bluuebunny/crossref_metadata_2025_split huggingface dataset:
Polygenic score is associated with accelerated tau pathology accumulation in Alzheimer’s disease
Authors: Rubinski Anna , Frerich Simon , Malik Rainer , Franzmeier Nicolai , Ramirez Alfredo , Dichgans Martin , Ewers Michael ,   Disease Neuroimaging Initiative
Published: December 2022

AbstractBackgroundProgression of fibrillar tau is a key driver of neurodegeneration and cognitive decline in Alzheimer’s disease (AD), however which factors predict the rate of tau accumulation at the patient‐level is unclear. Here we propose to employ a polygenic score (PGS) for the prediction of tau accumulation and cognitive changes in AD, which could be useful for selection of individuals with faster tau progression in clinical trials.MethodsWe included 231 ADNI participants with longitudinal measurements of tau‐PET, amyloid‐PET, cognitive data and genotype data. We computed a PGS based on 85 independent lead SNPs from two recent large GWAS (DOI:10.1101/2020.10.01.20200659; DOI:10.1038/s41588‐021‐00921‐z), excluding all APOE variants. Using linear mixed effect models, we computed the individual rates of change in each of the biomarkers. In linear regression models we tested whether PGS can predict the rate of tau‐PET changes in Braak‐stage ROIs (Figure 1A) and cognitive changes. In order to assess whether amyloid mediates the effect of PGS on tau accumulation we performed sensitivity analyses in subgroups categorized by amyloid status as well as tested the interaction between the PGS and global amyloid‐PET. We further estimated sample size required for detection of hypothetical treatment effect on the rate tau accumulation using power analysis.ResultsHigher PGS was associated with higher accumulation rates of tau‐PET in cortical regions (Braak 3+4:β=0.306, pFDR<0.001; Braak 5+6:β=0.262, pFDR<0.001; Figure 1B). A higher PGS was further associated with faster decline in episodic memory (β=‐0.223, pFDR<0.001; Figure 1C) and global cognition (β=0.280, pFDR<0.001; Figure 1C). The observed effects of PGS on cognitive changes were mediated by higher tau‐PET accumulation (Figure 2). We found a synergistic effect between PGS and elevated amyloid‐PET levels on the rate of tau‐PET accumulation such that the PGS effects on tau‐PET accumulation were stronger particularly at elevated amyloid levels (Figure 3). Selection of individuals with highest PGS yielded a 32‐33% saving in required sample size to detect a treatment effect on tau accumulation.ConclusionHigher polygenic score is associated with faster tau accumulation and may be a useful tool for risk stratification in disease‐modifying treatments on tau.
Using an external control to contextualize efficacy data from patients with prodromal and mild Alzheimer’s disease treated with gantenerumab in SCarlet RoAD and Marguerite RoAD open‐label extension studies
Authors: Delmar Paul , Huang Zhiyue , Neve Anuja , Klein Gregory , Kerchner Geoffrey A. , Fontoura Paulo , Baudler Monika , Doody Rachelle S. 
Published: December 2022

AbstractBackgroundGantenerumab, a human monoclonal antibody targeting aggregated beta‐amyloid (Abeta), is a potential disease‐modifying treatment for early (prodromal‐to‐mild) Alzheimer’s disease (AD). SCarlet RoAD (SR) (NCT01224106) and Marguerite RoAD (MR) (NCT02051608) were two Phase III trials with open‐label extensions (OLEs), during which participants were treated with up to 1,200 mg/month of subcutaneous gantenerumab for up to 5 years. Substantial Abeta removal was confirmed without new or unexpected safety findings. This work aims to evaluate the gantenerumab treatment effect during the SR and MR uncontrolled OLE studies by using an external control group based on the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort.MethodParticipants from the ADNI studies were weighted using the inverse probability of treatment weighting method1 to make their demographics and baseline characteristics more comparable to the patients in the OLE stages of the pooled SR and MR studies. In the weighted sample, the treatment effects of gantenerumab, per change from the OLE Baseline in Clinical Dementia Rating – Sum of Boxes (CDR‐SB), Alzheimer’s Disease Assessment Scale – Cognitive subscale 13 (ADAS‐Cog13), and Mini‐Mental State Exam (MMSE) at Weeks 104 and 156 were investigated by a mixed‐effect model of repeated measure.ResultsApplying inclusion and exclusion criteria from the ongoing GRADUATE gantenerumab trials (NCT03444870, NCT03443973) to the SR and MR OLE cohorts, 164 participants from the SR and MR OLE studies and 1,218 participants from ADNI were selected. After weighting, the demographics and baseline characteristics were comparable between the two populations. A comparison of relative reductions between the pooled participants in SR and MR OLE studies and weighted ADNI participants can be found in Table 1.ConclusionsWhen comparing participants in the SR and MR OLE studies to a matched ADNI control group, a slower progression was observed with gantenerumab treatment. Specifically, gantenerumab showed effects on slowing cognitive decline in the SR and MR OLE studies compared with weighted ADNI participants on the CDR‐SB and ADAS‐Cog13 scales, although with a smaller effect on MMSE. The efficacy and safety of gantenerumab in early AD participants will be assessed in the two ongoing Phase III GRADUATE trials.1. Austin PC & Stuart EA, 2015; Stat Med. 34:28
Multi‐modal Analysis and Modeling of Human Neurodegenerative Disease to Reveal Disease Mechanisms and Biomarkers
Authors: Marsh Samuel E , Murphy Sarah , Kamath Tushar , Gazestani Vahid , Therrien Martine , Dolan Michael John , Jereb Sasa , Reyes Miguel , Gobom Johan , Clish Clary , Hacohen Nir , Zetterberg Henrik , Leinonen Ville , Macosko Evan , Stevens Beth 
Published: December 2022

AbstractBackgroundMicroglia have emerged as key players in the pathogenesis of neurodegenerative conditions such as Alzheimer’s disease (AD), taking on distinct transcriptional and functional states. While the ability to profile complex tissues at single‐cell resolution in postmortem brain tissue provides insight into disease‐associated cellular states within the brain, more is required to understand how these changes modulate disease pathogenesis. Building on foundational transcriptomics, the advances in multi‐modal profiling of genomics and proteomics allows for a greater understanding of neuroimmune dysfunction in neurodegenerative disease.MethodTranscriptomic datasets are often confounded by variability in collection and sequencing methodologies. We have optimized tissue dissociation and cell isolation protocols to avoid many of the pitfalls commonly found in bulk and single‐cell transcriptomic studies. Using these optimized protocols, we have begun assessing paired samples (blood, brain biopsy, and cerebrospinal fluid (CSF), from patients at risk for AD to understand neuroimmune changes in early‐phases of AD. We have also characterized the transcriptional and functional responses of human induced pluripotent stem cell (iPSC) microglia in response to a variety of neurodegenerative brain‐relevant challenges, including amyloid, apoptotic neurons and synaptic debris.ResultUsing scRNA‐seq on fresh mouse and human tissue we have identified a dissociation‐induced signature in microglia that is highly prevalent in current literature, and developed an experimental methodology to prevent this artifact. We have also identified a similar signature in post‐mortem tissue via snRNA‐seq that may be the result of acute‐pre/post‐mortem processes (Marsh et al., 2022). Powerfully, we also have cerebrospinal fluid (CSF) from the same patients, allowing us to correlate proteomic and transcriptomic analyses to determine the connections between disease‐associated transcriptomic cell states and analyte biomarkers. We can then use the iPSC microglia (iMGLs) to understand how altered transcriptomic states and biomarker profiles may alter microglial functions to elucidate mechanisms by which microglia contribute to disease pathogenesis.ConclusionOptimization of experimental and analysis methods along with extensive multi‐modal profiling of the same patients will lead to greater understanding of the neuroimmune landscape of neurodegenerative disease to better enable development of novel predictive biomarkers and therapeutic targets.
sTREM2 affects cytokine expression profiles in THP‐1 cell model.
Authors: Arsenault Ryan , Li Qiao , Zhang Wandong 
Published: December 2022

AbstractBackgroundTREM2 is an innate immune receptor expressed on myeloid cells such as microglia and macrophages and is involved in several crucial cellular response pathways including activation and inflammation. TREM2 is cleaved from cell surface by ADAM10/17 releasing as soluble TREM2 (sTREM2) and is reported to be elevated in CSF of AD patients. The relationship between inflammation and sTREM2 remains largely uncharacterized.MethodTHP‐1 cells were used as a myeloid model. Cells were cultured and treated with different concentrations of human recombinant sTREM2 at 2‐, 4‐, 6‐, and 8‐hour time points. LPS was used as a positive control. RT‐qPCR was used to analyze the expression of several key inflammatory and anti‐inflammatory cytokines. A commercial monoclonal rat anti‐human TREM2 IgG antibody was pre‐incubated with sTREM2 before treatment to assess its ability to mitigate effects of sTREM2 in culture.ResultLPS significantly stimulated the expression of TNF‐α, IL‐1β, and IL‐6 as compared to control at all time points, and IL‐10 to a lesser extent. 0.1µg/mL sTREM2 was capable of stimulating the expression of several key pro‐inflammatory cytokines such as TNF‐α, IL‐1β, and IL‐6 post‐treatment. 0.1µg/mL sTREM2 also stimulated the expression of anti‐inflammatory cytokines IL‐10 and CCL17 post treatment. 1.0µg/mL sTREM2 was also capable of stimulating the expression of these cytokines while seemingly affecting the expression of anti‐inflammatory cytokines more consistently. Pre‐incubation of sTREM2 with monoclonal antibody was sufficient at alleviating the expression of TNF‐α, IL‐10 and CCL‐17 induced by exogenous sTREM2. However, the expression of IL‐1β and IL‐6 were amplified following either treatment with antibody alone or sTREM2+antibody.ConclusionExogenous sTREM2 at a lower concentration (0.1 µg/mL) seems to stimulate expression of several pro‐inflammatory cytokines, while sTREM2 at both a lower (0.1 µg/mL) and a higher concentration (1µg/mL) appear to stimulate the expression of anti‐inflammatory cytokines more consistently in our myeloid cell model. Possibly indicating that different concentrations of sTREM2 may have different effects on cytokine expression profiles in the cell model. Co‐incubation of sTREM2 with a monoclonal anti‐human TREM2 antibody was sufficient to neutralize the effects of sTREM2 on inducing the expression of some cytokines but promoted others.
Deciphering the clinico‐radiological heterogeneity of dysexecutive Alzheimer’s disease using unsupervised machine learning techniques
Authors: Corriveau‐Lecavalier Nick , Barnard Leland R , Lee Jeyeon , Botha Hugo , Graff‐Radford Jonathan , Machulda Mary M. , Knopman David S. , Lowe Val J. , Boeve Bradley F. , Petersen Ronald C. , Jack Clifford R. , Jones David T. 
Published: December 2022

AbstractBackgroundDysexecutive Alzheimer's disease (dAD) is a relatively early‐onset variant of AD primarily degrading core executive functions in the absence of predominant behavioral symptoms. Clinical observations suggest substantial variability in clinical, cognitive and neuroimaging profiles within this syndrome. In this presentation, we will discuss our ongoing work disentangling this heterogeneity using unsupervised machine learning techniques.MethodWe collected clinical, neuropsychological and multimodal imaging (MRI, FDG‐PET, amyloid‐PET, tau‐PET) data on 52 dAD patients assessed in our behavioral neurology clinic at Mayo Clinic Rochester. We first performed a spectral clustering analysis based on FDG‐PET to delineate latent patterns of network degeneration (referred as “eigenbrains”) and assessed the relationships between these eigenbrains and clinical and cognitive symptomatology. We then performed a hierarchical clustering on these eigenbrains to derive data‐driven subtypes of dAD. We compared clinical and cognitive data between subtypes, and then compared the imaging profiles to 52 amyloid‐negative age‐ and sex‐matched controls.ResultSix eigenbrains explained approximatively 48% of the variance in FDG‐PET patterns and primarily reflected heteromodal to primary motor/sensory, left‐right hemispheric asymmetry, and anterior‐to‐posterior gradients of macro‐scale cortical organization (Fig 1). These eigenbrains differentially related to reported age at symptom onset, degree of clinical impairment, and performance on a wide range of cognitive domains (executive functions, episodic memory, and visuospatial). Hierarchical clustering revealed four dAD subtypes (diffuse, biparietal, left‐hemisphere, right‐hemisphere). These subtypes differed in reported age at symptom onset and cognitive profile, where the heteromodal‐diffuse subtype exhibited an overall worse clinical picture and the biparietal had a milder profile compared to other subtypes, which was not explained by disease duration. Additionally, spatial patterns of tau distribution and neurodegeneration overlapped with patterns of FDG‐PET hypometabolism in each subtype, whereas patterns of amyloid deposition were similar across subtypes (Figs 2 & 3).ConclusionAlmost half of the variance in macro‐scale patterns of hypometabolism in this dAD cohort was accounted for by six eigenbrains. These eigenbrains captured the inter‐individual variability in age at symptom onset and cognitive impairment. Four dAD subtypes derived from these eigenbrains revealed meaningful differences in clinical, cognitive, and imaging profiles. Recognizing this heterogeneity has significant clinical implications for diagnosis, prognosis, and symptom monitoring.
A gene expression signature for Alzheimer’s from finger prick blood spotted on a filter paper card
Authors: Seligmann Bruce , Babic Milos , Scully Kathleen , Yeakley Joanne M , Sahagian Gregory 
Published: December 2022

AbstractBackgroundThere is an unmet need for a minimally invasive clinical test using samples collected by medical staff or by self‐collection to screen persons at risk for Alzheimer’s disease (AD) for initial diagnosis as well as for monitoring progression. Addressing this need is even more challenging for underserved and rural populations. Currently, use of whole blood has required venipuncture and RNA extraction. None‐the‐less, AD gene expression signatures using RNA extracted from whole blood have been reported by a number of groups. We have developed a direct, extraction‐free TempO‐Seq® assay of gene expression using blood from a finger prick spotted on filter paper. This novel method is perhaps the simplest and least invasive method of obtaining a blood sample and performing a test that can be used to identify a diagnostic Alzheimer’s signature.MethodThe targeted sequencing of the whole transcriptome via the TempO‐Seq® gene expression assay (Yeakley, PLosOne doi.org/10.1371/journal.pone.0178302) was adapted to utilize blood spotted on filter paper. Samples were obtained under an IRB‐approved protocol from normal volunteers and patients clinically diagnosed with AD or Parkinson’s disease (PD).ResultA protocol that eliminated interference by components of whole blood with enzymes used in molecular biology assays was successfully implemented. This permitted a TempO‐Seq assay to be carried out without extraction of RNA from the filter paper blood spots. Highly expressed genes were attenuated to increase the sensitivity with which AD biomarker genes could be measured. The shelf‐life of blood spotted filter paper stored at room temperature was greater than 6 months. AD, PD, and normal control blood samples were assayed and a proposed gene expression signature for AD was identified.ConclusionUse of a simple gene expression‐based assay of blood from a finger prick spotted on filter paper to diagnose AD is feasible. The spotted blood sample is stable for months at room temperature, permitting self‐collection or assisted collection and mailing of samples for testing.
Menopause age and hormone therapy use moderate PET tau and amyloid association: findings from the Wisconsin Registry for Alzheimer Prevention
Authors: Coughlan Gillian T , Koscik Rebecca Langhough , Betthauser Tobey J , Boyle Rory Thomas , Jonaitis Erin M. , Wenzel Allen , Christian Bradley T , Gleason Carey E. , Klinger Hannah , Properzi Michael J , Schultz Aaron P. , Hanseeuw Bernard J , Rentz Dorene M. , Johnson Keith A. , Sperling Reisa A. , Johnson Sterling C. , Buckley Rachel F. 
Published: December 2022

AbstractBackgroundSex differences in tau deposition are apparent in clinically normal older adults. Abnormal β‐amyloid (Aβ) may strengthen this association between sex and tau. Whether hormone therapy (HT) and menopause influence this higher tau retention in women and whether this is contingent upon levels of Aβ burden is unclear. We examined differences in the cross‐sectional association between Aβ and regional tau deposition as a function of sex, HT‐exposure and age‐at‐menopause.MethodData were collected from 292 cognitively unimpaired individuals from the Wisconsin Registry for Alzheimer’s Disease (mean age 67.43; 193 women [66%]; 106 APOE ε4 carriers [37%]) who underwent dynamic0‐70 [C‐11] Pittsburgh Compound‐B [PiB] and [F‐18]‐MK‐6240 PET. The PiB distribution volume ratios (DVR) index reflects cortical Aβ burden. 90 [46.6%] women reported use of HT (past/current). Seven a priori tau regions previously demonstrating sex differences were selected (entorhinal cortex, amygdala, inferior temporal gyrus, middle and inferior temporooccipital gyri, superior parietal lobule and fusiform gyrus). Linear regressions (covarying current age) examined the sex*PiB‐DVR‐index interaction for each tau‐PET outcome and a preclinical Alzheimer’s cognitive composite (PACC). Similar models were examined in women alone for the same outcomes, investigating HT*PiB‐DVR‐index and age‐at‐menopause*PiB‐DVR‐index interactions (modeled separately).ResultWomen exhibited higher tau‐PET with an increasing PiB‐DVR‐index relative to men (FDR p’s: <0.002 in 5 of 7 tau regions; Fig 1). The HT*PiB‐DVR‐index analyses indicated that women with a higher PiB‐DVR‐index and self‐reported HT use exhibited higher tau in five regions (Fig2). Exploratory analyses suggested the HT*PiB‐DVR‐index interaction was strongest in women over the median current age (63.5years). The age‐at‐menopause* PiB‐DVR‐index interaction was significant in all regions and for the PACC, revealing subtle cognitive deficits in women with earlier age‐at‐menopause.and a higher PiB‐DVR‐index burden (Fig3).ConclusionReplicating previous studies, tau deposition was elevated in women compared with men. Hormone therapy use and earlier age‐at‐menopause influenced the association between Aβ and tau and between Aβ and cognition. Cognitively unimpaired women with elevated Aβ burden may be vulnerable to hormonal changes related to hormone therapy and early menopause and should be prioritized for future anti‐tauopathy clinical trials.
Differences in self and proxy assessments regarding motivation, quality of life and care dependency of people with dementia considering a technology‐based intervention
Authors: Zuschnegg Julia , Schüssler Sandra , Paletta Lucas , Holter Magdalena , Lodron Gerald , Orgel Thomas , Russegger Silvia , Schneeberger Michael , Fellner Maria , Steiner Josef , Pansy‐Resch Sandra , Prodromou Dimitrios , Brunsch Sebastian , Carnevale Lorenzo , Lammer Lara , Roller‐Wirnsberger Regina 
Published: December 2022

AbstractBackgroundSelf‐reported assessments of people with dementia (PwD) are sparsely used in research, which may be due to the progressive impairment of cognitive functioning and higher time expenditures for assessments. Proxy assessments by healthcare professionals or relatives are often used instead. The aim was to investigate whether a technology‐based intervention significantly influences self and proxy assessments of PwD’s quality of life (QoL), motivation, and care dependency.MethodData from the RCT of the project AMIGO were used. 32 community‐dwelling people with mild to moderate dementia and their relatives received either a humanoid social robot combined with a tablet‐based dementia training (IG) or a tablet‐based dementia training only (CG). Self and proxy versions of three standardized measurements (AES, DEMQoL, PAS) assessing motivation, QoL, and care dependency were used and analyzed using descriptive statistics and Wilcoxon signed‐rank tests.ResultCompared with proxy assessments by relatives, PwD rated themselves better in all outcomes, regardless of group allocation or time points. At baseline, the median differences (MD) differed significantly between self and proxy assessments in IG and CG participants regarding PwDs’ motivation (16.0, p<0.001; 9.0, p<0.001) and care dependency (11.0, p = 0.014; 7.0, p = 0.002), while for QoL this was only the case in the CG (11.0, p = 0.035) and not in the IG (5.0, p = 0.139). After intervention, all outcomes in the IG and CG were significantly differently rated by PwD and relatives demonstrated by the MD for motivation (8.0, p<0.001; 12.0, p = 0.0101), QoL (16.0, p = 0.0023; 16.5, p = 0.030) and care dependency (12.0, p = 0.006; 4.5, p = 0.019).ConclusionThere are significant differences of assessments between relatives and PwD, which could be due to a reduced illness insight of PwD, different foci of PwD and relatives on scale domains (e.g., psychosocial, physical), or an influence of relatives' attitudes and burden. However, QoL in the IG was not perceived differently at baseline, but after the intervention. This finding as well as the significant increase of self‐reported QoL, but the non‐significant proxy evaluation in the main study, highlight the PwDs’ ability to assess themselves and the necessity to involve them in research evaluations.