bluuebunny/crossref_metadata_2025_split huggingface dataset:
Donepezil‐indolyl hybrids as multipotent cholinesterase/monoamine oxidase inhibitors for the potential treatment of Alzheimer’s disease
Authors: Krastev Kaloyan Yuliyanov 
Published: December 2023

AbstractBackgroundNumerous laboratory and clinical studies have evidenced that MAO‐B inhibitors are a potential therapeutic approach for the treatment of AD. Thus, drugs used to inhibit activated MAO, including rasagiline, ladostigil and selegiline, may provide neuroprotection against AD by improving cognitive impairment, modulating the proteolytic cleavage of APP and decreasing levels of Aβ protein fragments that accumulate in the brain. Future clinical studies on MAO inhibitors for the treatment of AD may provide further insights into the mechanism of action of antioxidants as therapeutic agents for AD.MethodSeries of donepezil‐indolyl hybrids were prepared and characterized via highresolution mass spectrometry, 1H nuclear magnetic resonance and 13C nuclear magnetic resonance techniques. In vitro fluorometric assay (by Amplex® UltraRed reagent to detect hydrogen peroxide or peroxidase activity in biological samples or enzymes.) was used to investigate the activity of the synthesized compounds on both MAO‐A and MAO‐B isozymes as well as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) by Ellman method with modifications.ResultThe biological evaluation of molecules 1‐30 showed that most of these compounds are potent, in the nanomolar range, and selective AChEI, with moderate and equipotent selectivity for MAO‐A and MAO‐B inhibition. In overall, compound 11, as a potent and selective dual AChEI, showing a moderate MAO inhibitory profile, can be considered as an attractive multipotent drug for further development on two key pharmacological targets playing key roles in the therapy of Alzheimer’s disease.ConclusionThe pharmacological profile of compound 11, as well as the fact that it is a readily available compound in a short synthetic sequence, in good chemical yields, prompts us to select it as a lead‐compound for further optimization in our current research programme targeted to the preparation of new molecules for the potential treatment of AD.
The role of Ataxin‐2 in Drosophila models of C9orf72‐related FTD expressing dipeptide‐repeats of a physiologically relevant length
Authors: Harper Nikki S. , Prokop Andreas , West Ryan J. H. 
Published: December 2023

AbstractBackgroundFrontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two devastating, incurable, early‐onset neurodegenerative diseases, which share a clinicopathological spectrum of disease; linked by a hexanucleotide (GGGGCC) repeat expansion within the C9orf72 gene. Bidirectional sense and antisense translation of C9orf72 repeat RNA produces five dipeptide repeat proteins (DPRs) which aggregate within neurons, disrupting a range of cellular processes, including stress granule dynamics. It is hypothesised that under conditions of chronic cellular stress, stress granule dysregulation could augment the concentration of aggregation‐prone proteins, such as TDP‐ 43, leading to the formation of pathological inclusions, characteristic of FTD/ALS. Furthermore, inhibition of stress granule assembly through ataxin‐2 knockdown has been shown to be protective in in vivo TDP‐43 models.MethodPreviously, using Drosophila, we have established the first, and currently only, in vivo models expressing DPRs of a pathologically and physiologically relevant repeat length. Combining primary neuronal cultures and in vivo analysis of these models we investigate the effect of DPRs on stress granule dynamics and the integrated stress response (ISR), and establish whether inhibition of stress granule assembly, through ataxin‐2 knockdown, is protective against DPR toxicity.ResultIn select Drosophila DPR models we identify a role for ataxin‐2 in DPR‐dependent toxicity, observe stress granule accumulation, and identify potential therapeutic targets upstream in the ISR pathway, to mitigate DPR toxicity.ConclusionComprehensive characterisation of the mechanism by which DPR toxicity affects the ISR and stress granule dynamics, is essential to establish therapeutic targets, such as ataxin‐2, for C9orf72‐mediated FTD/ALS.
Dynamic change of hierarchical core voxels of functional brain network in aging
Authors: Kim Hyun Joo , Kang Hyejin , Lee Dong Soo 
Published: December 2023

AbstractBackgroundMany methods were developed to assess the functional intervoxel connectivity to better understand the brain function in individuals. In this study, k‐core percolation method was assessed to reveal the dynamic hierarchical structure on resting‐state fMRI (rsfMRI) on voxel‐level and the feasibility of the method was evaluated by applying it in the aging process.MethodTotal 150 individuals were included in this study; 38 young healthy individuals from Seoul National University (SNU), and 32 aged healthy, 22 mild cognitive impairment‐converter (MCI‐C), 26 mild cognitive impairment non‐converter (MCI‐NC), and 32 Alzheimer’s disease (AD) subjects from Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. K‐core percolation method, a voxel‐based approach was applied to reveal the hierarchical structure of voxels in the brain. k
max‐core and coreness k values derived from k‐core percolation characterizing the time‐varying core voxels were visualized on various plots to display the dynamic hierarchical structure more intuitively. Analysis was done in both static, dynamic studies, and in positive, negative correlations. Coreness k value map on brain T1 MRI was generated for further evaluation of the distribution of coreness k values.ResultDynamic hierarchical structure of voxels on various plots revealed time‐varying change of k
max‐core voxels and coreness k values, reflecting the dynamic change of brain function in an individual, which was not fully reflected on static study. Dynamic flow pattern was different in positive and negative correlations, portraying the dynamic brain function in different neuronal networks. Asymmetric, unsynchronized distribution was deteriorated in the aging process on corneas k map and the asymmetry indexes of coreness k values revealed distinctive difference between young and aged healthy groups. The difference was more evident on dynamic study than static study. Also, as the age increased, coreness k values decreased, representing decreased connectivity in aging. However, asymmetry and decrease of coreness k values were not deteriorated by the severity of cognitive impairment.ConclusionInvestigation of dynamic functional connectivity with k‐core percolation on voxel‐level revealed time‐varying change of hierarchical structure of voxels in the aging process. With this method, characteristics of dynamic hierarchical structure of an individual can be discovered and have shown possibility of further clinical application.
A Pilot Study Assessing Central Cholinergic Integrity in Individuals with Down Syndrome Using [18F]‐FEOBV PET and Basal Forebrain Cholinergic Anatomy
Authors: Russell Jason K , Conley Alexander C , Boyd Brian , Schlossberg Rachel , Rosenberg Adam J , Acosta Lealani Mae Y. , Shokouhi Sepideh , Newhouse Paul A 
Published: December 2023

AbstractBackgroundDown Syndrome (DS) individuals express an extra copy of chromosome 21, which contains the gene for APP, producing a higher risk of developing Alzheimer’s Disease (AD). By 40 years old, amyloid plaques and tau neurofibrillary tangles are present in most individuals with DS, with AD progression risk being greater than 90%. In AD, the cholinergic basal forebrain projections degenerate and are known to play a significant role in cognitive deficits. We assess the integrity of the cholinergic system directly in individuals with DS utilizing [18F]‐FEOBV PET imaging.MethodSeven individuals (19‐50 years old) with DS, not exhibiting AD symptoms on neuropsychiatric assessment, completed a FEOBV PET scan (6.5mCi dose) and MRI. Participants over 25 years old were recruited from the TRC‐DS study, where individuals undergo multimodal imaging assessment, including brain amyloid and tau PET imaging. A Brodmann area (BA) atlas from MRIcron and Freesurfer cortical and subcortical parcellations were registered to participants’ MRI scans and transformed to native PET space. Regional FEOBV uptake was normalized to supraventricular white matter generating standard uptake value ratios (SUVRs). Initial analysis assessed uncorrected associations between FEOBV SUVR, cholinergic basal forebrain volumes, Ch1‐3 (medial septum, vertical and horizontal limbs of the diagonal band of Broca and Ch4 (basal nucleus of Meynert), and age.ResultIndividuals with DS displayed region‐specific uptake comparable to FEOBV data in normal non‐DS individuals published by other groups. FEOBV SUVRs in the posterior cingulate cortex positively correlated with left and right Ch1‐3 and right Ch4 volumes (r>0.79, p<0.05), with a trend observed with left Ch4 volumes (r = 0.73, p = 0.064), while FEOBV SUVR in the posterior cingulate cortex displayed a trend towards a negative association with age (r = ‐0.73, p = 0.063). Additionally, trends to positive correlations were observed between basal forebrain cholinergic nuclei volume and BA5, 24, and 44. (r>0.67 and p<0.1).ConclusionGiven comparable results to previously published data in normal non‐DS individuals, FEOBV PET imaging appears a valid modality for assessing cholinergic integrity in individuals with DS. Initial analysis suggests associations between specific cortical regions, cholinergic basal forebrain volumes, and age. Ongoing assessments will investigate associations between FEOBV uptake, cognition, and amyloid deposition.
Identification of new electrophysiological biomarkers of Alzheimer’s disease with fast periodic visual stimulation and electroencephalography
Authors: David Justine , Quenon Lisa , Hanseeuw Bernard J , Ivanoiu Adrian , Oziat Julie , Koessler Laurent , Rossion Bruno 
Published: December 2023

AbstractBackgroundDespite Alzheimer’s disease (AD)’s prevalence in the population, its current biological and neuropsychological markers have many inconveniences (e.g., variability, invasiveness, cost …). The identification of new biomarkers is therefore essential to monitor and predict patients’ cognitive reserve and its evolution.MethodsFor this purpose, electroencephalographic recording (EEG) and fast periodic visual stimulation (FPVS) were coupled to obtain objective, sensitive, reliable, and easy‐to‐use evoked cognitive electrophysiological biomarkers (Rossion et al., 2020). FPVS consists in the presentation of visual stimuli at a defined frequency that produces EEG responses at the exact same stimulated frequency. 15 diagnosed AD patients (CSF‐positive for AD biomarkers) and 14 healthy controls matched in sex and age (Fig.1) were tested with a recently validated FPVS paradigm (Volfart et al., 2021) consisting in the presentation of different written words belonging to the same semantic category (cities) at a frequency of 4 words per second (base frequency: 4Hz). Words from a different semantic category (animal) appeared every 4 stimuli (i.e, oddball frequency: 1Hz). EEG responses at 1Hz reflect subject’s implicit semantic categorization ability. EEG signals were analysed in the frequency domain to compare the response amplitudes between the two groups.ResultsWhile healthy controls had a clear significant 1Hz EEG amplitude response over the left occipito‐temporal cortex (0.22 ± 0.26 µV, Z = 7.3, p<.001), this response wasn’t significant for AD patients (0.04 ± 0.11 µV, Z = 0.6, p>.05) (CTR vs. AD: F(1,17.3) = 4.88, p = .04) (Fig.2). There was also a significant difference between the two groups for the EEG response at the base frequency (AD: 1.13 ± 0.73 µV; CTR: 1.86 ± 0.92 µV; F(1,25.2) = 5.34, p = .03), reflecting impairment at more general visual word processing, independently of the semantic categorization. Patient’s base frequency response amplitude was significantly correlated with the score obtained at verbal fluency neuropsychological test (r = 0.73, p <.01). AD patients can be discriminated from healthy elderly participants with better accuracy using base frequency amplitude response (AUC = 0.74, p<.05) than oddball frequency amplitude response (AUC = 0.72, p = .05) (Fig.3).ConclusionThese preliminary observations suggest that combined FPVS‐EEG of written words offers promising cognitive EEG biomarkers for AD patients.
Living with a person with young onset dementia ‐ spousal experience
Authors: Håkansson Tania , Karlsson Staffan , Svensson Hilda 
Published: December 2023

AbstractBackgroundBeing of working age, and simultaneously needing to help a person with young onset dementia has specific consequences for spouses. Research to date has been sparse concerning this specific group of spouses.MethodNine spouses were included and interviewed in the study. The interviews were analyzed using content analysis.ResultThe results showed that the spouses experienced an emotional impact that varied from feelings of loneliness, frustration, and worry, to peace of mind. They expressed that they used coping strategies, which included adopting a positive mindset, adapting to inabilities, adopting an avoidant approach, and finding ways to recharge. Spouses also experienced a call for support from informal as well as formal support.ConclusionThe spouse of a person with young onset dementia goes through a range of emotional experiences and has resourceful ways of handling everyday life. The degree of support is varied which leaves more to be desired from healthcare providers.
Omega‐3 fatty acid derivatives associated with reduced risk of cognitive impairment in older adults
Authors: Nelson Kendra L , Mass Baba , Bateman Trey , Craft Suzanne , Voruganti Saroja 
Published: December 2023

AbstractBackgroundCognitive decline etiology is not fully understood, and many pathways undoubtedly play a role. Oxidative stress, inflammation, and other factors likely modify one’s risk. To understand metabolic underpinnings of cognitive impairment, untargeted metabolomics were performed, and the data analyzed.MethodUntargeted metabolomics were conducted, using UPLC‐mass spectrometry, in 167 fasted plasma samples obtained from the Wake Forest Alzheimer’s Disease Research Center. Subjects without diagnosis of mild cognitive impairment or any form of dementia per the National Alzheimer’s Coordinating Center’s criteria were deemed cognitively normal (n = 102), and comparisons were made between these subjects and subjects diagnosed with cognitive impairment (n = 65). For each of the 1,627 biochemicals assessed, Mann‐Whitney U tests were performed to determine if differences existed between cognition groups. Further investigation was performed via multinomial regression stratified by APOE genotype and by BMI category (<18.5, 18.5‐24.9, 25‐29.9, 30+ kg/m2), adjusted for sex, age, race, and educational attainment.ResultMann‐Whitney U testing identified 101 metabolites significantly different among those with cognitive impairment versus those without. Adjusted, stratified regression abrogated most associations, though several metabolites continued to show notable differences between groups. Elevation of eicosenedioate was associated with increased odds of cognitive impairment for both normal weight (OR 1.62, 95% CI [0.93,2.82], p = 0.08) and overweight/obesity groups (OR 1.79, CI [0.88,10.51], p = 0.07), nearing statistical significance. In those with overweight or obesity, elevation of three omega‐3‐derived fatty acids were significantly associated with decreased odds of being cognitively impaired (OR 0.08‐0.13, CI[0.006,0.99), p = 0.009‐0.049). Five omega‐3 derived fatty acids were also significantly associated with decreased risk of cognitive impairment among those APOE genotype E3/E3 (OR 0.09‐0.21, CI [0.01,0.82], p = 0.01‐0.02). Several additional metabolites of interest, including alpha‐tocopherol (OR 0.06, CI [0.06,1.45]), ergothioneine (OR 0.27, CI [0.06,1.18]), and carotene diols (OR 0.08, CI [0.006,1.24]) approached significance in association with reduced cognitive impairment risk.ConclusionIn untargeted metabolomics, metabolites across a range of pathways were found to be associated with cognitive impairment. Upon adjustment for key, many omega‐3 fatty acid‐ derived metabolites continued to be associated with reduced risk of cognitive impairment.
Modulation of hippocampal protein expression by a brain penetrant biologic TNF‐α inhibitor in the 3xTg Alzheimer’s disease mice
Authors: Jagadeesan Nataraj , Roules Grace Anne Chuli , Chandrashekar Devaraj V , Yang Joshua , Kolluru Sanjana , Sumbria Rachita K 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is a chronic neuroinflammatory condition and the proinflammatory cytokine, tumor necrosis factor alpha (TNF‐α), is a key mediator of neuroinflammation in AD. Biologic TNF‐α inhibitors (bTNFIs) can block cerebral TNF‐α if these large molecules cross the blood‐brain barrier (BBB). Thus, a model bTNFI, the extracellular domain of type II TNF‐α receptor (TNFR) which can bind to and sequester TNF‐α, has been reengineered to enable brain delivery by fusion with a mouse transferrin receptor antibody (TfRMAb). TfRMAb binds to the BBB TfR to deliver the TNFR into the brain via receptor‐mediated transcytosis. Previously, we found the TfRMAb‐TNFR to be protective in a mouse model of amyloidosis (APP/PS1) and tauopathy (PS19), and the aim of the current study was to investigate its effects in a mouse model that combines both amyloidosis and tauopathy (3xTg‐AD mice).MethodEight‐month‐old female triple transgenic 3xTg‐AD mice were injected intraperitoneally with saline (n = 11) or TfRMAb‐TNFR (3 mg/kg; n = 11) three days per week for 12 weeks. At the end of treatment, brains were processed for hippocampal immunohistochemistry and high‐resolution multiplex NanoString spatial proteomics using the GeoMx protein assays for neuroscience.ResultTfRMAb‐TNFR treatment significantly reduced mature β‐sheet rich Aβ plaques and increased plaque‐associated microglial localization around larger plaques in the 3xTg mice. Further, TfRMAb‐TNFR increased plaque‐associated microglial TREM2 compared with saline‐treated 3xTg mice. From a total of 64 target proteins studied using spatial proteomics (comparing protein expression in the Aβ‐plaque bearing vs. plaque‐free regions), 39 (61%) differentially expressed proteins (DEP) were identified in the 11‐month‐old 3xTg mice, comprising of proteins related to neurodegeneration (10% of DEP), neuroinflammation (41% of DEP), amyloid (21% of DEP) and tau (10% of DEP) pathology, autophagy (10% of DEP) and other pathways (8% of DEP). TfRMAb‐TNFR treatment modulated proteins involved in Aβ clearance and processing, microglial function, RNA processing, and neurodegeneration. Majority of these proteins were relevant to microglial function (∼ 40%).ConclusionThe study highlights that TfRMAb‐TNFR modulates several proteins involved in AD pathology and progression and largely suggests a microglia‐centric mechanism of action of this treatment in the 3xTg mice.
A 2.5D residual U‐Net for improved amyloid PET harmonization preserving spatial information
Authors: Shah Jay , Sohankar Javad , Luo Ji , Chen Yinghua , Li Shan , Protas Hillary D. , Chen Kewei , Reiman Eric M. , Li Baoxin , Wu Teresa , Su Yi 
Published: December 2023

AbstractBackgroundMultiple amyloid tracers with varying characteristics pose a significant challenge to standardized interpretation and quantification of amyloid PET measurements. We previously demonstrated that a deep learning based 2D residual inception encoder‐decoder network (RIED‐Net) architecture improved harmonization of florbetapir (FBP) and PiB PET. However, 2D networks fail to capture spatial information among image slices and 3D networks with more parameters require larger datasets and powerful computation for training. Here, we investigate the performance of a 2.5D approach to further improve harmonization preserving spatial information.Method92 PiB‐FBP image pairs from Open Access Series of Imaging Studies (OASIS) were processed using established pipelines to extract regional standard uptake value ratios (SUVRs), mean cortical SUVRs (mcSUVRs), and SUVR images. A 2.5D U‐Net model with residual connections was implemented to learn the nonlinear mappings from the image pairs. Input to the network is a stack of 3 adjacent FBP slices along a particular view, providing extra spatial information about volumetric data. The output of network is a stack of corresponding 3 PiB slices. Multi‐slice output avoids averaging/blurry effects common in traditional 2.5D approaches. 10‐fold cross‐validation was implemented on axial, coronal and sagittal views separately to generate synthetic PiB SUVR imaging from FBP data. The average synthetic PiB image from axial, coronal and sagittal views was used for performance evaluation. Correlation was evaluated between the virtual PiB mcSUVR derived from imputed PiB vs. the real PiB mcSUVR and voxel‐wise between the imputed vs. real PiB SUVR images.ResultThe agreement of mcSUVR improved from r = 0.90 between PiB and FBP to r = 0.95 between synthetic and real PiB SUVR images (p<0.0001) in cross‐validation dataset. Additionally, imputed PiB SUVR images were visually more similar to real PiB SUVR images than FBP. Voxel‐wise correlation improved from 0.88 to 0.93 (p<0.0001).ConclusionOur proposed 2.5D Residual U‐Net for synthetic imaging was able to learn voxel‐wise nonlinear associations between FBP and PiB images. The model trained in 2.5D approach with additional spatial information, was able to significantly improve agreements of amyloid burden measurement from two tracers and generate PiB SUVR images that are visually more similar to real PiB SUVR images than FBP.
The role of group motivation in post COVID‐19 cognitive rehabilitation treatment
Authors: Alves Larissa Scoralich , Dutra Letícia Silva , Shigaeff Nadia 
Published: December 2023

AbstractBackgroundCognitive rehabilitation is an effective treatment for remission of cognitive symptoms resulting from various pathologies. In Long Covid, it is known that the occurrence of cognitive symptoms is a result of the action of the virus in the brain, but the effectiveness of this technique for such patients has not yet been described. Furthermore, there is evidence that rehabilitation has its effect enhanced when individuals are engaged in treatment. Thus, the present report aims to describe the experience of a group of patients with cognitive symptoms from Long Covid undergoing cognitive rehabilitation treatment and discuss the effect of their motivation.MethodWe performed a cognitive rehabilitation intervention for individuals with cognitive symptoms after COVID‐19 infection. Six patients were followed up in 20 sessions and motivation and engagement were observed based on attendance at sessions and from patients ́ speeches during the therapeutic process.ResultThe participants had an average of 80% attendance at cognitive rehabilitation sessions. They also reported on the important role that the group played in the treatment, such as understanding that they were not the only individuals who had difficulties, which motivated them to continue the treatment and not give up, despite the fact that it was long (20 sessions). It was also noticed that the encouragement between them, based on the supportive relationships that were formed in the groups, was important to keep them focused on recovery.ConclusionParticipants in a group can identify with each other and realize that their difficulties are also present in others, which can help to face the difficulties of the treatment process and favor additional motivation. Thus, it is recommended that rehabilitation treatment be carried out in groups of patients. Lastly, interpersonal relationships among group members represent support and increased social support networks.