bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efforts toward discovering inhibitors of the SYK SH2–FCER1γ interaction as potential Alzheimer’s disease chemical probes and therapeutics
Authors: Sikdar Arunima , Bashore Frances M. , Katis Vittorio , Bradshaw William , Rygiel Karolina , Du Yuhong , Wang Dongxue , Leisner Tina , Hardy Brian P. , Kireev Dmitri B. , Pearce Kenneth H. , Fu Haian , Frye Stephen V. , Axtman Alison D. 
Published: December 2023

AbstractBackgroundSpleen associated tyrosine kinase (SYK) plays a potential role in several neurodegenerative conditions. To date, a few pharmacological inhibitors have been developed, targeting the ATP‐binding kinase domain, and some of these inhibitors have been reported to show beneficial effects on the pathophysiology of Alzheimer’s (PMC: 9179326).In 2015, the Accelerating Medicines Partnership: Alzheimer’s Disease (AMP‐AD) Knowledge Portal analyzed and identified SYK and the FC gamma receptor (FCεR1γ) as targets for Alzheimer’s Disease (AD), through multidimensional human “omic” (genomic, epigenomic, RNAseq, and proteomic) data (PMID: 26853544). Thus, the interaction between FCER1G p‐ITAM and SYK tandem SH2 domain was selected for further target validation and small molecule hit discovery efforts through the portfolio of novel targets to treat the Alzheimer’s disease via the Target Enablement to Accelerate Therapy Development for Alzheimer’s Disease (TREAT‐AD) program were initiated. As part of the TREAT‐AD effort, we aim to provide experimental validation of a SYK–FCεR1γ interaction inhibitor for AD and begin drug discovery campaigns to identify novel inhibitors of this interaction, with the goal of developing an in vivo chemical probe.MethodUsing purified SYK tandem‐SH2 (tSH2) domain protein, a time‐resolved fluorescence energy transfer (TR‐FRET) based assay platform was developed with a fluoroprobe‐labeled phospho‐ITAM peptide of FCεR1γ. This assay was miniaturized for ultra‐high‐throughput screening (uHTS) of 100K compounds in parallel with a DNA encoded library (DEL) screening approach (Ref: X‐Chem). The hits from these screening methods were evaluated in secondary assays in an attempt to validate the initial hits.ResultWe have previous crystallography data of the SYK tSH2 domains bound to phospho‐ITAM peptides and have established a TR‐FRET based assay to discover and characterize inhibitors of the interaction between the FCεR1γ peptide and SYK tSH2 domains. Several thio‐uric acids hit compounds have been identified from uHTS. Most of them demonstrate potency in the TR‐FRET based assay of <10 µM. Although, orthogonal experimental validation is still under process.ConclusionThrough the TREAT‐AD program, we have explored the SYK–FCεR1γ interaction and demonstrated novel screening strategies, which can be further exploited to generate novel inhibitors of this interaction.
An analysis of psychosocial predictors of cognitive impairment in older people living in social housing ‐ data from longitudinal study: “Porto. Importa‐se”
Authors: Martins Sónia , Alves Hélder , Machado Idalina , Melo Sara , Guedes Joana 
Published: December 2023

AbstractBackgroundCognitive Impairment (CI) is a growing public health problem among the older population, with well‐established risk factors. However, the role of psychosocial predictors still needs to be clarified. This study aimed to analyze whether psychosocial factors may be predictors of CI in older persons.MethodIn the framework of “Porto. Importa‐se” longitudinal project, this study included older persons (≥70y.o. living alone and couples ≥75y.o.), living in social housing in Porto city, Portugal. The research protocol included: Six‐item Cognitive Impairment Test (CI), Barthel and Lawton Index (Basic/Instrumental Activities of Daily Living‐BADLs/IADLs), Geriatric Depression Scale‐15 (depressive symptoms) and Lubben Social Network Scale‐6 (social isolation). Loneliness was assessed with a categorical question: Do you feel lonely?. A logistic regression analysis was conducted to identify predictors of CI. Odds Ratio (OR) and its 95% Confidence Interval (95%CI) were calculated. A p<0.05 was considered statistically significant.ResultOf the 1213 older persons (mean age 81±5.7) included, most were female (74%) and 36% had low education level (<4years). About 11% were severely dependent on IADLs and 27% presented CI. Around 35% of participants were at risk of social isolation, 54% reported loneliness and 48% showed depressive symptoms.The logistic regression model was statistically significant [X2(5,N = 1213) = 148.596,p<.001], explaining 19.7%(Nagelkerke R2) of variance in CI (correctly classified 77% of cases). The adjusted model had a moderate sensitivity (63%) and specificity (78%). The oldest persons (≥80 years old) were 1.77 as likely to have CI than younger (OR = 1.77, 95%CI[1.3, 2.4]). Those with less education (<4years) were 0.26 times as likely to present CI than reference group (≥4years) (OR = 0.26, 95%CI[0.2, 0.4]) and females 1.5 times more than males (OR = 1.50, 95%CI[1.0, 2.2]). Older persons at risk of social isolation were 1.85 as likely to have CI (OR = 1.85, 95%CI[1.4, 2.5] and those with depressive symptoms were 1.39 likely to present CI (OR = 1.39, 95%CI[1.0, 1.9]).ConclusionOlder age, female gender, low education, depressive symptoms and social isolation were predictors of CI. The existence of potentially modifiable factors (e.g., social isolation, depression), means that CI prevention is possible through the implementation of effective individual and community‐level interventions, aiming to protect older persons from CI.
Safety profile of pimavanserin therapy in elderly patients with neurodegenerative disease‐related neuropsychiatric symptoms: a Phase 3b study
Authors: Alva Gustavo , Cubała Wiesław J. , Berrio Ana , Abler Victor , Coate Bruce , Pathak Sanjeev 
Published: December 2023

AbstractBackgroundPatients with neurodegenerative diseases including Parkinson’s disease often experience neuropsychiatric symptoms, including hallucinations and delusions, apathy, and agitation.1,2 These symptoms can greatly impair daily function and lead to reduced quality of life and significant caregiver burden. These patients are generally elderly and often frail. Treatment options are limited, representing a substantial unmet need. Pimavanserin, a 5‐HT2A receptor inverse agonist/antagonist, is FDA‐approved to treat hallucinations and delusions associated with Parkinson’s disease psychosis.3
MethodThis Phase 3b, multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group study evaluated the safety of pimavanserin (34 mg) versus placebo in frail adults and elderly patients with neuropsychiatric symptoms related to neurodegenerative disease. The primary endpoint was safety and tolerability as measured by treatment‐emergent adverse events. Secondary safety endpoints included change from baseline in motor (Extrapyramidal Symptom Rating Scale‐Abbreviated [ESRS‐A]) and cognitive function (Mini‐Mental State Examination [MMSE]) at Week 8. Suicidality was assessed using the Columbia‐Suicide Severity Rating Scale (C‐SSRS) or Global Clinician Assessment of Suicidality (GCAS). Exploratory efficacy endpoints included Clinical Global Impression‐Severity (CGI‐S) and ‐Improvement (CGI‐I), 5‐level version of EQ‐5D (EQ‐5D‐5L), and Sleep Disorders Inventory (SDI).ResultOverall, incidence of TEAEs were similar between pimavanserin (n = 392) and placebo (n = 392); 29.8% reported ≥1 TEAE (pimavanserin: 30.4%; placebo: 29.3%) and 1.8% reported serious TEAEs (pimavanserin: 2.0%; placebo: 1.5%) (Table 1). TEAEs leading to discontinuation or study termination were reported in 2.6% and 2.3% of patients on pimavanserin and placebo, respectively. The most frequently reported TEAEs included urinary tract infection (pimavanserin: 6.4%; placebo: 4.1%) and headache (pimavanserin: 2.0%; placebo: 3.8%). Mortality due to TEAEs was similar between groups (0.5% each). Pimavanserin did not impact motor‐ or cognition‐related function (ESRS‐A and MMSE, respectively); an improvement was seen in CGI‐I (MMRM LSM [SE]: ‐0.2 [0.07], p = 0.0140] and sleep function (SDI) at Week 8 (MMRM LSM [SE]: ‐0.3 [0.06], p<0.0001] compared to placebo (Figures 1, 2); no differences were observed across other measures.ConclusionPimavanserin was well tolerated in patients with neuropsychiatric symptoms related to neurodegenerative disease, consistent with the known safety profile of pimavanserin, informing its use in Parkinson’s disease psychosis. Pimavanserin was not associated with cognitive decline or motor dysfunction.
Comparison of Human Primary microglia and Human iPSC derived microglia cells as in vitro models for microglia activation
Authors: Bsibsi Malika , Lo Kimberly , Zanella Matteo , Geerts Lieke , Kostense Stefan , De Groot Jeroen , Fisher David F , Vlaming Marijn 
Published: December 2023

AbstractBackgroundMicroglia are resident immune effector cells in the CNS and play an essential role in neuroinflammation, ischemic and neurodegenerative disease. Therefore, microglia cells are considered a potential therapeutic target for neurodegenerative diseases. To fully understand the role of microglia, the preferred strategy would be to study primary human microglia isolated from post‐mortem human brain tissue. Microglia can be isolated from both control and diseased human brain tissue with confirmed neuropathology. However, the obvious limitation on brain collection and yield of isolated cells restricts the ability to perform screening studies. Induced pluripotent stem cells (iPSCs)‐derived microglia, may provide a suitable alternative for screening studies and large‐scale compound validation. Yet, to effectively use iPSC‐derived microglia, one must characterize the extent to which these cells faithfully represent biological processes in primary brain tissue.MethodHere, we compared the gene expression and cytokine release from primary human microglia cells obtained from tissue provided by the Netherlands Brain Bank and iPSC‐derived microglia.ResultExposure of primary and iPSC‐derived microglia to LPS resulted in increased TNF‐α secretion in a concentration and time dependent manner. LPS‐mediated TNF‐α secretion was strongly inhibited by dexamethasone. Priming of primary and iPSC‐derived microglia with LPS and treatment with nigericin, a potent inflammasome activator, resulted in robust secretion of IL‐1β and IL‐18. Furthermore, nigericin induced IL‐1β and IL‐18 release was blocked by the inflammasome inhibitor MCC950 in both cell types. In addition, similarly to in‐house differentiated microglia, commercially available iPSC‐derived microglia (Bit.bio) showed a strong expression of specific markers as well as cytokine response upon LPS treatment.ConclusionTaken together, we successfully demonstrated that primary and iPSC‐derived microglia respond similarly to LPS and nigericin treatment. For these reasons, these cell types could serve as a reliable tool for evaluating the potency and efficacy of prospective drugs for multiple neurological diseases associated with microglia activation, such as Alzheimer’s and Parkinson’s Disease.
A novel DYRK1a inhibitor, DYR533, reduces tau pathology and TNF alpha in the 3xTg‐AD and PS19 mouse models
Authors: Bartholomew Samantha , Winslow Wendy , Rokey Samantha , Hulme Christopher , Dunckley Travis , Velazquez Ramon 
Published: December 2023

AbstractBackgroundDual specificity tyrosine phosphorylation kinase 1a (DYRK1a) directly phosphorylates tau and amyloid precursor protein and is upregulated in postmortem brain tissue of patients with disorders including Alzheimer’s (AD) and Picks disease (a tauopathy). Our lab has shown that treatment with a DYRK1a inhibitor (DYR219) reduced Aβ plaque deposition and decreased phosphorylated tau at Serine 396 (pTauSer396) in the 3xTg‐AD mouse model. Here, we developed and tested a novel DYRK1a inhibitor (DYR533), which has an increased half‐life and bioavailability, in 3xTg‐AD mice that develop both Aβ and pathological tau, and PS19 mice that develop solely pathological tau.MethodWe dosed eight‐month‐old 3xTg‐AD and four‐month‐old PS19 mice daily with either 1.0‐, 2.5‐, or 5.0‐mg/kg DYR533 or a vehicle dose for two or four months respectively per model. Treatment start age occurred at the onset of neuropathology. Mice underwent rotarod testing to assess motor function and water maze testing to assess spatial learning and memory, with testing starting 2 weeks prior to the end of treatment. Blood and brain tissue were collected for neuropathology assessment. We assessed Aβ 40‐42 in the 3xTg‐AD mice, and pTauSer396 and the pro‐inflammatory cytokine tumor necrosis factor (Tnf)α in the hippocampus of both models. Blood plasma was extracted and analyzed for Tnfα levels.ResultIn both 3xTg‐AD and PS19 mice, DYR533 reduced soluble and insoluble fractions of pTau Ser396 in a dose dependent manner. Notably, DYR533 in 3xTg‐AD mice reduced pTau at threonine 217, which was recently identified as an early marker of AD progression. Soluble cortical Aβ42 levels were significantly reduced in the 1.0 mg/kg and 5.0 mg/kg 3xTg‐AD groups. DYR533 significantly reduced the levels of Tnfα in blood plasma and the hippocampus of both 3xTg‐AD and PS19 mice.ConclusionIn conclusion, the DYRK1a inhibitor, DYR533, reduces pTauSer396, as well as blood plasma and hippocampal levels of Tnf α in both 3xTg‐AD and PS19 models. Ongoing efforts include testing the effects of DYR533 in a rodent model of Down syndrome (Ts65Dn), which harbors three copies of DYRK1a, and completion of 3xTg‐AD and PS19 experiments. Thus far, these results support DYR533 as a potential therapeutic for AD and the tauopathies.
NODDI May Be More Sensitive to Neurodegenerative Changes Than Structural MRI
Authors: Yu Xi , Gebre Robel K , Przybelski Scott A. , Reid Robert I. , Raghavan Sheelakumari , Lesnick Timothy G. , Lowe Val J. , Machulda Mary M. , Knopman David S. , Petersen Ronald C. , Kantarci Kejal , Graff‐Radford Jonathan , Jack Clifford R. , Vemuri Prashanthi 
Published: December 2023

AbstractBackgroundNeurite orientation dispersion and density imaging (NODDI) measures from diffusion MRI provide information about tissue microstructure. Our goal was to compare the sensitivity of NODDI to structural MRI (sMRI) in capturing neurodegenerative changes in the gray matter due to aging and dementia.MethodWe included 815 participants [644 cognitively unimpaired (CU), 103 MCI, 68 AD] from the Mayo Clinic Study of Aging (MCSA) and Mayo ADRC with sMRI and multi‐shell diffusion MRI. We assessed gray matter volumes scaled by head size and cortical thicknesses from sMRI and neurite density index (NDI) and isotropic volume fraction (ISOVF) from NODDI. Pairwise Spearman correlations were calculated between imaging measures and Tau‐PET SUVRs in Braak I‐II, III‐IV, and V‐VI regions of interest (ROI) in participants ≥ 60 years. Separate multivariable linear regression models were fit for the prediction of brain age using sMRI and NODDI in 515 CU participants. The predicted age gaps were calculated as chronological age minus predicted age in the remaining participants. We compared age gaps computed by sMRI and NODDI using disease surrogates (APOE4 genotype, AD pathologies via PET, WMH via FLAIR‐MRI, vascular risk, cognition via MMSE).ResultBraak ROIs, sMRI, and NODDI measures were correlated. The correlations between ISOVF and Tau‐PET SUVRs were stronger than correlations between NDI, volume, and thickness and Tau‐PET SUVR (Fig.1). MMSE was more associated with ISOVF than Tau‐PET and other imaging measures. The sMRI regression models had a higher mean absolute error (MAE) of 4.13 years than NODDI models with an MAE of 4.02 years. The NODDI model better predicted age gap separation between CU, MCI, and AD compared to the sMRI model (Fig.2). The NODDI predicted age gap showed stronger correlations with global amyloid‐PET SUVR, meta‐ROI Tau‐PET SUVR, CMC, APOE4, and MMSE (Fig. 3).ConclusionNODDI, especially ISOVF, had stronger correlations with MMSE and Tau‐PET SUVRs across all Braak ROIs. The brain age prediction model trained using NODDI was more sensitive in detecting neurodegeneration changes than sMRI based on associations with disease surrogates. Our work suggests that NODDI in gray matter may be a more sensitive surrogate of neurodegeneration compared to sMRI.
In vivo TurboID proximity labeling to capture astrocyte proteomic and transcriptomic signatures under homeostatic and neuroinflammatory conditions
Authors: Ramelow Christina C , Sunna Sydney N , Rayaprolu Sruti , Nelson Ruth S , Sampson Maureen , Xiao Hailian , Cheng Lihong , Kumar Prateek , Seyfried Nicholas T , Sloan Steven A , Rangaraju Srikant 
Published: December 2023

AbstractBackgroundDespite decades of research into the cellular and molecular contributions of brain cell types to Alzheimer’s disease (AD) pathogenesis, there are no glial‐specific disease‐modifying therapies. To address this, our group has developed the innovative cell‐specific in vivo biotinylation of proteins (CIBOP) approach to quantify astrocyte‐specific in vivo proteomic and transcriptomic contributions to AD under homeostatic and neuroinflammatory conditions.MethodIn the CIBOP approach, TurboID, a biotin ligase, is selectively expressed in the cell type of interest using a conditional Cre/lox genetic strategy to label the cellular proteome. Using mass spectrometry (MS)‐based proteomics, we have found that TurboID biotinylates many RNA‐binding and ribosomal proteins. Leveraging this, we extended the CIBOP approach to obtain representative cell type‐specific transcriptomes, along with the proteome. We crossed astrocyte specific Cre (Aldh1l1‐Cre‐ert2) and Rosa26TurboID/wt floxed mice for astrocyte‐specific proteomic labeling (astrocyte‐CIBOP). Astrocyte‐CIBOP and control (Cre‐only) mice received tamoxifen, followed by biotin‐containing water and systemic lipopolysaccharide (via intraperitoneal injections) to induce a neuroinflammatory state. Biofluids (CSF and plasma) and cortical tissue were collected. While maintaining RNA‐protein interactions, cortical tissue was lysed, biotinylated proteins were enriched via streptavidin beads, and then RNA was eluted. Immunofluorescent microscopy (IF) and biochemical assays were performed to confirm astrocyte‐specific proteomic biotinylation.ResultWestern blot analysis of the cortex and CSF confirmed biotinylation of the cellular proteome of astrocyte‐CIBOP mice under homeostatic and neuroinflammatory conditions when compared to controls. IF images show that the biotinylation signal is astrocyte specific, proteomic labeling does not impact astrocyte morphology, and high levels of signal was detected at astrocytic end‐feet. RNA gel electrophoresis shows low RNA yield from control mouse brain streptavidin pulldowns, and high levels of RNA from astrocyte‐CIBOP brain pulldowns. MS‐based proteomics of astrocyte‐derived biotinylated proteins and RNA‐sequencing from biotinylated protein‐RNA interactions are underway.ConclusionWe validate the CIBOP approach to capture the cortical Aldh1l1‐positive astrocyte proteome and transcriptome in vivo under homeostatic and neuroinflammatory conditions and demonstrate labeling of astrocyte‐derived CSF proteins. Our novel in vivo cell type‐specific and native‐state dual ‐omics approach provides complementary transcriptomic and proteomic information to investigate disease mechanisms, discover new biomarkers, and identify novel therapeutic targets.
A short‐hybrid scale for detecting anosognosia from the prodromal stage of Alzheimer’s disease
Authors: Andrade Katia , Guieysse Thomas , Houot Marion , Pantazis Dimitrios 
Published: December 2023

AbstractBackgroundWhile not originally developed for this purpose, evidence suggests that the Healthy Aging Brain Care Monitor questionnaire (HABC‐M; Monahan et al, 2012, 2014) may be a valuable instrument for assessing unawareness of cognitive decline (i.e., anosognosia) from preclinical stages of Alzheimer’s disease (AD) (Cacciamani et al, 2017). This is relevant because anosognosia may delay AD diagnosis and therapeutic interventions, with adverse consequences for patients and caregivers. However, several open questions remain: What is the actual effectiveness of this instrument across the AD spectrum? How do the cognitive, functional, and psychological subscales of the HABC‐M differ in their sensitivity to anosognosia in AD? Does the caregiver burden subscale provide additional information about AD patient’s anosognosia? The present study aimed to address these specific questions.MethodsThe HABC‐M was administered to 60 participants (30 AD patients and 30 healthy controls) and their partners (caregivers/informants). A measure of self‐awareness was then estimated by computing the discrepancy scores between the participants and their partners for the different subscales of HABC‐M (with the exception of the caregiver burden subscale, which is a caregiver‐exclusive questionnaire). To evaluate whether these measures can discriminate between patients at different stages of AD and controls, we fit linear models adjusted for age, sex, and education, and computed receiver operating characteristic curves.ResultsAll HABC‐M discrepancy scores, as well as the caregiver burden score, were able to discriminate controls from patients in distinct AD stages. For best performance, the area‐under‐curve for the HABC‐M cognitive subscale discriminated prodromal AD versus controls with a value 0.88 [95% CI: 0.78;0.97]. Adding the caregiver burden score raised it to 0.94 [0.86;0.99].ConclusionThe HABC‐M cognitive subscale (six items) can detect anosognosia from the earliest stages of AD. Separately, the caregiver burden subscale (four items) may corroborate the suspicion of anosognosia. A short‐hybrid scale combining these 10 items, instead of the 31 items of the total HABC‐M questionnaire, could provide a practical and efficient instrument for detection of anosognosia in the clinical setting. Importantly, such an instrument could further contribute to a timely AD diagnosis.