.000) differentiated aMCI and dementia from CU with high predictive accuracy. The results were significant for plasma p‐tau 181 too with AUC 0.7869 (95% CI, 0.6474 to 0.9265), along with serum p‐tau 181 with AUC 0.7623 (95% CI, 0.6292 to 0.8954).ConclusionPlasma and serum p‐tau 181 and NfL may be potentially useful and cost‐effective biomarkers for differentiating cognitively unimpaired elderly individuals from those at aMCI and dementia stages in general health care settings.
Longitudinal changes in blood flow, vessel pulsatility, and trans‐capillary pulse wave delay in small vessel disease and amyloid biomarker positive
Authors: Rivera‐Rivera Leonardo A. , Du Lianlian , Langhough Rebecca E , Jonaitis Erin M. , Betthauser Tobey J , Burghy Cory , Cody Karly Alex , Chin Nathaniel A. , Eisenmenger Laura B. , Johnson Sterling C , Johnson Kevin M. 
Published: December 2023

AbstractBackgroundThis work characterized longitudinal changes in cerebrovascular health in humans with and without presence of small vessel disease (SVD) and amyloid‐β using different neuroimaging techniques.MethodParticipants (n = 41) were biomarker characterized into three groups: amyloid and SVD negative (A‐V‐; “control”), SVD positive (A‐V+), and amyloid positive (A+V‐). All were cognitively unimpaired except two participants clinically diagnosed with MCI (A‐V+) and dementia (A+V‐) (Table 1). MRI:
Vascular imaging: Whole‐brain 4D‐Flow data were acquired to characterize cerebrovascular health. Two MRI time‐points were used to establish 4D‐Flow‐based longitudinal changes. Measurements were extracted from intracranial arteries and veins and included blood flow, vessel pulsatility index, and trans‐capillary pulse wave delay (TPWD). TPWD was defined as the time shift between arterial and venous cardiac waveforms. Structural imaging: TIV‐normalized WMH volumes were segmented from T2‐FLAIR images and used as surrogate for SVD. V+/‐ thresholds were determined from Gaussian Mixture Model on 930 participants. PET: Amyloid‐β burden was assessed using 11C‐PiB PET imaging. Amyloid positivity was established as mean cortical PiB DVR >1.16. Vascular changes were assessed using Kruskal‐Wallis followed by multiple comparisons (P<0.05 significance).ResultAfter ∼4.5 years, middle cerebral arteries (MCAs) blood flow decreased significantly more in amyloid than SVD groups, while vessel pulsatility increased significantly more in amyloid compared to SVD (Fig.1). TPWD shortened significantly in SVD compared to amyloid and control groups. All groups showed a decreased in blood flow, increased in vessel pulsatility and shortening of TPWD with time. At the time of the last MRI visit, MCAs blood flow was somewhat higher in SVD compared to amyloid and control groups, but not significantly (Fig.2). Vessel pulsatility was similar between groups, yet slightly higher in SVD and amyloid groups. TPWD was significantly shorter in SVD compared to the amyloid group.ConclusionThis work demonstrates the feasibility to measure longitudinal cerebrovascular changes using 4D‐Flow MRI in the context of SVD and AD biomarker positive groups. Preliminary results indicate 4D‐Flow‐based vascular markers can detect differences between SVD and amyloid groups both longitudinally and cross‐sectionally. Cerebrovascular changes in A+ suggest decreased metabolism and increased macro‐vessel stiffness, while findings in SVD positive supports stiffness of the micro‐circulation and capillaries.
Associations of GFAP, NfL, Aβ42/40, and pTau231 with global cognition in LEADS
Authors: Kostadinova Ralitsa V. , Hammers Dustin B. , Logan Paige E. , Manchella Mohit K. , Nemes Sára , Fagan Anne M. , Foroud Tatiana M. , Blennow Kaj , Zetterberg Henrik , Kramer Joel H. , Aisen Paul S. S , Carrillo Maria C. , Rabinovici Gil D. , Dickerson Brad C. , Apostolova Liana G. , Dage Jeff L. 
Published: December 2023

AbstractBackgroundHistorically, Alzheimer’s disease (AD) biomarkers have been used to identify the presence of pathology and have been shown to change well ahead of symptom onset. While previous research has evaluated plasma pTau231 and its associations with cognition, little to none of this research has focused on early‐onset AD (EOAD) populations. Here we investigate how select plasma biomarkers are associated with global cognitive measures in early‐onset cognitive impairment.MethodThe current sample included 367 Longitudinal Early‐Onset AD Study (LEADS) participants (aged 41 to 65) categorized as amyloid PET‐positive EOAD, amyloid PET‐negative EOnonAD, or cognitively normal (CN). Each participant had baseline global cognitive (Mini‐Mental State Examination [MMSE], Montreal Cognitive Assessment [MoCA], Clinical Dementia Rating Scale sum of boxes [CDR‐SB], and ADAS‐Cog13) and plasma biomarker assessments (Simoa‐HDx N4PE kit: Aβ42/40, phosphorylated Tau [pTau231], Neurofilament light protein [NfL], and glial fibrillary acidic protein [GFAP]). Partial correlations were used to check for associations with cognitive performance controlling for age, sex, and years of education. Fisher r‐to‐z transformations were conducted to compare the performance across diagnostic groups.ResultPartial correlations in the pooled sample showed moderate associations between cognition and plasma pTau231, GFAP and NfL (r = .42‐.50, p<.001) and weaker associations with Aβ42/40 (r = .25‐.33, p<.001). When split into diagnostic groups, the NfL and GFAP correlations were significant in both EOAD and EOnonAD, but not CN. The pTau231 correlations were significant only in EOAD. Aβ42/40 correlations were non‐significant within specific diagnostic groups. No differences were observed in the magnitude of the cognitive and biomarker associations between EOAD and EOnonAD samples (ps>.05).ConclusionAs expected, the neurodegenerative biomarkers pTau231 and NfL showed stronger association with cognition compared to the marker for brain amyloidosis (Aβ42/40). The nonspecific markers for neurodegeneration (NfL) and brain astrogliosis (GFAP) showed associations in both EOAD and EOnonAD while the markers specific to AD were only significant in EOAD. Plasma biomarkers show great promise for AD diagnosis and monitoring.
Transcriptomic Profiling Across Age, APOE and Sex for Models of Alzheimer’s Disease at a Single Cell Resolution
Authors: Li Yaqiao , Hao Yanxia , Yoon Seo Yeon , Grone Brian , Ding Leonardo , Blumenfeld Jessica , Oskotsky Tomiko , Huang Yadong , Sirota Marina 
Published: December 2023

AbstractBackgroundAdvanced age, apolipoprotein E4(APOE4), and female sex are well‐established risk factors for Alzheimer’s Disease(AD). Almost two‐thirds of people with AD are women. The APOE4 genotype, the strongest genetic risk factor for AD, is associated with higher AD risk in women than in men between ages 55 to 70. We propose to study the interplay between these risk factors by analyzing single‐nucleus RNA‐sequencing(snRNA‐seq) data of the hippocampus of human APOE4 and APOE3 knock‐in(KI) female and male mice across age.MethodsA sex‐balanced cohort of APOE3‐KI and APOE4‐KI homozygous mice were sacrificed at 6 (young), 12 (adult), and 18 (old) months of age(Figure1A). Single nuclei were prepared from the hippocampus from each mouse and sequenced. Demultiplexed fastq files were aligned to a custom reference genome mm10‐1.2.0, using Cellranger v2.0.1. Quality assurance, count normalization, clustering, cell type identification, and differentially expressed gene(DEG) analysis were performed using Seurat4.0.ResultsOur dataset consists of a total of 527,395 cells covering 27,153 genes. A total of 36 cell clusters were determined with six major brain cell types including astrocytes, microglia, oligodendrocytes, oligodendrocyte precursor cells, and excitatory and inhibitory neurons (Figure1B). We investigated the abundance of each cell type and found that cellular composition is consistent across ages, APOE genotypes, and sexes for all cell types except astrocytes. Astrocyte abundance is significantly higher in old females compared to old males(padj = 0.025, Tukey’s multiple comparison test) and in APOE4 young males compared to APOE3 young males (padj = 0.042)(Figure1C).Sex and age stratified differential gene expression analysis comparing APOE4 versus APOE3 astrocytes reveals many shared DEGs between young and adult males but not with old males, while females have few consistent DEGs across the three age groups(Figure1D). We identified several DEGs associated with plasma membrane assembling and post‐synaptic transmission and signaling that are upregulated in APOE4 old females versus APOE3 old females while downregulated in APOE4 young females, young and adult male compared to their APOE3 counterparts.ConclusionWe identify clear interplay between age, APOE genotype, and sex in mouse models of AD and investigate the interaction and convergence of these risk factors at a single cell resolution.
Single‐nuclei transcriptomic identifies type‐specific neuronal cell vulnerability and non‐neuronal molecular changes in Amnestic and Logopenic Variant Primary Progressive Aphasia Alzheimer’s disease
Authors: Pereira Felipe Luiz , Lew Caroline , Li Song Hua , Soloviev Alexander , Spina Salvatore , Seeley William W. , Suemoto Claudia Kimie , Leite Renata Elaine Paraizo , Newell Kathy L , Ghetti Bernardino Francesco , Murray Melissa E. , Grinberg Lea T. 
Published: December 2023

AbstractBackgroundIndividuals with neuropathological criteria for Alzheimer’s disease (AD) may manifest with atypical clinical syndromes. Past work showed that the neurobiological basis for these differences is related to specific neuronal vulnerabilities for tau pathology. For instance, amnestic cases have a higher burden of neurofibrillary changes in CA1. In contrast, logopenic variant primary progressive aphasia (lvPPA) cases have a higher tau burden in the superior temporal gyrus (STG). Single‐cell technology enables investigations on the molecular basis of differential neuronal vulnerability in AD. Therefore, we investigated factors underlying selective vulnerability using brain samples from individuals with pure AD with different clinical manifestations.MethodsnRNA Sequencing using the Chromium Single Cell 3′ (10X Genomics, USA) on nuclei cells extracted from the CA1 sector and posterior STG of postmortem brain tissue of 24 individuals either meeting pathological criteria for AD (A3B3C3; 12 amnestic and eight lvPPA) and healthy controls (A≤1B≤1C≤1; n = 4) (Table 1, Fig. 1A/B). Bioinformatics analyses were conducted using Cell Ranger and R software. Comparisons between cell subpopulations were conducted with Wald statistical test, and p‐values < .05 were considered significant.ResultAfter quality control, we recovered 98,180 nuclei with a mean of 2,130 genes per nuclei. Upon cross‐sample alignment and t‐stochastic neighborhood embedding clustering (Fig. 1C), we found 21 excitatory neuronal subpopulations (Exc‐sub) in CA1 and 26 in STG, and 22 and 27 inhibitory neuronal subpopulations (Inh‐sub) in CA1 and STG, respectively; 16 astrocytes subpopulations in both areas and 20 microglia subpopulations in CA1 and 17 in STG (Fig. 2). One STG Exc‐sub, expressing CUX2 and LAMP5 genes showed vulnerability in lvPPA patients. Also, one STG Inh‐sub, expressing the ADARB2 gene, showed vulnerability for all AD patients. Furthermore, two astrocytes subpopulations (one in both areas and one in STG) and three STG microglia subpopulations showed proportional composition changes comparing AD patients and HC.ConclusionOur preliminary study identified a vulnerable population of excitatory neurons related to lvPPA. We are conducting validation studies using quantitative pathology to confirm these results. Furthermore, analysis of a higher number of cases is ongoing and will continue to inform on factors associated with neuronal vulnerability.
Amyloid beta (1‐42) peptide suppression of macroscopic homomeric Kv1.2 and heteromeric Kv1.1/1.2 currents is calcium‐ and calcineurin‐dependent: Implications for Alzheimer’s disease
Authors: Jamshidi Dina , DeBoeuf Kristi , Farley Joseph 
Published: December 2023

AbstractBackgroundThe roles of Aβ in the pathogenesis of Alzheimer ’s disease (AD) include disruption of: 1) Ca2+ homeostasis, 2) synaptic communication, and 3) learning‐ and memory‐related synaptic plasticity and neuronal excitability mechanisms. Exactly how these abnormalities arise is incompletely understood. Our lab has focused on the involvement of voltage‐gated potassium channels (VGKCs) in several of these processes. VGKCs are activated during an action potential and regulate Ca2+ influx. Inhibition of VGKCs can lead to synapto‐ and neuro‐toxicity. Kv1.x family subunits can assemble as functional homomers or select heteromers; Kv1.1 is often co‐expressed with Kv1.2. We’ve previously found that: 1) Aβ peptides suppress both Kv1.1 and Kv1.2 homomeric channel activities, as well as Kv1.1/1.2 heteromeric activity, 2) Aβ suppression of Kv1.1 was partially (∼ 50%) dependent on intracellular calcium [Ca2+]i, being reduced by exposure of cells to the calcium chelator BAPTA‐AM, as well as by cyclosporine A (CsA), an inhibitor of PP2B/calcineurin (CaN). Here we asked if Aβ‐suppression of Kv1.2 and Kv1.1/1.2 currents was similarly dependent on [Ca2+]i, and CaN in the case of Kv1.2.MethodsStage V/VI Xenopus laevis oocytes from Ecocyte Bioscience (Austin, TX) were injected with Kv1.2 cRNA for homomeric expression. Heteromeric expression was produced by co‐injection of Kv1.1 and 1.2 cRNAs. Macroscopic currents were measured 2‐3 days later using TEVC.ResultsBath application (1 μM) of Aβ(1‐42) produced significant suppression of Kv1.2 (46%, n = 10) and Kv1.1/1.2 (41%, n = 8), 30 min following Aβ application. These suppressions were significantly greater than those of DMSO‐exposed control cells: 2% for Kv1.2 (n = 15), p< .002; 11% (n = 7) for Kv1.1/1.2, p <.02. BAPTA‐AM treatment (n = 9; 50 μM for 1 hr, followed by 3X wash) greatly reduced Aβ‐suppression of Kv1.2 current (from 46% to 18%, p < .002). CsA exposure (n = 6, 10 μM for 12 hr) completely blocked Aβ suppression (from 46% to ‐4%, p < .0001). BAPTA‐AM (n = 5) also significantly attenuated suppression of Kv1.1/1.2 current (from 41% to 10%, p < .02).ConclusionOur results suggest that Aβ‐disruption of [Ca2+]i can lead to suppression of Kv1.1 and 1.2 activities through CaN activation, and thereby contribute to hyperexcitabilty phenotypes in AD.
Locus coeruleus MRI contrast is associated with Complement factor C3b in cerebrospinal fluid
Authors: Neumann Laura , Hayek Dayana , Sarkar Mousumi , Heinzinger Nils , Hämmerer Dorothea , Schneider Anja , Fließbach Klaus , Teipel Stefan , Spottke Annika , Brosseron Frederic , Jessen Frank , Düzel Emrah , Heneka Michael T. , Maass Anne , Betts Matthew 
Published: December 2023

AbstractBackgroundDegeneration of the Locus coeruleus (LC) is associated with Alzheimer’s disease (AD) pathology and cognitive decline. Recent evidence from animal models indicates that this relationship may be mediated by neuroinflammation. Here we examined how LC MRI contrast is related to CSF biomarkers of neuroinflammation in humans.MethodThe LC as well as the Substantia nigra (SN) were visualized and segmented using neuromelanin‐sensitive T1‐weighted FLASH‐MRI images acquired at 3T and MRI contrast values were calculated as previously described (Betts et al., 2019b). A cohort of 65 participants with MRI contrast and CSF data from the DZNE longitudinal cognitive impairment and dementia (DELCODE) study (20 HC, 22 SCD, 16 MCI, 7 AD dementia; 53.8% female) were included in the analyses. We performed correlational analyses to test for associations between LC and SN contrast with a panel of 4 Principal Components (PC) created from a Principial Component Analysis on 16 individual inflammation‐related CSF biomarkers (Fig. 1). Both bivariate and partial correlation analyses were performed between PCs and MRI contrast values using sex, age, site and CSF levels of AD pathology, namely Aß42/40‐ratio and phosphorylated tau, as covariates (see Fig. 2).ResultWe found a significant positive association between LC MRI contrast and the inflammatory component PC4 including the proinflammatory complement factors C3 and C3b across the entire sample (r = 0.365, p = 0.003). Additional post‐hoc correlational analyses showed this association with LC MRI contrast was mainly due to a correlation with C3b (r = 0.349, p = 0.004). A significant positive association was still observed (r = 0.347, p = 0.008) in a subgroup of individuals comprising healthy older adults and individuals with a risk of AD dementia (HC, SCD and MCI) as shown in Fig. 2. In contrast, no significant associations between SN MRI contrast and any neurodegenerative or inflammatory measure were observed indicating effects were specific to the LC.ConclusionThe results demonstrate LC MRI contrast is associated with complement factors in CSF, in particular complement factor C3b in healthy older adults and individuals with a risk of AD dementia. Further analyses are required to determine if elevated complement factors may predict degeneration of the LC and subsequent cognitive decline.
Exploring inflammation‐related protein expression and its relationship with TSPO PET in Alzheimer
Authors: Benedet Andrea Lessa , Antônio De Bastiani Marco , Brum Wagner Scheeren , Pola Ilaria , Rahmouni Nesrine , Tissot Cécile , Therriault Joseph , Pascoal Tharick A. , Blennow Kaj , Zetterberg Henrik , Zimmer Eduardo R , Ashton Nicholas J. , Rosa‐Neto Pedro 
Published: December 2023

AbstractBackgroundDeveloping evidence highlight the importance of neuroinflammation in the progression of Alzheimer’s disease (AD) pathophysiology. It has been shown that inflammatory mechanisms affect both amyloid and tau deposition in the brain. However, given the complexity of the immune cascades and the unknown interactions between the peripheral and central nervous systems in the disease, it has been challenging to identify biomarkers that reflect a given inflammatory state in this context. Thus we aim here to further explore inflammation‐related proteins for potential biomarker utility in AD.MethodParticipants from the TRIAD cohort incorporating within the AD spectrum, and with available TSPO PET ([11C]PBR28) imaging data, had their cerebrospinal fluid (CSF) (n = 100) and plasma (n = 169) samples analyzed using Proximity Extension Assay (PEA) technology targeting 368 inflammation‐related proteins (Olink). LIMMA models evaluated the differential protein expression according to TSPO PET status (positivity attributed by 3 SD above the mean ROI‐SUVR of young participants), adjusting for age and brain amyloid load (PET). Associations were FDR corrected for multiple comparisons. Gene ontology (GO) was used for enrichment analysis on relevant results.ResultPreliminary results identified several proteins that are in higher concentration in the CSF of TSPO positive in comparison with TSPO negative participants (Figure 1). The enrichment analysis (Figure 2) unveiled terms related with cytokine and chemokine signaling pathways as well as with the regulation of mitogen‐activated protein kinase (MAPK) cascade, which is an interesting finding given the frequently reported association between MAPK cascade and AD.ConclusionThe initial assessment of the data revealed encouraging preliminary findings. However, more detailed analyses will be performed in both CSF and plasma to further investigate potential biomarkers and how they coverage between amyloid and tau deposition.