bluuebunny/crossref_metadata_2025_split huggingface dataset:
Optimal combination of CSF phosphorylated‐tau forms to predict Alzheimer’s disease pathological burden as measured by PET
Authors: Collij Lyduine E. , Gobom Johan , Janelidze Shorena , Ossenkoppele Rik , Smith Ruben , Strandberg Olof , Stomrud Erik , Palmqvist Sebastian , Mattsson‐Carlgren Niklas , Zetterberg Henrik , Blennow Kaj , Hansson Oskar 
Published: December 2023

AbstractBackgroundRecently, we demonstrated the sensitivity of a novel CSF mass spectrometer‐based assay, which enabled the assessment of multiple phospho‐tau (pTau) forms (pT181, pS199, pS202, pT205, pT217, pT231, and pS396) and two non‐phosphorylated peptides. Initial results suggested that there may be disease associated differences across pTau species. Here, we aimed to investigate the associations between these CSF pTau forms and Alzheimer’s disease (AD) core pathologies as measured by PET.MethodsWe included 352 participants from the BioFINDER‐2 cohort with available CSF mass‐spectrometry quantification and who underwent [18F]flutemetamol and [18F]RO948 PET to assess amyloid‐β (Aβ) and tau burden, respectively (Table1). Aβ burden was determined globally and in an early accumulating region (precuneus). Tau burden was determined for a temporal meta‐ROI and Braak stages (I‐II, III‐IV, V‐VI). The ratio of tau phosphorylated to non‐phosphorylated peptides was additionally determined for pS199, pS202, pT205, pT217. CSF pTau‐forms (ratio‐)levels were log‐transformed. To assess the contribution of Aβ and tau burden on pTau‐forms (ratio‐)levels, we ran multivariable linear regression models including both Aβ and tau PET measures as independent variables, covarying for age and sex. Next, we determined the parsimonious model (i.e. minimal number of predictors within 2 Akaike points of optimal model) of pTau‐forms (ratio‐)levels using R package MuMIn to predict Aβ and tau PET burden in the different ROIs.ResultsIn the whole cohort, all CSF pTau‐forms peptide concentrations, except for pS396, were associated with both Aβ and tau PET burden, though to different extents (Figure1). pT217 and pT231 were more strongly associated with Aβ, while pS199 and pT205 were more strongly associated with tau. In Aβ‐positive subjects (Figure1C/D), the association with tau increased across pTau‐forms. For the multivariable parsimonious models, pTau217 consistently showed the strongest contribution to predicting amyloid and tau burden across ROIs (Table2&3). pT231 was also selected when early amyloid burden was assessed. pT205 was only selected to predict tau burden in early ROIs when corrected for the non‐phosphorylated peptide (Table3). In addition, sex significantly contributed to predicting tau‐PET burden across ROIs.ConclusionWe provide further evidence that measurement of multiple phosphorylated‐tau species could be used to track AD disease progression.
Seizures exacerbate tau spread in the 5XFAD mouse model
Authors: Barbour Aaron J , Hoag Keegan , Li Xiaofan , Zebrowitz Sydney E , Lee Virginia M. M.‐Y. , Talos Delia M , Jensen Frances E 
Published: December 2023

AbstractBackgroundCentral to the progression of Alzheimer’s disease (AD) is the spread of pathological tau along neuronal connections. This aspect of pathological progression can be recapitulated in WT mice by intracerebral injection of human AD brain derived tau lysate (AD‐tau). AD‐tau spread is enhanced in the amyloidosis mouse model, five times familial AD (5XFAD), suggesting that tau propagation is facilitated by β‐amyloid (Aβ) plaques. Once assumed to simply be a biproduct of Aβ‐induced hyperexcitability, a bidirectional relationship between seizures and AD progression has been established. Our lab has demonstrated worsened tau and Aβ pathology and cognitive deficits in AD patients with seizure history and in seizure‐kindled 5XFAD mice. Thus, we hypothesized that seizures would exacerbate the spread of AD‐tau in the 5XFAD mouse model and that 5XFAD mice would show increased seizure susceptibility and related neuronal activity.MethodTo investigate seizure‐pathology interactions, we crossed the 5XFAD mouse model with targeted recombination in active populations (TRAP; 5X‐TRAP) mice to permanently label seizure‐activated neurons. We injected AD‐tau unilaterally into the hippocampus and overlying cortex (1 µg/site) at 3 months of age in 5X‐TRAP and WT‐TRAP littermates. Seizures were induced with pentylenetetrazol (PTZ) kindling 2‐3 weeks following surgery and seizure‐activated neurons were labeled (tdTomato) on the final day of kindling via 4‐hydroxytamoxifen administration (50 mg/kg). Mice were euthanized three months post AD‐tau injection and immunohistochemistry for phospho‐tau (AT8) was performed.ResultWe found that kindled 5X‐TRAP mice show increased pathological tau (% AT8 coverage) in the dentate gyrus (DG) and CA1 contralateral to injection site compared to non‐kindled mice (p<0.05). We also found a trend towards elevated AT8 in the ipsilateral DG across seizure kindled groups (p = 0.083) and that 5X‐TRAP mice showed increased AT8 in the ipsilateral CA1 compared to WT‐TRAP (p<0.05). Further, we found a trend towards increased seizure susceptibility (0.059) in 5X‐TRAP mice and significantly increased seizure activated neurons (tdTomato+) in the DG of kindled 5X‐TRAP mice compared to WT‐TRAP (p<0.05).ConclusionOverall, our data further indicate a bidirectional relationship between seizures and AD. We also demonstrate that seizures facilitate the spread of pathological tau, thus suggesting that targeting seizure activity may slow AD progression.
A brain‐seeded fibril amplification models the aggregation process of tau in Alzheimer’s disease for drug discovery
Authors: Santambrogio Alessia , Metrick Michael , Löhr Thomas , Horne Robert , Vendruscolo Michele 
Published: December 2023

AbstractBackgroundThe microtubule‐associated protein tau is implicated in the development of a class of diverse neurodegenerative disorders, referred to as tauopathies, with symptoms of dementia and parkinsonism. Tauopathies comprise more than 20 clinicopathological entities, including Alzheimer’s disease, which accounts for 70% of dementia cases worldwide. In combination with clinical diagnosis and neuropathology, the reconstruction of different tau filaments by cryogenic electron microscopy (cryo‐EM) further points to the presence of distinct tau folds. The knowledge of these disease‐specific aggregate conformers provides a platform for the establishment of novel diagnostic methods and more tailored therapeutic approaches.MethodIn order to investigate this problem, this project aims to selectively amplify tau in vitro from human brain homogenates affected by Alzheimer’s disease (AD) and Pick’s diseases (PiD). Kinetic analysis for drug discovery for the specific process of tau aggregation that takes place in Alzheimer’s disease was performed.ResultStrain discrimination was achieved, with a significant acceleration relative to the off‐target control, suggesting formation of two different fibril structures. Cryo‐EM was performed to confirm whether the in vitro AD‐like tau aggregates resembled those extracted from brains.We identify specific tau aggregation inhibitors, through in silico docking to binding sites on the surface of the cryo‐EM structure of tau fibrils adopting an AD fold.ConclusionThe application of this line of research is illustrated by a study of the aggregation kinetics of AD‐like tau fibrils, and of its potential in drug discovery. In perspective, the approach that we present offer novel opportunities for the systematic in vitro study of the tau aggregation process as it may happen in the human brain.References(WHO), W. H. O. et al. (2019). Dementia fact sheet.Alzheimer’s disease facts and figures. Alzheimer’s and Dementia
18, 700‐789 (2022).Chia, S. et al. Structure‐Based Discovery of Small‐Molecule Inhibitors of the Autocatalytic Proliferation of alpha‐Synuclein Aggregates. Mol Pharm (2022).
Safety, Pharmacokinetics and Immunogenicity of Single and Multiple Ascending Doses of the Anti‐Tau Therapeutic Antibody E2814: A Phase 1, First‐In‐Human (FIH) Study in Healthy Subjects
Authors: Rawal Sumit , Yagi Takuya , Boyd Peter , Aluri Jagadeesh , Wildsmith Kristin R , Reyderman Larisa 
Published: December 2023

AbstractBackgroundE2814 is an anti‐tau therapeutic monoclonal antibody (mAb) which is being developed as a potential disease‐modifying therapy for Alzheimer’s disease (AD). E2814 inhibits the propagation of pathological tau species by binding to the microtubule binding region (MTBR). This study evaluated safety, pharmacokinetics (PK), and immunogenicity of single and multiple doses of E2814.MethodsThis randomized, placebo‐controlled study evaluated 5 single ascending doses (SAD) and 4 multiple ascending doses (MAD) in healthy subjects. Subjects (n = 8/cohort) received single or multiple (every 4 weeks) 1‐hour IV infusions of E2814 (or placebo). Safety was evaluated through a review of adverse events (AE), clinical laboratory test results, physical examination, electrocardiogram results, and vital signs. Serial blood and CSF samples for measurement of serum and CSF E2814 concentrations by a validated electrochemiluminescence (ECL) assay were obtained at prespecified time‐points. The serum PK parameters were estimated using non‐compartmental analysis. Anti‐drug antibodies (ADA) in serum were measured by a validated ECL assay.ResultsE2814 has an adequate single and multiple dose safety profile. No treatment‐emergent serious AEs, severe AEs, infusion‐related reactions, or dose limiting events were observed. There was a dose‐related increase in serum and CSF E2814 exposures. The median time to maximum E2814 concentrations in serum was 1.5 to 2 h. The half‐life of E2814 was 23 days which is typical of mAb. In SAD, serum AUC and Cmax were approximately dose proportional at lower doses and greater than dose‐proportional at higher doses. In MAD, accumulation based on Cmax and AUC was ∼1.2 and 1.3‐fold, respectively by the third dose in all dose group. The serum‐to‐CSF concentration ratio ranged between 0.1 to 0.3%. The immunogenicity to E2814 was low. In SAD, 5 subjects had transient low level ADA titers by last study day. In MAD, 1 subject had a confirmatory positive ADA at baseline prior to dose on Day 1. PK in the ADA positive subjects was comparable to that of ADA negative subjects.ConclusionE2814 presented an adequate safety and immunogenicity profile in healthy adults. E2814 PK was comparable to that with other mAbs. These results support further development of E2814 as a potential disease‐modifying therapy for AD.
Identification of Hippocampal and Amygdala Subfields Predictive of MoCA Scores in Patients with Dementia with Lewy Bodies
Authors: Sudhakar Tejaswi D , Levendovszky Swati Rane , Zabetian Cyrus P , Tsuang Debby W , Pillai Jagan A. , Rao Stephen M. , Oguh Odinachi , Lippa Carol , Lopez Oscar L. , Berman Sarah , Irwin David J. , Galasko Douglas R. , Litvan Irene , Marder Karen , Honig Lawrence S. , Fleisher Jori E , Galvin James E , Bozoki Andrea , Taylor Angela , Sabbagh Marwan , Wint Dylan , Cholerton Brenna , Leverenz James B , Olson Valerie 
Published: December 2023

AbstractBackgroundHippocampal and amygdala subfields variably affect cognitive impairment in neurodegenerative diseases. Subfields of these regions can be well segmented using modern neuroimaging tools but their role in neurodegenerative disease is under active investigation. In this study, we identified hippocampal and amygdala subregions predictive of cognitive performance and motor symptoms severity measured by MoCA (Montreal Cognitive Assessment) and MDS‐UPDRS III, respectively, in patients with dementia with Lewy Bodies (DLB).MethodWe selected all participants with probable DLB (N = 48, mean age = 71±7 years, 15% female) enrolled in the Dementia with Lewy Bodies Consortium (DLBC) as of July 2022, with concurrent measures of 3D T1 MRI sequence, MoCA, and MDS‐UPDRS III scores. We performed cortical reconstruction and volumetric segmentation of hippocampal subfields and nuclei of the amygdala using FreeSurfer (v 7.2). We used combat harmonization to account for site and scanner differences. We trained and applied a bootstrapped, bidirectional stepwise regression model of 29 predictor variables comprised of sub‐fields and mean cortical thickness against MoCA and MDS‐UPDRS III, respectively, with an 80‐20 train‐test split ratio, and 5000 repetitions, corrected for age and sex.ResultSubfield segmentation is shown in Figure 1A. The best fitting model for MoCA included mean cortical thickness, parasubiculum, hippocampal and amygdala transition area, corticoamygdaloid transition area, and CA3 body (Figure 1B, adjusted R2 = 0.51). The best fitting model for MDS‐UPDRS III included the cortical nucleus of the amygdala and CA1 body (Figure 1C, adjusted R2 = 0.22). This model was considered a poor fit. We considered MoCA for further analysis and closely predicted scores in our 20% partitioned test sample (Figure 2A, R2 = 0.38).ConclusionWe report model‐based selection of hippocampal and amygdala subfields to predict MoCA scores in DLB. Atrophy in these regions has been associated with global cognitive deficit in mild cognitive impairment and Alzheimer disease cohorts. The model fit for MDS‐UPDRS III scores was poor, providing evidence that these brain regions do not serve a role in motor control.
Lithium protects against ApoE4 mediated calcium dysregulation and mitochondrial dysfunction and cell damage in iPSCs from a sporadic Alzheimer’s disease patient
Authors: Liang Ge , Anchipolovsky Samuel , Zhang Roland , Das Ipsita , Ayala Benjamin , Xu Xandro , Tsai Li‐Huei , Wei Huafeng 
Published: December 2023

AbstractBackgroundWe hypothesized that lithium inhibits critical upper stream Ca2+ dysregulation via inhibition of methyl‐D‐aspartate (NMDARs) and/or InsP3 (InsP3Rs) receptors and downstream mitochondria dysfunction and cell death in a cell model of sporadic Alzheimer’s Disease (SAD).MethodInduced pluripotent stem cells (iPSCs) were derived from the skin fibroblasts of a SAD patient with parental ApoE4/E4, and then gene‐edited to isogenic ApoE3/E3 cells as control. Cells were cultured with mTeSR1 plus medium on Matrigel‐coated plates, differentiated to NPC by Dual‐SMAD inhibition. Mitochondrial function and cell viability of both ApoE4/E4 vs. ApoE3/E3 iPSCs were determined using MTT reduction assay. Cells were pretreated with lithium and then challenged with glutamate for 24 hrs. Calcium concentration in cytosol space ([Ca2+]c) was measured using jellyfish‐specific photo protein aequorin‐based probes or microscopy Fura‐2 dye. Mitochondria oxygen consumption rate (OCR) and ATP production were measured using the Seahorse ® Mito Stress Assay.ResultCompared to ApoE3/E3 cells, ApoE4/E4 cells have significantly decreased cell viability, which could be inhibited by lithium at clinically low concentrations. ApoE4/E4 iPSCs had significantly increased baseline levels of [Ca2+]c and a significantly higher elevation of [Ca2+]c after glutamate treatment than its isogenic ApoE3/E3 iPSCs. Lithium at a clinical concentration (1mM) significantly inhibited the pathological elevation of baseline [Ca2+]c in ApoE4/E4 iPSCs. Lithium‐inhibited mitochondria proton leak as an indicator of cell damage induced by glutamate (15mM) in ApoE4/E4 iPSCs. Glutamate induced mitochondrial and cell damage dose‐dependently. Lithium at a clinically low concentration (0.25mM) significantly inhibited glutamate (15mM)‐induced mitochondria and cell damage in ApoE4/E4 iPSCs. Glutamate treatment for 24 hours significantly inhibited the proliferation of NPCs derived from SAD iPSCs with parental ApoE4/E4 and isogenic E3/E3. Lithium (1mM) significantly inhibited the glutamate‐mediated impairment of ApoE3/E3 NPCs proliferation.ConclusionOur results suggest that ApoE4 plays an important role in critical upstream Ca2+ dysregulation and downstream mitochondrial dysfunction and cell damage, particularly under the stress of glutamate excitotoxicity. Lithium at clinically low concentrations ameliorated critical Ca2+ dysregulation and AD pathologies, warranting further studies to repurpose lithium as future effective drug for AD treatment.
The Intra‐ and Inter‐regional Relationship Between Alzheimer’s Disease Neuropathologic Change (ADNC) and Limbic‐predominant Age‐related TDP‐43 Encephalopathy Neuropathological Change (LATE‐NC)
Authors: Oh Jae Won , Yu Lei , Sperling Reisa A. , Bennett David A. A , Schneider Julie A , Yang Hyun‐Sik 
Published: December 2023

AbstractBackgroundLimbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC) is found in over half of pathologically confirmed Alzheimer’s disease (AD) dementia cases. However, the region‐specific relationship between AD neuropathologic change (ADNC) and LATE‐NC remains unclear. Here, we investigated the intraregional and interregional associations between ADNC and LATE‐NC.MethodsWe analyzed multi‐regional postmortem neuropathology data from the Religious Orders Study and the Rush Memory and Aging Project (ROSMAP). Quantitative ADNC burden was assessed with amyloid‐β (Aβ) and tau immunohistochemistry in 8 brain regions. The Aβ burden was averaged across all regions, given strong inter‐regional correlations. Semi‐quantitative LATE‐NC burden was assessed with TDP‐43 immunohistochemistry in 7 brain regions, scored in 6 grades. Hippocampal sclerosis (HS) was defined as a severe neuronal loss in a mid‐hippocampal coronal section, irrespective of ADNC or LATE‐NC burden. We assessed the association between regional LATE‐NC and global Aβ burden, adjusting for APOE ε4, age at death, and sex. Then, we tested the intra‐ and inter‐regional associations between LATE‐NC and tau, adjusting for Aβ, APOE ε4, age at death, and sex. We performed a post‐hoc subgroup analysis in participants without HS.ResultsWe analyzed the data from n = 1264 deceased ROSMAP participants (Table 1). Global Aβ was positively associated with LATE‐NC in most regions (Fig.1A). Interestingly, even after accounting for Aβ and APOE ε4, tau and LATE‐NC were positively associated within the entorhinal (t = 7.29, p = 5.4×10−13) and midfrontal cortex (t = 4.33, p = 1.6×10−5) but not within the hippocampus (Fig.1B, bold boxes). Tau and LATE‐NC were positively correlated across most interregional pairs (Fig.1B) except for negative associations between hippocampal tau (CA1/subiculum) and frontal LATE‐NC. There was no association between hippocampal tau and frontal LATE‐NC in the HS(‐) subgroup (n = 1143; inferior frontal, p = 0.67; midfrontal, p = 0.15), suggesting that extensive hippocampal neuronal loss in HS(+) cases could have artifactually driven the negative association between hippocampal tau and frontal LATE‐NC.ConclusionsAβ was positively associated with LATE‐NC in most regions. Even after adjusting for Aβ and APOE ε4, tau was positively associated with LATE‐NC across most regions, except for hippocampal tau and frontal LATE‐NC. Further studies are required to determine the underlying mechanisms linking ADNC and LATE‐NC.
NINDS funding opportunities for Alzheimer’s Disease‐Related Dementia therapy development
Authors: Roof Rebecca , Mcgavern Linda , Boshoff Chris , Lavaute Timothy , Cywin Charles , Thomas Shruthi , McCartney Amber J , Corriveau Roderick A 
Published: December 2023

AbstractBackgroundGoal 1 of the National Plan to Address Alzheimer’s Disease (AD) is to prevent and effectively treat AD and AD‐related dementias (ADRD) by 2025. Toward this goal, NINDS plans 14 ADRD funding opportunities for 2024 to support training, basic mechanisms, translational, and clinical research for ADRD. Here, we describe ADRD translational therapy development initiatives, which include 1) multi‐target validation, 2) early‐stage therapy development, 3) genome editing and 4) animal model development and validation. Note, ADRD specific funding opportunities are not required. ADRD researchers can also take advantage of NINDS existing programs such as the NIH Blueprint for Neurotherapeutics (BPN) for Small Molecule or Biologic therapy development. These programs support optimization, manufacture, IND‐enabling studies and first in human clinical trials through a combination of grants and complementary access to NIH‐provided CROs and consultants.MethodAll concepts discussed here are approved, however NIH cannot guarantee future funding opportunities, award mechanisms, or funding allocation. A funding opportunity is only official when published in the NIH Guide.ResultMulti‐Target Validation for ADRD concept has the goal to support research that would validate multiple targets for future therapy development that better reflect the complexity of disease.Early‐Stage Therapy Development concept would support the development of small molecule or biologic therapeutics and would be a reissue of RFA‐NS‐22‐059, which supported assay development, therapeutic screening, optimization, and in vivo efficacy work in preparation for later‐stage programs.Genome Editing for ADRD concept would support early translational research focused on somatic cell gene editing with the expectation that studies will address feasibility of the gene editing approach and would be a reissue of RFA‐NS‐23‐017.PAR‐23‐154 “Development and Validation of Models for Alzheimer’s Disease‐Related Dementias (ADRD)” supports the development and validation of clinically‐ and pathophysiologically‐relevant models of ADRD that can be used for future therapy development. Models should reflect multiple aspects of the human condition and include internal, face, construct, and predictive validation to the extent possible.ConclusionThrough these initiatives, NINDS hopes to provide a comprehensive pipeline for ADRD therapy development from target validation to the clinic.