bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tau pathology vulnerable neuronal subpopulation in Alzheimer’s disease
Authors: Kwon Taekyung , Lin Gen , Chancellor Sarah E. , Wachter Astrid , Abdourahman Aicha , Bennett Rachel E , Liao Fan , Pastika Timothy , Tamm Joseph A. , Venkat Nandini , Yanamandra Kiran , Grinberg Yelena , Kummer Markus P. , Das Sudeshna , Dellovade Tammy L. , Karran Eric H , Talanian Robert V. , Biber Knut , Ried Janina S , Serrano‐Pozo Alberto , Langlois Xavier , Hyman Bradley T. 
Published: December 2022

AbstractBackgroundTau pathology is known as a primary driver of neurodegeneration in Alzheimer’s disease (AD). Understanding its underlying molecular mechanism is critical in expanding our knowledge of AD pathogenesis and developing novel AD therapeutic strategies. However, interrogating tau induced neurotoxicity mechanisms has been difficult due to heterogeneous susceptibility of neurons to tau pathology. Here, we aim to identify the most vulnerable neuronal subpopulation to tau pathology in AD and reveal more clear molecular mechanisms of tau induced neuro‐toxicity/degeneration by analyzing gene expression changes in the vulnerable population.MethodWe performed single nuclei RNA sequencing and tau biochemistry from same tissue blocks of the same AD patients (5 brain regions of 32 AD donors with various Braak stages). About 1.5x106 neurons were enriched in total by NeuN antibody‐based flow cytometry sorting and these cells were clustered into 15 neuronal subpopulations based on their similarity in gene expression. We tested for association between relative neuronal population abundance and tau pathology readouts (phospho‐T231 ELISA, HT7‐HT7 SIMOA and HEK seeding). Based on the strength of correlation, we identified the neuronal subpopulation that reduces relative abundance in association with its tau pathology.ResultWe identified a tau vulnerable neuronal population that showed strong negative correlation between its relative abundance and tau pathology readouts in BA20 and BA46. The population was one of largest excitatory subpopulation distinguished by marker genes, CBLN2 and LINC00507. This outcome was supported by multiple published transcriptomics studies and histologically validated by multiplexed in situ hybridization and immunohistochemistry. Differential gene expression analysis of the vulnerable neuronal population identified a list of genes that potentially links tau pathology and neuronal death.ConclusionThis study with large number of captured neurons for single cell transcriptomics and quantitative tau pathology readout for direct comparison to transcriptomics data enabled the discovery of a vulnerable neuronal subpopulation in more precise manner and revealed genes related to tau associated neurotoxicity more clearly. This result serves as a great starting point to further interrogate fundamental mechanisms of tau‐driven neurodegeneration in AD and accelerate therapeutic target and biomarker discovery.
Impaired retinal capillary function in patients with clinical Alzheimer’s disease
Authors: Jiang Hong , Simms Ava Gaye Yanique , Baumel Bernard , Rundek Tatjana , Wang Jianhua 
Published: December 2022

AbstractBackgroundExtensive evidence indicates that vasculopathy, especially the level of microcirculation, contributes to neurodegeneration in AD. However, it is not easy to direct monitor cerebral microcirculation. The retinal microvasculature has been used as a surrogate to study cerebral vascular changes. Indeed, decreased retinal microvascular network densities were reported in patients with AD. The goal of this project is to determine the retinal capillary function (RCF, the efficiency of blood flow transferring in the capillary network) in patients with Alzheimer’s disease (AD).MethodTwenty patients (age 60‐84, mean ± SD: 72.8 ± 7.7 yrs) with AD and 14 age‐matched cognitive normal controls (CN, age 62‐81, mean ± SD: 68.6 ± 6.7 yrs) were recruited. There were no differences in vascular risk factors including smoking, hypertension, hyperlipidemia, type 2 diabetes, and cardiovascular disease between groups (Chi‐square test, all P > 0.05). One eye of each subject in both groups was imaged. Retinal blood flow (RBF) was measured using a Retinal Function Imager and retinal capillary density (RCD, expressed as fractal dimension Dbox) was measured using optical coherence tomography angiography. RCF was defined as the ratio of RBF to RCD.ResultRCF was 1.62 ± 0.56 nl/s/Dbox (mean ± SD) in the AD group, which was significant lower than that (2.56 ± 0.25 nl/s/Dbox, P = 0.0001) in the CN group. The change of RCF in the AD group represented 28% lower than the CN group. RCF was significantly related to RBF in the AD group (r = 0.98, P < 0.05) and the CN group (r = 0.65, P < 0.05).ConclusionOur study is the first to demonstrate the impaired retinal capillary function in patients with AD. The alteration of RCF was mainly due to decreased retinal blood flow, which the capillary network can transfer. The RCF may be developed as a biomarker to study cerebral microcirculation in patients with AD.
Altered PLD3 exonuclease activity impacts on lysosomal and mitochondrial homeostasis
Authors: Van Acker Zoë P. , Bretou Marine , Sannerud Ragna , Damme Markus , Annaert Wim 
Published: December 2022

AbstractBackgroundPhospholipase D3 (PLD3) is a single‐pass type II membrane protein that is majorly localized to late endosomes/lysosomes (LE/Lys) where it functions as a 5'‐3' exonuclease that degrades ssDNA. Whereas PLD3 has been identified as risk factor for late‐onset Alzheimer’s disease (LOAD), knockout studies have resulted in conflicting data regarding its impact on the amyloid precursor protein metabolism. Moreover, the substrates for PLD3 in LE/Lys remain unexploredMethodCRISPR/Cas9 gene editing was used to generate PLD3 knockout (KO) SH‐SY5Y cells that were subsequently stably rescued with wild‐type PLD3 and coding‐variants (M6R & V232M). All cell lines were evaluated for morphological and functional alterations of the LE/Lys compartment, including lipid profiling and analysis of the nucleotide content of LE/Lys magnetically isolated from the different cell lines. We optimized a PLD3 activity assay and analyzed the LE/Lys nucleotide content as a means to identify PLD3 substrates.ResultWe report that a PLD3 KO and LOAD‐associated risk variants lead to a significant lysosomal pathology, comprising an increase in the size of LE/Lys, more LAMP1 immunoreactivity, a reduced catabolic activity, an increased propensity for leakage and a marked increase in cholesterol content and in storage lipids. At the ultrastructural level, this is accompanied with the appearance of multilamellar bodies, sometimes including mitochondrial remnants. This is suggestive for a defective mitophagy, which we confirm on the light microscopy level using mKeima assays. Furthermore, we provide support for a role of PLD3 in the homeostatic degradation of mtDNA. We argue that when PLD3’s role is compromised, this leads to a build‐up of the lysosomal nucleotide content, impacting on the normal functioning of LE/Lys. We are currently analysing alterations in downstream cellular signaling pathways, including the TLR9 cascade.ConclusionCollectively, our findings subscribe a key role for PLD3 exonuclease activity in lysosomal homeostasis. Its dysfunction, as occurs in LOAD, leads to the co‐occurrence of lysosomal and mitochondrial defects.
The Image and Multimodal Classification for Alzheimer's Disease by Convolutional Neural Network and Combination with Long Short‐Term Memory using Tau‐PET images
Authors: PARK SANG WON , Yeo Na Young , Kim Jung‐Kyeom , Yum Sujin , Jang Jae‐Won 
Published: December 2022

AbstractBackgroundWe performed image and multimodal classification based on Convolutional Neural Network(CNN) and Combination with Long Short‐Term Memory(LSTM) using 2D and 3D Tau‐PET images for cognitively normal(CN), mild cognitive impairment(MCI), and Alzheimer's disease(AD) patients.MethodTotal of 276 subjects(CN=138, MCI=75, AD=63) were investigated in this study for CN‐MCI and CN‐AD classification. All subjects investigated in this study were diagnosed at baseline. Data were obtained from the Alzheimer's disease Neuroimaging Initiative(ADNI). The acquired images were converted voxel and pixel sizes to (1,1,1) and (1,1) by resizing for CNN‐LSTM using 2D axial images and CNN using 3D images. Axial images for 2D CNN‐LSTM deep learning were extracted from 3D images by selecting only axial value in array of 3D voxel. In the case of 2D images, 72 images per patient were used and sequentially arranged to perform deep learning analysis. The multi‐modal deep learning was applied to perform a fusion model using structured data such as clinical information (age, sex, education, MMSE, CDRSB) with images. The clinical information were divided into four groups (Table 1). The transfer learning was conducted for the CN‐MCI classification in 2D and 3D, respectively, using weights obtained from CN‐AD, respectively. All models were validated based on a five‐Stratified‐KFold.ResultThe average classification accuracies for CN‐AD using only images were 91.2 % and 84.6 % in 3D CNN and 2D CNN‐LSTM, respectively. Similarly, the average classification accuracies for CN‐MCI using only images were 82.6 % and 72.2 % in 3D CNN and 2D CNN‐LSTM, respectively. All modeling except 2D CNN‐LSTM for CN‐MCI classification exhibited a synergistic multi‐modal effect (Table 1).ConclusionBoth the CN‐MCI and CN‐AD classification could be performed using tau‐PET images and clinical information. The results indicate that these methods may be applied to facilitate a clinical decision support system for diagnosing dementia.
A novel episodic memory test optimized for smart phone high‐frequency assessments
Authors: Anwyl‐Irvine Alexander L , Kaula Alexander J , Cashdollar Nathan , Taptiklis Nick , Cormack Francesca K 
Published: December 2022

AbstractBackgroundDecline in episodic memory is a strong marker of neurodegenerative diseases, making it an important target for cognitive assessment. We present a new remote, repeatable, and brief assessment of episodic memory and visual short‐term memory (VSTM) for smart phone deployment. We evaluated this task for sensitivity to age and established cognitive measures of memory and attention.MethodThe task consists of a learning phase where participants see a sequence of items, then are asked to replicate the item order and location by dragging and dropping these items on‐screen. A recall phase follows a minimum 12‐hour delay, with replication of the earlier response. Each session takes less than 2 minutes. The first phase supplies metrics of spatial and order precision VSTM, with the second phase characterising long‐term episodic memory.Experiment 1 (n=133) compares the task with CANTAB assessments of visuospatial memory. In Experiment 2 (n=80) the novel task was repeated twice daily for a week, alongside momentary mood ratings, and a more comprehensive battery of CANTAB tasks at baseline.In Experiment 1, multiple regression and dominance analyses explore the independent and shared variance of measures in explaining age. In Experiment 2, clustering and multivariate autoregressive models outline differences in timeseries relationships between mood and memory, and age.ResultExperiment 1 revealed that CANTAB measures and novel spatial and order metrics were correlated with age (r=.20 to r=.37, adjusted P= <.05). Multiple regression showed models with CANTAB Paired Associate Learning (PAL) score, and delayed novel spatial metrics were significantly predictive of age (t= ‐4.08, 3.17, p <.005). The dominance analysis revealed novel immediate precision overlapped with existing measures in predicting Age, while delayed precision had more unique variance (4.6% vs 0.62% unique sample variance explained in Age, accounting for PAL).Experiment 2 characterised variance in individual learning curves over time and differing autoregressive processes associated with age and CANTAB measures.ConclusionWe present a brief novel episodic memory task that can be deployed remotely, with delayed spatial precision significantly predictive of healthy Ageing. Additionally, we show this test’s suitability as a repeated assessment, compatible with high‐frequency study designs in older populations.
nSMase2 inhibition reduces tau propagation in Alzheimer’s Disease mouse models
Authors: Tallon Carolyn , Bell Benjamin J , Malvankar Medhinee , Thomas Ajit G , Yoo Seung Wan , Pal Arindom , Wu Ying , Coleman Kaleem , Joe Tawnjerae R , Sharma Anjali , Eren Erden , Zhu Xiaolei , Kannan Rangaramanujam M , Kapogiannis Dimitrios , Haughey Norman J , Rais Rana , Slusher Barbara S 
Published: December 2022

AbstractBackgroundAlzheimer’s Disease (AD) is the most common form of dementia worldwide and is characterized by progressive neurodegeneration and cognitive decline, putatively driven by the accumulation Amyloid‐b and hyperphosphorylated Tau. Clinical trial successes focusing on reducing Amyloid‐b plaque levels in patient brains have been modest, spurring a renewed focus on tau. Tau spreads throughout the brain along anatomical pathways, correlating strongly with the disease progression severity. Recent evidence has highlighted extracellular vesicles (EVs) in enabling transcellular transmission of pathological tau in the brain in a ‘prion‐like’ manner and identified the inhibition of EV biogenesis via small‐molecule inhibitors of nSMase2 as a potential therapeutic avenue. However, presently available tool compounds are unsuitable for clinical development.MethodTo improve upon current inhibitors, we performed high‐throughput screening followed by extensive chemistry and identified two classes of compounds. The first, PDDC, has excellent potency, oral bioavailability, and brain penetration, as well as in vitro and in vivo EV inhibition. The second, DPTIP, has higher potency, but poor oral pharmacokinetics and modest brain penetration. To circumvent these limitations, we conjugated DPTIP to a brain‐targeting hydroxyl‐dendrimer delivery system (D‐DPTIP) and demonstrated CNS target engagement following oral dosing. We then chronically administered PDDC and D‐DPTIP to PS19 transgenic mice and WT mice seeded with an AAV‐hTau vector unilaterally stereotaxically injected into the CA1 hippocampal region. After chronic dosing, we quantified the levels of phosphorylated tau in the hippocampus in the PS19s and the contralateral dentate gyrus in the AAV‐hTau seeded model. We also characterized isolated neuronally‐derived plasma EVs from these mice.ResultPS19 mice treated with PDDC had significantly reduced hippocampal tau and increased neuronal counts compared with vehicle. Additionally, PDDC treatment reduced the release of neuronally‐derived EVs into circulation with lower tau level trends. Similarly, seeded mice treated with either PDDC or D‐DPTIP had reduced tau staining intensity in the contralateral dentate gyrus. Importantly, neither compound induced significant toxicity in either model.ConclusionObserving significant reductions in tau burden in two separate AD models provides proof of concept for nSMase2 inhibition in slowing tau propagation, highlighting the promise of tested compounds as potential AD therapeutics.
Boswellic acids (K‐Vie™) improves clinical cognitive scores and reduces systemic inflammation in patients with mild to moderate Alzheimer’s disease.
Authors: Karima Saeed , Aghamollaii Vajiheh , Tafakhori Abbas , Baram Somayeh Mahmoodi , Balenci Laurent , Lanctôt Krista L. , Kiss Alexander , Mahdavi Meisam , Rajaei Shima , Shateri Somayeh , Mokhtari Farzad , Fotouhi Akbar , Riazi Ali 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) remains an incurable neurodegenerative disorder. Neuroinflammation has been now recognized as an important player in the pathogenesis of AD. We conducted a clinical trial to measure whether boswellic acids (K‐Vie™, an enriched Boswellia extract) can improve cognitive and neuropsychiatric symptoms while reducing inflammation in patients with AD.MethodWe conducted a placebo‐controlled clinical trial including a total of 85 patients with mild‐to‐moderate (based on MMSE) Alzheimer’s disease randomized to Boswellia (n = 43) and placebo (n = 42) groups. The treatment doses were 400 mg K‐Vie™ capsule, thrice a day (1200 mg/day), versus matching placebo.ResultOf 85 patients, 43 were assigned to Boswellia and 42 to the placebo group. There were 8 dropouts. The median age of study participants was ∼71 (range, 63‐85) for the Boswellia and ∼70 (range, 61‐81) for the placebo group with 54.5% females and 45.5% males. After 6 months of treatment, there was a significant increase of the MMSE scores with a 1.7 (df = 39, 95% CI 1.2 to 2.1) unit in the Boswellia group compared to ‐1.4 (df = 36, 95% CI ‐2.0 to ‐0.9) unit decrease in the placebo group. There was also a significant decrease of the CDR‐SOB scores in the boswellia group with ‐0.8 (df = 39, 95% CI ‐1.1 to ‐0.6) unit difference, whereas the placebo group saw a 0.8 (df = 36, 95% CI 0.4 to 1.2) unit increase from baseline to 6 months. The analysis of neuropsychiatric symptoms (NPI‐Q) revealed a significant ‐3.4 (df = 27, 95% CI ‐6.1 to ‐0.8) unit decrease, whereas the placebo group did not show a significant change (p = 0.08) (df = 23, 95% CI ‐0.4 to 6.9). Patients receiving Boswellia showed a significant decrease as compared to placebo in plasma levels of several key pro‐inflammatory cytokines including IL‐6 (F(1,38) = 71.1, p<0.0001), TNF‐α (F(1,35) = 14.8, p = 0.0005), and IL‐1α (F(1,38) = 33.4, p<0.0001) as well as a significant increase in the plasma level of amyloid‐β42/amyloid‐β40 ratio (F(1,36) = 19.3, p<0.0001). No serious adverse events were observed during the trial.ConclusionThis study suggests that a reduction of systemic inflammatory biomarkers correlates with improvement in brain and cognitive function. Decreasing inflammation may represent a novel avenue to effectively treat AD.
A longitudinal investigation of physical and cognitive activities and the outcome of trajectories of AD neuroimaging biomarkers: The Mayo Clinic Study of Aging
Authors: Krell‐Roesch Janina , Syrjanen Jeremy A. , Bezold Jelena , Barisch‐Fritz Bettina , Trautwein Sandra , Woll Alexander , Stokin Gorazd B. , Vemuri Prashanthi , Eugene Scharf L. , Fields Julie A. , Kremers Walter K. , Lowe Val J. , Jack Clifford R. , Knopman David S. , Petersen Ronald C. , Vassilaki Maria , Geda Yonas E. 
Published: December 2022

AbstractBackgroundPhysical and cognitive activities are associated with decreased risk of mild cognitive impairment and dementia. However, the longitudinal associations between physical and cognitive activities with trajectories of Alzheimer’s disease (AD) neuroimaging biomarkers among older adults free of dementia remain unclear.MethodWe conducted a longitudinal study derived from the population‐based Mayo Clinic Study of Aging, including individuals aged ≥ 50 years who were free of dementia. Participants had information on physical and cognitive activity engagement in midlife (ages 30‐45 for participants aged 50‐69; ages 50‐65 for participants aged ≥ 70) and late‐life (12 months prior to baseline assessment), and AD biomarker assessments. We calculated linear mixed‐effect models to examine the association between baseline physical and cognitive activity composite scores for mid‐ and late‐life, and trajectories for individual yearly change in amyloid deposition (measured by PiB‐PET), tau burden (measured by Tau‐PET), regional glucose hypometabolism (measured by FDG‐PET), cortical thickness (measured by MRI), and white matter hyper intensities (WMH, measured by FLAIR‐MRI). The models were adjusted for age, sex, and APOE ɛ4 carrier status.ResultThe sample included 2755 persons (52% males; 2462 cognitively unimpaired, 293 with MCI). The mean [SD] age was 72.7 [9.8] years; 774 participants were APOE ɛ4 carriers. Although, overall, participants showed an increase in amyloid deposition, tau burden, WMH, and a decrease in glucose metabolism and cortical thickness over time, those with higher late‐life physical activity experienced less pronounced increase in Tau‐PET SUVR over time [estimate for late‐life physical activity with time interaction: ‐0.002; 95% CI ‐0.004, ‐0.000; p = 0.034]. In addition, participants with higher cognitive activities in midlife [est. for midlife cognitive activity with time interaction: 0.001; 95% CI 0.000, 0.003; p = 0.026] and late‐life [est. for late‐life cognitive activity with time interaction 0.002; 95% CI 0.001, 0.003; p = 0.005] had less pronounced decrease in FDG‐PET SUVR over time. There were no further significant interactions.ConclusionPreliminary findings suggest significant associations between 1) late‐life physical activity and less tauopathy, and 2) cognitive activities in mid‐ and late‐life with less synaptic dysfunction over time. Further research is needed to validate study findings.
WVE‐005, a stereopure antisense oligonucleotide for MAPT silencing in tauopathies
Authors: DaleMaguire ElenaAbbie , Guo Lankai , Byrne Michael , Cannon Megan , Taborn Kris , Prakasha Priyanka Shiva , Longo Kenneth , Iwamoto Naoki , Kandasamy Pachamuthu , Shimizu Mamoru , Shum Pochi , Ranade Ashwini , Iyer Raghuvaran , Bowman Keith , Yang Hailin , Yin Yuan Benny , Liu Fangjun , Mohapatra Susovan , Macovei Lilia , Patil Saurabh , Lansita Janice , Hu Xiao Shelley , Smith Karen , Goyal Jaya , Narayanan Padma , Rhodes Ken , Panzara Michael , Vargeese Chandra 
Published: December 2022

Abstract
Background: Tau is a neuronal scaffolding protein which aggregates intracellularly upon hyperphosphorylation to form neurofibrillary tangles (NFT). NFTs are a hallmark of various microtubule associated protein tau (MAPT)‐associated neurodegenerative diseases, including Alzheimer’s disease, frontotemporal dementia, and progressive supranuclear palsy. Currently, there is no approved treatment targeting Tau pathology, nor any other disease‐modifying therapy for these diseases. Wave Life Sciences has developed a stereopure antisense oligonucleotide to reduce MAPT expression in patients with MAPT‐associated neurodegenerative diseases.
Method: Using Wave’s proprietary PRISM platform, we designed and screened stereopure oligonucleotides targeting MAPT in vitro and identified a lead sequence. PN chemistry was applied to the lead sequence in subsequent studies to further improve pharmacological properties. In vitro target engagement was measured in human iCell neurons after treatment with Wave’s oligonucleotide, WVE‐005, or a published reference stereorandom oligonucleotide under gymnotic conditions. For in vivo analysis, transgenic mice received a single dose of 12.5, 25, 50, or 100µg oligonucleotide, and target engagement was measured after 4 weeks. To measure duration, transgenic mice received a single 100µg ICV dose and target engagement was tracked over 6 months. Finally, oligonucleotides were tested in non‐human primates (NHP) in a 12mg single‐dose intrathecal (IT) study. MAPT mRNA levels were quantified by qPCR, and intracellular distribution was evaluated by ViewRNA.
Result: WVE‐005 showed dose‐dependent silencing of MAPT mRNA in iPSC‐derived neurons with an IC50 of 84nM. In a dose‐response study, 12.5µg and 25µg WVE‐005 led to 50% knockdown after 4 weeks in hippocampus and cortex, respectively, in transgenic mice. WVE‐005 led to >77% MAPT mRNA knockdown at 12 weeks post 100µg dosing, with knockdown of approximately 50% persisting 6 months post‐injection. In NHPs, WVE‐005 showed improved distribution and potency compared to non‐PN oligonucleotide with the same sequence. WVE‐005 decreased MAPT expression across NHP brain regions 28 days post‐single dose much greater than the non‐PN oligonucleotide and was detected in neuronal and glial cells.
Conclusion: WVE‐005 potently and durably decreased MAPT mRNA expression in vitro and in multiple animal models, including throughout CNS upon IT administration in NHPs. These data support continued evaluation of WVE‐005 as a potential therapeutic for MAPT‐associated neurodegenerative diseases.