bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of stable, orally bioavailable small molecule positive modulators of HGF/MET signaling for the treatment of cognitive impairment.
Authors: Taylor Robert W , Boatman Doug , Johnston Jewel , Kneip Maya , Church Kevin 
Published: December 2022

AbstractBackgroundPositive modulators of the HGF/MET system likely represent a valuable therapeutic class with the potential to impact a variety of disorders, including neurodegenerative diseases and indications with cognitive impairment. Preclinical and clinical studies have established the therapeutic potential of fosgonimeton (ATH‐1017), a small molecule injectable positive modulator of the HGF/MET system that is currently in clinical trials in patients with Alzheimer’s disease and Parkinson’s disease. At Athira Pharma, Inc., we have worked to expand the platform of HGF/MET positive modulators by identifying small molecules with a range of properties with the potential to meet therapeutic and delivery needs of patients across neurological diseases.MethodBuilding on the MET receptor augmentation activity of fosgonimeton, we designed a screening funnel to evaluate chemical variants with desired physiochemical properties. We synthesized a panel of small molecules intended to promote pharmacokinetic stability and tested each variant for in vitro activity via MET phosphorylation. Active molecules were then tested for in vitro stability, in vivo pharmacokinetics, and in vivo efficacy in a scopolamine‐induced spatial memory test.ResultWe identified a panel of molecules with novel chemistry, biochemical activity in vitro, and favorable physiochemical properties. Among these active molecules, several were selected to move into advanced testing. In pharmacokinetic evaluation, these molecules efficiently distributed to the brain and other target tissues following oral administration. Selected molecules were advanced to in vivo efficacy testing, which resulted in reversal of scopolamine‐induced spatial memory deficits in rats as assessed in the Morris water maze.ConclusionNovel, stabilized small molecule positive modulators of HGF/MET demonstrated procognitive effects following oral delivery. Further development of these compounds may have the potential to provide an array of administration options for patients with neurodegenerative or cognitive disorders.
The Added Value of Global Amyloid Burden in Predicting Cognition in the MEMENTO Cohort
Authors: Ackley Sarah F , Calmasini Camilla , Swinnerton Kaitlin N. , Bouteloup Vincent , Chêne Geneviève , Dufouil Carole , Glymour M. Maria 
Published: December 2022

AbstractBackgroundGlobal amyloid‐PET is associated with cognition and cognitive decline, but most research on this association does not account for past cognitive information. We assessed the prognostic benefit of amyloid‐PET measures for future cognition when prior cognitive assessments are available, evaluating the added value of amyloid measures beyond information on multiple past cognitive assessments.MethodThe French MEMENTO cohort (a cohort of outpatients from French research memory centers in order to improve knowledge on Alzheimer’s disease and related disorders, via DPUK) includes older outpatients with incipient cognitive changes, but no dementia diagnosis at inclusion. Global amyloid burden was assessed using positron emission tomography (amyloid‐PET) for a subset of participants at baseline or during follow up; semiannual cognitive testing was subsequently performed. Our analytic sample included 488 individuals who underwent amyloid‐PET scans and with at least 4 subsequent mini‐mental state examination (MMSE) scores available. We predicted MMSE scores using demographic characteristics (age, sex, marital status, and education) alone or in combination with information on prior cognitive measures. The added value of including amyloid burden as a predictor in these models was evaluated by the percent reduction of the mean‐squared error (MSE). All models were conducted separately for evaluating the added value of dichotomous amyloid positivity status compared to continuous amyloid standardized uptake‐value ratio.ResultAdding amyloid burden to a model adjusting for only demographic characteristics reduced the MSE of predictions by 6.35% (95% CI: [1.50%, 12.63%]) and 12.04% (95% CI: [3.37%, 22.48%]) for binary and continuous amyloid, respectively. If the model included one past MMSE measure, the MSE improvement was only 4.08% (95% CI: [1.12%, 7.93%]) when adding binary amyloid and 7.87% (95% CI: [2.46%, 13.92%]) when adding continuous amyloid.Improvements in model fit were even smaller with the addition of amyloid burden when more than one past cognitive assessment was included. For models incorporating one or more past cognitive assessments, differences in predictions associated with adding information about amyloid amounted to a fraction of one MMSE point on average.ConclusionGlobal amyloid burden did not appreciably improve cognitive predictions when past cognitive assessments were available.
Synchronized sigmoidal mixed‐effects model for dynamics of cognitive decline relative to onset of Alzheimer’s disease in aging adults in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study.
Authors: Kang Kaidi , Dumitrescu Logan , Mukherjee Shubhabrata , Lee Michael L. , Choi Seo‐Eun , Scollard Phoebe , Gibbons Laura E , Trittschuh Emily H , Mez Jesse B. , Saykin Andrew J. , Gifford Katherine A. , Buckley Rachel F. , Crane Paul K. , Hohman Timothy J. , Gao Xiaoting , Di Jianing , Liu Dandan ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2022

AbstractBackgroundModeling the dynamics of Alzheimer’s disease (AD) biomarkers over the entire continuum of AD progression is important, yet challenging due to limited resources to collect longitudinal biomarkers from the aging population with fully observed clinical spectrum of AD. This study proposed and applied a synchronized sigmoidal mixed‐effects model to characterize dynamics of longitudinal memory performance using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). The model leveraged time to AD onset as the time scale and additionally allowed inclusion of participants without AD onset, drastically expanding future applications.MethodADNI participants with observed mild cognitive impairment (MCI) and/or AD onset (n = 312, mean (SD) baseline age 74.9 (6.44) years) were included (Table 1). A memory composite previously built in ADNI was leveraged for all analyses. A synchronized sigmoidal mixed‐effects model was constructed for dynamics of memory performance with parameters for initial memory level, magnitude of decline, and half‐life of decline. For participants with observed MCI but not AD onset, an additional parameter (t0
) quantifying the time from MCI onset to AD was incorporated (Figure 1). We considered random effects for all parameters and allowed t0
to vary by age at MCI onset (nonlinearly), sex, apolipoprotein E (APOE)‐ε4 status and their interactions.ResultThe mean initial harmonized memory score is 0.24 (95% CI: 0.17‐0.32). The mean decline in the harmonized memory score is 1.53 (95% CI: 1.43‐1.64). The mean time when the harmonized memory score declined by half is 0.57 years before AD onset (95% CI: 0.32‐0.82). Female is associated with faster progression from MCI onset to AD (p = 0.002). Age at MCI onset is nonlinearly associated with MCI‐to‐AD progression (p < 0.001) and APOE‐ε4 status interacts with age at MCI onset on MCI‐to‐AD progression (p = 0.002) (Figure 2).ConclusionThe proposed synchronized sigmoidal mixed effect model can be used to characterize dynamics of AD biomarkers relative to AD onset using participants with and without AD onset. A model to estimate duration of MCI‐to‐AD progression can be simultaneously included for synchronization purpose, which identified gender, age at MCI onset and APOE‐ε4 status as factors associated with MCI‐to‐AD progression.
Neuroinflammation and microglial activation as target for therapeutic strategy: in vitro and in vivo models of study
Authors: Callizot Noelle , Henriques Alexandre , Rouviere Laura , Giorla Elodie , Waly Bilal El , Poindron Philippe 
Published: December 2022

AbstractBackgroundAlzheimer's disease (AD) is characterized by the extracellular accumulation of senile plaques composed of beta‐amyloid (Aβ) and the intracellular deposition of neurofibrillary tangles composed of hyperphosphorylated tau (Tp). Aβ oligomers (AβO) induce damage beginning with loss of synapses, followed by neurite network disorganization and neuronal death. Neuroinflammation plays an essential role in the disease. In AD patient brains, reactive microglia are closely colocalized with amyloid plaques, indicating their close link. Aβ‐activated microglia produce neurotoxic cytokines/chemokines which subsequently cause neuronal dysfunction and death.MethodUsing rat primary cultures of cortical neurons and microglial cells, generating a solution of AβO/protofibrils, playing with the concentration and time of exposure, we were able to mimic the early effects (acute neuronal loss) and the neuroinflammatory response.ResultAt the beginning of the exposure, we observed a Aβ phagocytosis, followed by a strong increase of TREM2/OX41 marker associated with cytokines release and CD206 (M2 marker) decrease over the time.In addition, microglial activation was deeply studied in the hippocampus of aged mice infused with the AβO/protofibril preparation. We observed progressive Tp accumulation associated with neurodegeneration and progressive activation of microglial cells (transition from a phagocytosis stage to a pro‐inflammatory stage with over‐expression of IBA1, CD68 immunoreactivity and production of pro‐inflammatory cytokines).ConclusionIn this work, we proposed vitro/vivo models showing differential and consecutive microglial responses to Aβ. These models are useful for targeting microglial in the pre‐disease period (in vitro) and for modulating the microglial response in the brain once the disease process is underway, and hold promise as a disease‐modifying treatment strategy.
Synaptic oligomeric Tau is an early event in tau‐affected brain regions in Alzheimer’s disease.
Authors: Dolcet Sònia Sirisi , Colom‐Cadena Martí , Querol‐Vilaseca Marta , Rose Jamie , Sánchez‐Aced Érika , Andrian Teodora , Pujals Sílvia , Horrocks Mathew , Lleó Alberto , Spires‐Jones Tara L 
Published: December 2022

AbstractBackgroundDeposition of fibrillar forms of tau‐neurofibrillary tangles (NFT) and neuropil threads (NT) follow a progressive pattern across brain regions as reflected by Braak stages. However, oligomeric forms of tau have been proposed to precede the appearance of fibrillar forms. Synapses are the earliest structure linked to Azheimer’s Disease cognitive loss, but whether tau pathology, fibrillar or oligomeric affects early this structure in each region remains unclear. This is mainly explained by the technical limitations to study oligomeric forms of tau and the visualization of synaptic terminals. We aim to investigate the presence of oligomeric tau at synapses of human AD cases and its relation to the presence of fibrillar forms of tau in different brain regions.MethodWe used array tomography microscopy to visualize single synaptic terminals on postmortem human samples from BA20/21 and BA17 brain regions of 10 AD and 10 controls with diverse Braak stages. Pre‐ and post‐synaptic terminals (synaptophysin and PSD95) and oligomeric tau (T22 antibody) were labelled. To compare synaptic tau with total fibrillar tau burden, NFTs and NTs were quantified from immunohistochemical sections (AT8 antibody) of the same cases and areas. We also studied the presence of tau in synapses using Western Blot experiments in synaptoneurosomes enriched fractions from the same cases and areas (Tau5 antibody). Finally, the presence at synapses of oligomeric and fibrillar tau was confirmed with other superresolution techniques such as electron microscopy, STORM and DNA‐PAINT.ResultWe found that 1) Oligomeric tau was found in both pre‐ and postsynaptic terminals, in a higher proportion of presynaptic terminals. 2) Oligomeric tau at synapses was found in areas without abundant fibrillar forms of tau. 3) A higher proportion of oligomeric tau when compared to phosphorylated tau was found at synaptic terminals in early affected cases. 4) Early synaptic oligomeric tau was found also by western blot of synaptoneurosomes, electron microscopy and STORM.ConclusionOur results suggest that synaptic oligomeric tau may be an early event at tau‐affected brain regions, preceding the phosphorylation of tau and the formation of fibrillar forms. Also, the findings may support the transsynaptic spreading of tau at early stages.
The presence of disease‐associated tau leads to adverse effects on the autophagy and endolysosomal pathway in a cell model of tauopathy
Authors: Pollack Saskia J , Dakkak Dina , Guo Tong , Gómez‐Suaga Patricia , Noble Wendy , Hanger Diane P 
Published: December 2022

AbstractBackgroundDysfunctions in the autophagy and endolysosomal pathways have been reported in Alzheimer’s Disease and related tauopathies. The presence of disease‐associated tau itself may play a role in damaging these pathways leading to its altered clearance. Minimal expression of a disease‐associated truncated tau species (Tau35) in mice results in a progressive tauopathy phenotype, including increased tau phosphorylation, cognitive and behavioural abnormalities and impaired protein clearance. In this study, we sought to explore the effects of Tau35 on the autophagy and endolysosomal pathway in cultured cells expressing Tau35 and from Tau35 mice.MethodChinese hamster ovary (CHO) cells stably expressing Tau35 (CHO‐Tau35) or full‐length human 2N4R tau (CHO‐FL) were generated. Primary cortical neurons from Tau35 transgenic and wild‐type mice were isolated and cultured for 14 days in vitro (DIV). Cells were fixed for immunocytochemistry or lysed to isolate protein/RNA for western blotting and RT‐qPCR to detect the effect of Tau35 expression on autophagy and lysosomal‐related proteins and genes.ResultCHO‐Tau35 cells exhibited a marked reduction in several autophagy and lysosomal‐related markers, including LC3‐II, LAMP2 and cathepsin D. CHO‐Tau35 cells also accumulated lipid droplets and showed disruptions in mammalian target of rapamycin complex 1 (mTORC1) activity and autophagic flux. Moreover, Tau35 expression also resulted in alterations in early endocytic markers, including EEA1. Similar reductions in autophagic and endosomal markers were observed in primary cortical neurons cultured from Tau35 mice. Notably, the nuclear translocation of transcription factor EB (TFEB), a key mediator of lysosomal biogenesis, as well as the transcription of several TFEB‐target genes, was significantly reduced in both CHO‐FL and CHO‐Tau35 cells.ConclusionOur findings suggest that disease‐associated truncated tau damages the clearance of cellular proteins and reduces TFEB‐mediated lysosomal biogenesis. Investigating whether autophagy is disrupted due to tau‐induced lysosomal dysfunction may lead to the identification of novel therapeutic targets for dementia.
APOE4 Impairs Microglia Response to Neurodegeneration in Alzheimer’s Disease
Authors: Rosenzweig Neta , Yin Zhuoran , Madore Charlotte , Butovsky Oleg 
Published: December 2022

AbstractBackgroundAPOE4 is the strongest genetic risk factor for late‐onset Alzheimer’s disease (AD). We previously identified that APOE signaling governs the transcriptional regulation from homeostatic to neurodegenerative microglia (MGnD). However, the underlying mechanism for APOE4‐mediated microglial dysregulation and its contribution to increased risk for developing AD, is unknown.MethodHere we aimed to dissect the impact of microglial APOE4 on AD pathology, using CX3CR1‐CREERT2 mice crossed to APOE‐KI(E3 and E4)fl/fl:APP/PS1.ResultWe identified reduced numbers of Clec7a+ MGnD‐microglia per plaque in APP/PS1:APOE4‐KI mice, despite their increased plaque load, compared with APP/PS1:APOE3‐KI mice. Moreover, APOE4‐KI mice challenged with labeled apoptotic neurons, failed to respond to acute neurodegeneration, depicted by reduced numbers of phagocytic MGnD‐microglia at injection site compared with APOE3‐KI mice. Here we show that conditional genetic deletion of APOE4 in microglia resulted in increased numbers of MGnD‐microglia in response to acute neurodegeneration and in APP/PS1 mice. scRNAseq analysis showed increased proportion of MGnD‐microglia in APP/PS1:APOE4 conditional KO mice, associated with reduced plaque pathology and increased astrocytic recruitment towards plaques. Furthermore, we show impaired induction of MGnD signature in AD brains of APOE4 carriers.ConclusionOur findings show that APOE4 is a negative regulator of MGnD‐microglia in AD, and that its genetic deletion restores the induction of MGnD signature associated with reduction in plaque pathology. Taken together, these findings identify a cell‐intrinsic role of APOE4 in the induction of dysfunctional MGnD microglia and their impaired response to neurodegeneration, which may provide new molecular targets to modulate and restore functional microglia in AD.
Potential for Re‐Identifying Brain PET Research Participants using Face Recognition
Authors: Schwarz Christopher G. , Kremers Walter K. , Lowe Val J. , Savvides Marios , Gunter Jeffrey L. , Senjem Matthew L. , Vemuri Prashanthi , Kantarci Kejal , Knopman David S. , Petersen Ronald C. , Jack Clifford R. 
Published: December 2022

AbstractBackgroundStudies of aging and dementia often acquire brain MRI and PET images, then de‐identify and share these widely with other researchers. It is known that research participants can potentially be re‐identified from brain MRI and CT using face recognition, but this has not been tested with PET imaging.MethodWe generated face reconstruction images of 182 volunteers using their existing amyloid (PiB), tau (FTP), and FDG PET scans from clinical GE PET/CT scanners, and we measured how often commercial automatic face recognition (Microsoft Azure) correctly matched these reconstructions with photographs of their faces. We additionally compared these match rates with face reconstructions from CT (from PET/CT) and MRI. When testing face recognition from PET scans, CT was used only during PET reconstruction, not for face recognition. We also validated our updated mri_reface software, originally developed to de‐identify (“de‐face”) faces in MRI, with new support for PET images. We measured face recognition rates before and after applying mri_reface to PET, CT, and MRI. In addition, we measured effects of de‐facing on biomarker measurements (global and regional SUVR) using 244 ADNI Florbetapir (FBP) amyloid PET scans with two automated pipelines: FreeSurfer 6.0 (PETSurfer) and an in‐house SPM12‐based pipeline.ResultRates of successful face recognition with PET ranged from 32‐41% (Table 1) across tracers. These were lower than MRI (98%) and CT (78%) but still concerning for participant privacy. Using mri_reface reduced face recognition to 0‐3.5% for PET, 5% for CT, and 8% for MRI. mri_reface had little effect on global amyloid SUVR measurements from ADNI PET images (Figure 1). ICC values between original and de‐faced images were 1.00 with biases and median absolute differences < 0.5%, across both pipelines. Effects on individual regions all had ICC values > 0.98 with biases and median absolute differences < 2%.ConclusionFace reconstructions from PET images have sufficient quality for potential re‐identification using publicly available face recognition technology. Research studies should consider using face de‐identification (de‐facing) software on PET images in addition to CT and structural MRI. Our free, automatic mri_reface software greatly reduced the potential for face recognition without substantially affecting SUVR measurements.
Dual tasking paradigm in clinical stages of early Alzheimer’s disease
Authors: Sorinas Jennifer , Cormack Francesca K , Taptiklis Nick , Vallejo Vanessa , Snædal Jón , Hannesdottir Kristin , Curcic Jelena 
Published: December 2022

AbstractBackgroundIn Alzheimer’s disease (AD) both motor and cognitive domains are impaired [1‐2]. However, these domains are usually assessed independently and even when performing dual‐task (DT) paradigms, the cognitive‐motor interaction (CMI) is not taken into account, which may lead to misinterpretation of the patient’s global state. To date, there are no precise markers to detect subtle signs of pre‐clinical neurodegeneration or to accurately monitor disease progression.MethodWe have evaluated the motor and cognitive components of a DT paradigm concurrently (Figure 1) with the aim to identify a sensitive marker of early AD. Fifty participants, aged 60 to 80 years, were included in the study and distributed across four cohorts of early AD [3]: 1) amyloid negative, cognitively healthy participants (control group), 2) amyloid positive pre‐symptomatic AD, 3) Mild Cognitive Impairment (MCI) due to AD and 4) mild AD. Two inertial gait measurement units (IMUs) (Physilog, GaitUp S.A.) were attached to each foot and a small wearable microphone (Wireless GO, RØDE) was used to record counting. Both timing [4] and gait features were extracted from raw data. Correct response rate (CRR) and gait speed were used to evaluate the CMI based on Plummer’s classification system [5]. Moreover two‐way ANOVA was carried out to evaluate the effect of cohort and cognitive load conditions on the CMI.ResultOur results show that there is a significant drop in both cognitive and motor performance while performing DT and that this drop is more pronounced with increased disease severity and as we increase the cognitive load of the task (Figure 2). Moreover, CMI shows a cognitive‐priority trade‐off in all cohorts (better/stable counting performance while walking becomes slower). However, when the cognition load is increased, in particular in more severe stages of disease, this shifts towards a mutual interference effect, i.e. where both counting performance declines and walking slows down (Figure 3).ConclusionTo our knowledge, this is the first feasibility study assessing the CMI at preclinical and early clinical stages of AD. Our preliminary results suggest that the DT paradigm is a sensitive method to detect early signs of neurodegeneration and monitor AD progression.