bluuebunny/crossref_metadata_2025_split huggingface dataset:
Re‐evaluating the choice of gamma stimulation frequency for potential treatment of Alzheimer’s disease: Novel invisible spectral flicker evokes gamma responses at various frequencies
Authors: Henney Mark Alexander , Hansen Bianca Laura , Hansen Luna Skytte , Grønberg Manja Gersholm , Thorning‐Schmidt Martin William , Hansen Henrik Enggaard , Nguyen Mai , Petersen Paul Michael , Clemmensen Line Katrine Harder , Carstensen Marcus Schultz , Madsen Kristoffer Hougaard 
Published: December 2023

AbstractBackgroundWith recent advances in the potential usage of visual gamma stimulation at 40 Hz for treatment of Alzheimer’s disease, there is reason to evaluate the use of other low gamma frequencies. The choice of 40 Hz is based on studies that describe “40 Hz” oscillations with considerable frequency variability. Results are also ambiguous on the acute effects of varying the frequency when stimulating with stroboscopic flicker in the low gamma range (30‐50 Hz). As stroboscopic visual stimulation may also affect adherence in clinical trials due to its inherent flickering, invisible spectral flicker (ISF) was proposed as a more comfortable alternative for entraining 40 Hz. This study investigates the ability of ISF to entrain gamma responses at several frequencies in the range of 36‐44 Hz.MethodTwenty healthy young volunteers were included in an electroencephalography (EEG) experiment (DTU Compute IRB Approval: COMP‐IRB‐2021‐01) with an initial eyes‐open baseline recording followed by a stimulation paradigm using ISF at nine different frequencies (36‐44 Hz, 1 Hz interval) in a randomized complete block design with five blocks. The responses were evaluated as the signal‐to‐noise ratio (SNR) averaged over the O1 and O2 electrodes at the stimulation frequency and analysed using mixed‐effect models with frequency as a fixed factor and subject and block as random factors. All two‐way interactions were included as random factors. Evoked responses were compared to baseline and between frequencies post hoc, correcting for multiple comparisons with Tukey’s method.ResultThe EEG power (Figure 1) showed that stimulus SNR values were significantly higher than baseline for all frequencies (P<.05, see Figure 2), but no stimuli resulted in significantly different SNR. There was significant subject effect (P<<.05), and one subject responded 1‐2 orders of magnitude higher than the others. This suggests higher variability between subjects than frequencies alone.ConclusionOur results indicate that ISF can induce steady‐state visually evoked potentials at several frequencies in the low gamma range of 36‐44 Hz. Across the population of participants, we found no preference or trend for any specific gamma stimulation frequency in the tested range.
Tau propagation out of the MTL areas to the isocortex is facilitated by the presence of amyloid.
Authors: Garbarino Sara , Campi Cristina , Pardini Matteo 
Published: December 2023

AbstractBackgroundAmyloid and tau proteins are known pathological signatures of Alzheimer’s disease. Tau in particular spreads in the brains following stereotypical spatiotemporal patterns which seem to be mediated by brain connectivity. Novel imaging techniques allow visualisation of in vivo tau distribution and, in combination with state‐of‐the‐art computational tools, provide new insights into its dynamics.MethodWe propose a network diffusion model to describe tau evolution from longitudinal Positron Emission Tomography data of 872 subjects from the Alzheimer’s Disease Neuroimaging Initiative. The model accounts for time‐ and region‐dependent production, clearance, propagation and saturation terms. Tau dynamics is enforced “trans‐synaptically” over an ideal healthy anatomical connectome. We use Bayesian inference, providing a tool for simulation and prediction of tau deposition and its dynamics parameters along its progression. We fit the model on 2 datasets: “amyloid+” and “amyloid‐“ (identified based on Ab42 levels in the CSF; 338 and 534 subjects respectively).ResultThe estimated tau progression and dynamic parameters show that propagation of tau out of the MTL areas (middle/inferior‐temporal; entorhinal; hippocampal) to the isocortex is facilitated by the presence of amyloid (Figures 1‐3) and progresses along the connectomes. Indeed, amyloid+ subjects show, on average, a progression of tau that (i) accumulates earlier in the entorhinal, hippocampal and MTL areas than amyloid‐ subjects; and (ii) reaches the isocortex within the estimated 25‐years progression window by propagating along the connections between the MTL areas and the isocortex (esp. frontal and parietal).ConclusionThis supports the hypothesis that regional amyloid‐tau interactions in MTL promote onset and acceleration of AD tau spreading.
Expression patterns of astrocyte mRNA under numerous in vitro disease conditions and its applicability in drug development
Authors: Yue Qian Q , Hoi Pui Man Maggie 
Published: December 2023

AbstractBackgroundReactive astrocytes have been observed surrounding amyloid beta (Aβ) plaques in Alzheimer’s disease (AD) patients and animal models. Researchers have pointed out the shortcomings of A1 and A2 classification. Our study aims to discuss the potentials of applying A1 and A2 genes in indicating astrocyte states and explore the relationship between inflammation‐related protein levels and A1 and A2 expression map under the treatment of human Aβ1‐42 oligomer (hAβ1‐42O) and compound TBN.MethodThis study was conducted using murine astrocyte cell line (C8‐D1A). We compared the mRNAs levels (A1 and A2) under numerous in vitro disease conditions, including lipopolysaccharide (LPS) (800ng/ml), LPS‐induced microglial secretion, oxygen‐glucose deprivation (OGD), hAβ1‐42O (2.5μM), low glucose (11mM), high glucose (44mM) treatment. We also compared mRNA levels (cerebellum, cortex, and hippocampi) in high dose STZ (ip.) (150mg/kg, 4 weeks)‐induced C5BL/6 mouse brain, which is usually applied to as AD model. Furthermore, we explored the relationship between the A1, A2 expression map and inflammation‐related protein expression levels in C8‐D1A treated with hAβ1‐42O and TBN.ResultsA1 and A2 genes were altered in different patterns under numerous stimuli. Microglial secretion (LPS), LPS, OGD, hAβ1‐42O mostly induced mRNA upregulation, while abnormal glucose induced hypofunction of most genes. In STZ brain, mRNA expression exhibited district‐dependent differences. hippocampi mRNA were mostly activated compared to cerebellum and cortex, which indicated that Aβ plaque closely relates to astrocyte activation. In vitro, hAβ1‐42O upregulates inflammation related signal proteins. TBN inhibited hAβ1‐42O induced mRNA upregulation (A1, A2, C3, Il6, Tnfα, Tgfβ) and protein secretion (Il6, Tnfα). TBN could also inhibit LPS‐induced inflammation in astrocytes and increase mRNA levels of Aβ degrading enzymes (Ide, Ece‐1) .ConclusionsIt seems that there is not a strict paradigm of A1 and A2 mRNA expression to indicate astrocyte state and mRNA upregulation is not strictly related to detrimental effects. TBN exerted anti‐inflammatory effects may increase Aβ degrading activity. It also ameliorated inflammation induced by hAβ1‐42O, which may indicate the therapeutical potentials of targeting the activation of mRNA (S1pr3, Timp1, Hsbp1, Cxcl10, Osmr, Cp, Ligp1, Fkbp5, S100a10, slc10a6, B3gnt5) to ameliorate hAβ1‐42O‐induced astrocytic inflammation.Cp, Ligp1, Fkbp5, S100a10, slc10a6, B3gnt5).
MRI deep learning demonstrates featured neuropathological deteriorations in the AD brain
Authors: Pan Dan , Zeng An , Song Xiaowei 
Published: December 2023

AbstractBackgroundDeep learning (DL) of non‐invasive brain structural magnetic resonance imaging (sMRI) has shown superb performance in differentiating Alzheimer’s disease (AD) from cognitively healthy participants (HC). Attention is needed to tackle AD pathological progression on sMRI using interpretable DL methods. Here, we studied the feasibility of DL in identifying neurodegenerative progression patterns in AD.MethodData applied to the study were from the multi‐centre Alzheimer’s Disease Neuroimaging Initiative (ADNI) and Open Access Series of Imaging Studies (OASIS) with 2,369 T1‐weighted brain images of 1,005 subjects. An interpretable DL technique named the ensemble 3‐dimensional convolutional neural network (Ensemble 3DCNN) was used to detect the longitudinal trajectory of sMRI changes during AD progression. The model used multiple 3D convolutional neural networks and a meta‐classifier to assess the degree of brain changes through generating an index score, named P‐score. The score was derived as the outcome of training and verifying the Ensemble 3DCNN model for difference in the whole‐brain sMRI between AD and HC. The predictive P‐scores values were used to analyze the sMRI images for mining neurodegenerative brain regions. In addition, dementia stages, and the temporal and spatial connectivity patterns of neurodegeneration progression were also analyzed.ResultBrain regions showing high P‐scores (> 0.73/1.00) included the amygdala, nucleus accumbens, agranular insular cortex, and the hippocampus, matching the isocortex, basal magnocellular complex, and transentorhinal regions identified in Braak staging. The P‐score increased over time in 82% of the degenerative brain regions. The impaired areas were often spatially connected, consistently across multiple time points in the progression of AD. The trajectory of regional brain changes displayed multiple patterns with complex individual variability.ConclusionThe interpretable 3D DL model demonstrated featured deteriorations on the AD sMRI images. The finding confirmed the neuropathological degeneration of AD and captured additional whole‐brain changes, especially, relating to the heterogeneity of AD expression.
Administration of mitochondrial fusion promoter during ischemia and at the onset of reperfusion exert neuroprotective effects in rats with cardiac ischemia/reperfusion injury
Authors: Chunchai Titikorn , Apaijai Nattayaporn , Janjek Sornram , Arunsak Busarin , Chattipakorn Nipon , Chattipakorn Siriporn C 
Published: December 2023

AbstractBackgroundAcute myocardial infarction (AMI) is one of the fetal cardiovascular diseases and a leading cause of death (1, 2). Our previous study demonstrated that pretreatment of mitochondrial fusion promoter (M1) provided neuroprotective effects on the brain following cardiac ischemia/reperfusion (I/R) injury (3). However, the effects of M1 given during ischemia and M1 given at the onset of reperfusion on brain pathologies following cardiac I/R have never been investigated.MethodSixteen male Wistar rats were randomly divided into either a sham‐operation (n = 8) or cardiac I/R (n = 24). In the cardiac I/R group, rats were then randomly divided into 3 subgroups, including the I/R operation with vehicle (0.9% sodium chloride solution for 15 minutes before I/R protocol, intravenous (i.v.) injection), the I/R operation with M1 administration during cardiac ischemia (2 mg/kg, 15 minutes after left anterior descending (LAD) coronary artery ligation, i.v. injection), and the I/R operation with M1 administration at the onset of reperfusion group (2 mg/kg at the beginning of reperfusion, i.v. injection). At the end of experimental protocol, rats were sacrificed and brains were obtained for further molecular investigation.ResultThe results demonstrated that cardiac I/R increased brain inflammation, caused microglial dysmorphology, caused brain mitochondrial dysfunction, increased tau hyperphosphorylation, and increased brain apoptosis (p<0.05, Figure 1). M1 given during ischemia and M1 given at the onset of reperfusion effectively attenuated brain pathologies following cardiac I/R by preserving microglial morphology, improving brain mitochondrial function, decreasing tau hyperphosphorylation, and decreasing brain apoptosis (p<0.05, Figure 1). Interestingly, M1 given during ischemia had better efficacy to suppressing brain inflammation, when compared to M1 given at the onset of reperfusion apoptosis (p<0.05, Figure 1).ConclusionThese findings suggest the administration of mitochondrial fusion promoter effectively decreased brain pathologies following cardiac I/R. The administration of mitochondrial fusion promoter during ischemia had greater suppression on brain inflammation than administration at the onset of reperfusion. The novel findings obtained from the present study provided the therapeutic strategies which can be translated into clinical settings for cardiac I/R injury.
Lower Endogenous Estrogens in APOE4‐Positive Postmenopausal Women Associated with Lower Regional Brain Volumes
Authors: Schroeder Rachel A , Thurston Rebecca C , Wu Minjie , Padilla Lisbeth , Aizenstein Howard J , Derby Carol A. , Maki Pauline M 
Published: December 2023

AbstractBackgroundDuring the menopause transition, levels of estradiol (E2) ecline. Although these changes are likely key determinants of cognition and brain structure during the menopause transition, how they are related to brain volume in women at elevated risk of Alzheimer’s disease (AD) is not known. We predict associations of endogenous E1 and E2 levels to regional brain volumes will depend on APOE4 carrier status, such that the associations between lower levels of E1 and E2 and lower regional brain volumes will be more positive among APOE4 carriers.MethodsParticipants were enrolled in MsBrain, a cohort study of postmenopausal women (n = 191, mean age 59.4 +/‐ 3.4 years, 45 APOE4 carriers, 84.3% white). Serum E1 and E2 were assessed using liquid chromatography‐tandem mass spectrometry. Cortical volume was measured and segmented by FreeSurfer software using individual T1w MPRAGE images. Cross‐sectional associations of interest were analyzed with APOE4 genotype (carrier versus noncarrier; excluding APOE2)ormone levels, and their interaction, as predictors and regional brain volumes (33 regions per hemisphere) as outcome measures using lme4 Package in R. Models controlled for, years of education, and body mass index.ResultsNeither APOE4 carrier status nor hormone levels were associated with brain volumes . However, significant interactions were observed between APOE4 carrier status and E2 levels in relation to volume of the right (p<.05) and left isthmus cingulate (p<.01), right and left middle temporal lobe (p<.05), and the left posterior cingulate (p<.05), such that the positive association between E2 and regional brain volumes was more positive among APOE4 carriers (Figure 1). Further, there was a significant interaction between APOE4 carrier status and E1 levels in relation to volumes of the right and left inferior parietal lobe (p<.05), right (p<.05) and left isthmus cingulate (p<.05), left cuneus (p<.05), left precuneus (p<.05), and left lingual gyrus (p<.05)(Figure 2).ConclusionAlthough some of these findings would be expected by chance, results suggest that lower levels of endogenous estrogens may be a risk factor for regional brain volume loss in female APOE4 carriers compared to non‐carriers.Supported by NIH RF1AG053504 and R01AG053504 (Thurston & Maki)
The electronic Person Specific Outcome Measure (ePSOM) development program in the US: A survey to understand what matters to individuals most about their brain health
Authors: Saunders Stina , Jannati Ali , Gomes‐Osman Joyce Rios , Morrow William Isaiah , Tobyne Sean , Muniz‐Terrera Graciela , Luz Saturnino , Ritchie Craig W. , Pascual‐Leone Alvaro 
Published: December 2023

AbstractBackgroundIt is essential both drug and lifestyle‐based interventions aimed to delay the onset of advanced cognitive decline deliver a meaningful outcome for the patient. In the early stages of Alzheimer’s disease and related dementias (ADRDs), patient‐reported outcome (PRO) measures should be used in parallel with biological investigations of ADRDs to provide a complementary endpoint offering further proof of intervention’s effectiveness from the patients’ point of view. The aim of the electronic Person‐Specific Outcome Measure (ePSOM) programme is to develop a scalable, easily accessible and efficient PRO tool for monitoring personally meaningful outcomes in early ADRD.MethodWe designed and ran an online nation‐wide study to understand what matters to people about their brain health in the US. The ePSOM US survey started in Jan 2023 and collects primarily free‐text responses along with sociodemographic information and self‐reported neurodegenerative disease diagnosis. Respondents are presented with five domains and asked to describe in their own words their brain‐health priorities. Free‐text data will be analysed using Natural Language Processing (NLP) techniques to identify the most common brain‐health priorities by key sociodemographic groups. We will also compare these results with previously published UK results to look for any notable differences between the US and UK respondents’ priorities.ResultThe survey aims to recruit n = 6,000 respondents. Data collection started early 2023 and is planned to be complete by Spring/Summer 2023. The previously published ePSOM UK study (Saunders et al., 2021) with n = 5,808 respondents resulted in over 80,000 free‐text responses and 184 unique priority themes about brain health. We will present the preliminary results of the US study at AAIC and contextualising the results in light of new pharmacological treatments approved for AD.ConclusionThis large‐scale population‐based study will offer an evidence base for what outcomes constitute a meaningful impact of new treatments. Previous work from our group suggests that brain health priorities shift along the preclinical, prodromal and dementia continuum. The ultimate aim of the ePSOM programme is to design an electronic outcomes app which would allow an individual to define the most important outcomes against which we should measure treatment success across a range of severities.
Transitioning from paper‐based to electronic data capture of neuropsychological assessment: A HABS‐HD study
Authors: Large Stephanie E , Conger Christopher , Davidson Sean , Johnson Leigh , O'Bryant Sid E. 
Published: December 2023

AbstractBackgroundThe HABS‐HD study is an epidemiological study of aging in diverse populations and began transitioning from entirely paper‐based charting to electronic data capture (EDC) in 2018. As the study evolved, the team realized that neuropsychological testing, scoring, and quality review consumed many resources and much staff time. This abstract aims to describe how the HABS‐HD study moved from paper‐based capture of neuropsychological data to EDC with a small data team.MethodThe HABS‐HD staff recognized the time commitment for scoring and reviewing scores for the neuropsychological assessment, which created a delay between a participant completing the study and the research diagnosis. Senior research assistants worked with internal developers to create an EDC for the neuropsychological assessment. The data core is small and consists of a director, an assistant director, two developers, two data entry personnel, and a clinician. Specific components were completed on paper to prevent an increase in equipment cost and maintain methodological consistency. These components were reviewed post‐assessment, and a senior research assistant directly entered the scores into the EDC.ResultThe EDC neuropsychological assessment was tested before going live. The team adapted data capture from the older method into the EDC. The new system allows the research director to obtain statistics of individual testers and provide more training as needed. It also permits more senior personnel to review the paper components and enter them directly into the EDC, which improves throughput.ConclusionSmaller data core teams can transition larger projects from paper methods to EDC. The change does not need to be entirely paper or electronic, but investigators should evaluate which methodologies function best for their populations. Finally, communication between the personnel capturing the data, reviewing the quality of the capture, and writing the EDC software is essential.
DNA methylation of candidate imprint control regions associated with Alzheimer’s disease in Non‐Hispanic Blacks and Non‐Hispanic Whites
Authors: Cevik Sebnem Eren , Skaar David A , Jima Dereje , Liu Andy , Whitson Heather , Jirtle Randy L , Hoyo Cathrine , Planchart Antonio 
Published: December 2023

AbstractBackgroundThere are more than 55 million people with dementia worldwide, and it is estimated that currently 6.5 million people are living with Alzheimer’s disease (AD) in the United States. AD exhibits racial disparities whereby the prevalence is 2‐fold higher in Non‐Hispanic Blacks (NHB) compared to Non‐Hispanic Whites (NHW). It is hypothesized that epigenetics and aberrant imprinting caused by early life exposure to adverse environmental agents may contribute to AD risk later in life, although to date a comprehensive assessment of the imprinting state of the genome in AD‐affected populations has not been reported.MethodsTo address this hypothesis, we investigated cytosine methylation at candidate imprint control regions (ICRs) in post‐mortem tissues (brain) of nine AD cases (5NHB, 4NHW) and eight controls (4NHB, 4NHW), using whole genome bisulfite sequencing. Furthermore, we performed a limited clinical study in which blood samples from six individuals, three AD patients (2NHB, 1NHW) and three controls (all NHB), were subjected to methyl‐sequencing. These data were analyzed against an expanded set of candidate ICRs previously described by our group (i.e., human imprintome) to identify regions of the genome exhibiting aberrant methylation in AD patients compared to controls.ResultsWe found differential methylation in DNA derived from post‐mortem tissues of AD cases compared to controls overlapping with the expanded set of ICRs in the human imprintome (79 in NHBs and 27 in NHWs), including candidate ICR on chromosome 17 near the NLRP1 inflammasome gene (5771207‐5771575; Hg38). When extended to blood from extant controls and patients, our analysis identified a single nucleotide polymorphism (CA → CG; rs12451480) within the candidate ICR on chromosome 17, that distinguishes controls (CA) from AD patients (CG), and in which the cytosine is methylated.ConclusionWe demonstrate concordance between the methylation state of post‐mortem brain‐ and blood‐derived DNA distinguishing controls from AD patients. Furthermore, the discovery of a SNP differentiating controls from AD patients, within a candidate ICR that alters its methylation state, is consistent with an aberrant imprinting phenomenon. Our results support the hypothesis that aberrant imprinting, as can result from adverse exposures during early development, may contribute to later risk of AD.