bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuronal populations in the inferior temporal gyrus with truncated tau inclusions occur as early as those with hyperphosphorylated tau inclusions in Alzheimer’s disease, however they do not completely overlap
Authors: Oh Ian Michael 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) features stereotypical spread of hyperphosphorylated tau (p‐tau) and beta‐amyloid. Although other pathological tau posttranslational modifications (PTMs) have been described in AD, a prevalent disease model preconizes that other tau PTMs always overlap with p‐tau, making the latter an excellent marker of tau pathology burden. We recently showed in experimental studies that truncated tau (tr‐tau), a pathological tau PTM generated via cleavage by active caspases, is as common as p‐tau in neurons at late AD stages; however, only about 40% of tr‐tau positive neurons also show p‐tau positivity. This makes tr‐tau a potential marker of AD previously invisible at neuropathological investigation or a potential target of diagnostic tool development. We sought to determine how early in AD tr‐tau is detected compared to p‐tau and to what degree tr‐tau and p‐tau neuronal populations overlap at early AD stages.MethodsWe used multiplex immunofluorescence to probe tr‐tau (D13, D402, D418, TauC3) and p‐tau (PHF1) species in the same tissue slides of postmortem human brain tissue of healthy controls and subjects at progressive AD stages. We quantified neuronal tau pathology and colocalization in digital images of inferior temporal gyrus (ITG) as representative of an area involved in p‐tau pathology in intermediate stages.ResultsOur preliminary analysis included 14 cases (4 controls, 10 AD) from all Braak stages (1:1:2:3:3:2:2 for Braak 0 through 6). Of the cases used in the study, 71% were male and the mean (SD) age of death was 82.3 (10.9). As expected, p‐tau was detected from Braak 4; however, we detected tr‐tau species from Braak 3 (Fig. 1). Both p‐tau and tr‐tau burden increased with Braak stage (Fig. 2). The overlap between tr‐tau and p‐tau positive neuron populations was 30.8% at Braak 4 (Fig. 3A) and increased to 54.6% at Braak 6 (Fig. 3B).ConclusionNeuronal tr‐tau deposits develop in AD as early as p‐tau pathology. Even in earlier stages, the % of overlapping is moderate. This corroborates tr‐tau as a potential biomarker of tau pathology in AD not covered by p‐tau screening. We are currently finalizing analysis of a much larger cohort including other brain regions.
Signatures of resolution reprogramming in amyloid‐challenged microglia
Authors: Hamlett Eric D , Kondrikova Galina 
Published: December 2023

AbstractBackgroundSpecialized pro‐resolving mediators (SPMs) promote inflammatory resolution and homeostasis and are thought to have specific reprogramming effects on innate immune cells like monocytes and microglia. Decreased SPM levels have been correlated with chronic neuroinflammation, late‐stage Alzheimer’s disease (AD) and neuropathology in humans, yet few studies have explored the signatures ofMethodThe Ts65Dn mouse develops amyloid hyperexpression, neuroinflammation and neurodegeneration. We administered the SPM, Resolvin E1 (RvE1), for 1 month to control and Ts65Dn mice and measured memory using a series of tasks. We quantified resolution signaling responses using standard immunoblot. We measured microglial activation using immunofluorescence and cell characterization software. We then challenged Human innate immune cell culture models (monocytes and microglia) with amyloid‐beta and tau oligomer activation and/or administered RvE1 to promote resolution. We will employ RNASeq to learn how RvE1 resolution reprogramming affects transcriptional outcomes in these cell culture models.ResultRvE1 significantly reduced microglial activation and cytokine expression in the Ts65Dn mice, suggesting broad effects on central and peripheral innate immunity. We discovered that chronic RvE1 leads to compensatory response in specific G protein coupled receptors within the resolution family and in the PPAR‐gamma receptor and to specific signaling events. We are quantifying transcriptional outcomes to better define the nuclear program that underlies resolution.ConclusionWe have demonstrated that RvE1 modulates inflammation in a mouse model. Understanding the molecular signatures of resolution reprogramming in cells will be key to identifying prognostic indicators and molecular mechanisms.
Neuronal stimulation‐regulated RNA splicing defects in tauopathies are corrected by treatment with a p75 NTR modulator
Authors: Latif‐Hernandez Amira , Moran‐Losada Patricia , Yang Tao , White Halle , Tran Kevin C , Liu Harry , Massa Stephen M. , Wyss‐Coray Tony , Longo Frank M. 
Published: December 2023

AbstractBackgroundLong‐term maintenance of synaptic adaptations, assessed by long‐term potentiation (LTP), relies on gene induction, and can be impaired by pathological forms of tau protein in Alzheimer’s disease and related dementias (ADRD). We have previously shown that alterations in activity‐dependent gene expression profiles present in tauopathy mice are normalized by LM11A‐31 (C31), a small molecule p75 neurotrophin receptor (NTR) signaling modulator. However, altered gene expression levels represent only part of the complexity of the activity‐regulated transcriptional program. Since neuronal stimulation regulates alternative splicing of a number of activity‐regulated transcripts, and its disruption is associated with dysfunctional changes in ADRD, we aim to identify potential alternative splicing events related to tau‐mediated synaptic dysfunction and whether such alterations are influenced by treatment with a p75 NTR modulator.MethodPS19 (P301S) and wildtype mice were treated with vehicle (Veh) or C31 by oral gavage at 6 months of age for 3 consecutive months. Gene translation‐ and protein synthesis‐dependent synaptic plasticity was induced by applying three events of theta burst stimulation (TBS). RNA sequencing on stimulated [(+) TBS] slices was used to generate activity‐related profiles of alternative splicing events at the isoform level.ResultWe identified axon guidance, glutamatergic synapse, long‐term potentiation and calcium signaling KEGG pathways among the top significant pathways with isoforms down‐regulated in (+) TBS PS19 relative to (+) WT slices. This isoform downregulation was substantially mitigated in (+) TBS slices from PS19 mice treated with C31 (see figure). For example, CACNA1H‐202, a splice‐variant that encodes a voltage‐gated calcium channel protein required for proper synaptic function, is found among the splice variants down‐regulated in Veh and up‐regulated in C31‐treated (+) TBS PS19 slices. Conversely, Prickle2‐204 isoform, associated with the formation of glutamatergic synapses, is up‐regulated in Veh and down‐regulated in C31‐treated (+) TBS PS19 slices. Currently, we are validating and examining the roles of these key C31‐modulated isoforms in neuronal function and synaptic strength as candidate molecular mechanisms involved in activity‐related effects contributing to tau‐induced neurodegeneration.ConclusionWe identified neuronal activity‐related mRNA isoform modulation by C31, indicating that p75NTR signaling might influence alternative splicing events that compromise synapse function in ADRD.
PARTIAL VOLUME CORRECTION TECHNIQUES FOR LONGITUDINAL TAU‐PET QUANTIFICATION: A COMPARISON STUDY
Authors: Costoya‐Sánchez Alejandro , Moscoso Alexis 
Published: December 2023

AbstractBackgroundThe selection of an appropriate Partial Volume Correction (PVC) is crucial for evaluating tau accumulation rates using 18F‐Flortaucipir (18F‐FTP). PVC can reduce the impact of off‐target binding, but it can also increase noise and variability. While these effects may be averaged on cross‐sectional studies, they might be of paramount importance when evaluating within‐subject longitudinal tau‐PET signal. The aim of this study is to evaluate the robustness of different PVCs for the evaluation of tau accumulation rates in longitudinal 18F‐FTP studies, as measured by their correlation with cognitive clinical progression.Method111 cognitively impaired subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with serial 18F‐FTP PET and T1 images, as well as cognitive performance evaluation available for a 2‐year follow‐up period, were included in the study. 18F‐FTP PET images were corrected by applying a traditional deconvolution PVC (Grey matter only), the reblurred Van‐Cittert (RVC) analytical PVC (grey + white matter), and 2 voxel‐based PVCs, the region‐based voxel‐wise correction (RBV) and the iterative Yang (iY). Longitudinal rates of change for the regional standard uptake value ratios (SUVR) of the temporal meta‐ROI were computed for the images corrected for the different PVCs, and their correlation with the rates of change of the ADAS‐Cog 11 cognitive performance metric was analyzed.ResultThe deconvolution PVC correction showed the strongest correlation between decreased cognitive performance and increased tau accumulation rates (p<0.001, ρ = 0.38), followed closely by the RBV (p<0.001, ρ = 0.36) and iY (p<0.001, ρ = 0.35) corrections (Fig. 1). In contrast, the RVC results (p = 0.03, ρ = 0.20) were comparable to not applying any PVC at all (p = 0.03, ρ = 0.21).ConclusionOur findings suggest that longitudinal FTP studies might benefit from the use of PVC techniques for the evaluation of tau accumulation rates. Tau uptake rates of change tracked the observed clinical progression more accurately after certain PVC corrections were applied. Moreover, a simple deconvolution PVC has been shown to perform similarly to more complex, voxel‐wise corrections such as the RBV and iY.
Combined effect of prebiotic and probiotic strains restores cognitive impairment via attenuating synaptosis in the hippocampus of mice fed with high fat diet and streptozotocin diabetes‐induced dementia
Authors: Obisesan Abiola Oluwatosin , Olaitan Olanrewaju Mojisola , Omosebiola Jesutosimi Oyindamola , Akawa Oluwole Abidemi , Olayinka Juliet Nnenda 
Published: December 2023

AbstractBackgroundDementia is known as neurodegenerative disease which causes decline in the cognitive domains of memory and thinking, leading to memory loss of an individual especially the aged. Diabetes mellitus causes brain structure changes and cognitive decline, and it has been estimated that diabetes doubles the risk for dementia. Probiotics combined with prebiotics on the other hand, seem to have a positive effect and reverse memory lossMethodThis study employed ninety (90) male bulb/c albino mice weighing between 25 and 28 grams (n = 15). Animals were housed in plastic cages at room temperature under good hygienic conditions, had free access to animal pellets and water ad libitum. Mice were fed with a high fat diet to imitate obesity after which Diabetes was induced by one administration of STZ (50 mg/kg, IP) freshly dissolved in citrate buffer following an overnight fasting on 22nd day. Probiotic strains and Prebiotics were administered with prepared suspension containing 107 and 109 CFU/ml of probiotics and prebiotics (3mg and 5 mg) body weight orally for pretreatment and posttreatment after streptozotocin induction.ResultResults from this study shown that there was a significant decrease in glucose levels of animals treated with probiotics and prebiotics combined supplementation in both pretreatment (HFDS +109 CFU/ml + 5 mg) and post‐treatment group (HFDS +109 CFU/ml + 5 mg) with insulin resistance. AChE levels significantly reduced at the combined probiotics and prebiotics pretreatment (HFDS +109 CFU/ml + 5 mg) and post‐treatment group (HFDS +109 CFU/ml + 5 mg). With relation to BDNF gene expression analysis, combined probiotics and prebiotics showed high expression of the BDNF gene in the combined probiotics and prebiotics pretreatment (HFDS +109 CFU/ml + 5 mg) and post‐treatment group (HFDS +109 CFU/ml + 5 mg). Administration of combined probiotics and prebiotics improved memory and learning, insulin resistance, animal weight, glucose levels and BDNF expression.ConclusionCombined probiotics and prebiotics demonstrated neuroprotective and anti‐neuroinflammatory activity in the experimental animals and was able to attenuate synaptosis and promote synaptogenesis in diabetic mice which started receiving treatment. The combined supplementation also restores cognitive impairment and memory function.
A hybrid algorithm of machine learning and optimization to identify Super‐Agers using rsfMRI data
Authors: Fili Mohammad , Parvin Mohammadiarvejeh , Hu Guiping , Willette Auriel A 
Published: December 2023

AbstractBackgroundAging and cognitive decline are often associated with each other. However, some adults called Super‐Agers have superior cognitive performance relative to age, with a comparable cognitive performance against healthy middle‐aged individuals. This study employs resting‐state functional Magnetic Resonance Imaging (rsfMRI) and demographic information to distinguish Super‐Agers from Cognitive Decliners.MethodFirst, Principal Component Analysis (PCA) is applied to a set of four cognition tests which were recorded for two‐time points, (baseline visit in 2006‐2010) and (follow‐up visit starting in 2014) to create the initial latent cognitive trajectories groups. Then, a hybrid algorithm of machine learning and optimization is developed to predict the latent groups using orthogonal neural networks. The proposed algorithm utilizes Bayesian Optimization to optimize the labeling procedure and a logistic regression model to classify participants.ResultWe compared the performance of the proposed algorithm against two groups of baseline models: 1) four models, each using only one of the cognition tests at a time for labeling; 2) two models, each with a restricted set of features (one using only demographics information, and the other one using rsfMRI data). The proposed algorithm outperformed the baseline models, achieving an AUC of 88% when distinguishing between Super‐Agers and Cognitive Decliners.ConclusionThe proposed algorithm is capable of distinguishing cognitive trajectories with high success. The combination of demographics and rsfMRI datasets improved the overall performance compared to individual datasets.
Association of Plasma β‐amyloid (Aβ) 42/40 and Incidence of Dementia in Black and White Older Adults
Authors: Jiang Xiaqing , Graff‐Radford Neill R , Younkin Steven G. , Yaffe Kristine 
Published: December 2023

AbstractBackgroundPlasma biomarkers such as Aβ 42/40 have emerged as important tools to detect dementia risk, although whether plasma Aβ 42/40 levels and the associations with dementia risk differ by race is unclear. As part of the Health, Aging, and Body Composition study, we compared the plasma levels of Aβ 42/40 ratio and the associations with 15‐year dementia risk by race among community‐dwelling Black and White older adults.MethodsWe studied 997 dementia‐free participants (55% women, 54% Blacks) aged 70‐79 years (mean age 74.5±2.9) enrolled at baseline (1997‐98). We defined incidence dementia over 15 years based on hospital records, prescription for dementia medication, or a decline ≥1.5 standard deviations in the Modified Mini‐Mental State Examination score. Stored plasma obtained one year after baseline was used to measure Aβ with Innogenetics INNO‐BIA assays at Mayo Clinic, Jacksonville, FL. Plasma Aβ42/40 ratio was categorized into low, medium, and high tertiles. We used linear regression to estimate the difference in log‐transformed Aβ42/40 in Black and White participants and back‐transformed the effect estimates. We assess the association between Aβ42/40 (by tertiles) and dementia risk using Cox proportional hazards model stratified by race. All models were adjusted for age, sex, hypertension, diabetes, high cholesterol, and obesity, and we tested for interactions by race.ResultsBlack participants had significantly lower Aβ42/40 than White participants (‐4.4%, 95% CI ‐8.1% to ‐0.6%). In stratified analysis, lower Aβ42/40 was significantly associated with an increased risk of incident dementia among Black participants: 27.8% in medium (hazard ratio [HR] 1.69, 95% CI 1.07 to 2.68) and 33.5% in low (HR 2.07, 95% CI 1.32 to 3.24) compared with 17.3% in high Aβ42/40 tertile. The associations were somewhat weaker but showed the same trend among White participants: 20.3% in medium (HR 1.49, 95% CI 0.85 to 2.61) and 22.9% in low (HR 1.59, 95% CI 0.92 to 2.76) compared with 15% in high Aβ42/40 tertile. The interaction between Aβ42/40 and race was not statistically significant.ConclusionAmong community‐dwelling, non‐demented older adults, plasma Aβ42/40 differs by race, although the association with dementia risk does not differ by race.
Surveying Willingness to Learn About and Share Results of Brain MRIs in South and East Asian Adults
Authors: Kota Karthik , Lee Woowon , Li Mei‐Ling , Marquez Melissa J , Estervil Jaunis J , Su Guibin J , Lopez Lisa Lanza , Dawson Allison , Sotelo Victor , Papas Julia , Bergren Stephanie , Hu William T. 
Published: December 2023

AbstractBackgroundDementia in South Asian (SA) and East Asian (EA) adults is often under‐reported by family due to stigma or under‐recognized by medical practitioners due to language barriers. Older SA and EA adults are also underrepresented in dementia research. While recruiting for a memory and aging study in the New York City/New Jersey (NYC/NJ) area, we noted hesitancy among older SA adults towards undergoing brain MRI analysis. We hypothesized that differences in attitudes towards MRI and brain health research may differ between older SA and other adults.MethodWe recruited a convenience sample of community‐dwelling adults in the NYC/NJ area from August 2022 to January 2023 to complete an anonymous survey on knowledge and attitudes towards MRIs and dementia. Topics and wording reflected concerns reported in the literature, including potential harms from MRI, desire to learn about incidental MRI findings, and stigmatizing beliefs. We specifically targeted SAs, but also recruited older Chinese and Korean adults.Result210 participants (n = 151 for 50+) completed the survey, including 69 (33%) SA adults. Chinese and Korean respondents had similar attitudes and perceptions, and were hereafter analyzed together as an EA group. Compared to non‐Hispanic White (White) respondents, SA and EA respondents were less interested in learning about incidental brain MRI findings. EA and White respondents were much more likely to share de‐identified brain MRI for research purposes than SA respondents, and this was mediated by future concern for dementia/stroke in EA, but not White, respondents. There was no difference in perception of MRI‐related harm or dementia‐related stigma.ConclusionSA and EA adults were both less interested in learning about incidental brain MRI findings than White adults, but the two Asian groups differed in willingness to share de‐identified MRI for research and concern for future dementia/stroke. In the absence of knowledge differences, these may be explained by cultural attitudes towards health and locus of control. Future studies on these factors are needed to promote research participation and dementia prevention among older SA adults.
Piloting a research registry for dementia: The Egyptian Dementia Network (EDN) registry
Authors: Heikal Shimaa Adel 
Published: December 2023

AbstractBackgroundDementia and aging problems are currently growing worldwide and are considered public health priorities. The availability of epidemiological and clinical data on the disease greatly impacts our understanding of the disease and, hence, improves disease management and prevention strategies. As part of the development of a national dementia registry for Egypt that would be of great importance as we currently lack the exact epidemiological data and rely only on estimates, the present study is aiming to pilot a cohort for the first national registry for dementia in Egypt, The Egyptian Dementia Network (EDN) registry.MethodEDN will provide a huge set of data as a promising platform for analyzing the prevalence, incidence, and major causes of the disease in Egypt. Our study will coordinate the track of early‐onset AD (EOAD) and vascular dementia cases, which have recently shown a rising pattern, based on the first 100 cases from each cohort and a similar number of matched controls collected from different centers across Egypt.ResultAs a first stage, we developed an SOP for the registry workflow, a network of collaborating centers, and a unified sheet for data collection (both clinical and epidemiological). We will then develop a tool to register the collected data. The use of big data analytics will help analyze the collected data and identify the major causes of dementia in Egypt.ConclusionAs a research registry, the main aim is to start understanding the causes, mechanisms, and courses of dementia in Egypt. The final long‐term goal is to validate the predictive ability of the registry data on the Egyptian HCAP (Harmonized Cognitive Assessment Protocol), where the ability of data to predict future dementia patients will be tested on a longitudinal cohort of aging population.
A novel Presenilin 2 mutation in two siblings with predominantly amnestic, early‐onset Alzheimer’s disease
Authors: Leochico Carl Froilan D. , Oliveira Ana Luiza Pinto , Masellis Mario , Mitchell Sara 
Published: December 2023

AbstractBackgroundFamilial, early‐onset Alzheimer’s Disease (AD) is a rare form of dementia resulting from autosomal dominant mutations in the amyloid precursor protein (APP), presenilin‐1 (PSEN1), or presenilin‐2 (PSEN2) genes with phenotypic diversity. PSEN2 mutations are rare and vary widely in age of onset.MethodCase report and literature review.ResultWe report a novel PSEN2 variant (c.359T>G, p.Ile120Ser) that has been clearly segregated in two siblings in their fifties, presenting as predominantly amnestic AD. One of the siblings was also heterozygous in the PSEN1 gene (c.118_120del, p.Asp40del). There was no evidence of C9orf72 repeat expansion in either sibling. A third sibling has also started manifesting cognitive impairments. Their strong family history of cognitive dysfunction suggests that the PSEN2 mutation is pathogenic, and the causative variant has never been reported in Medline and the Alzgene genetic database of PSEN2.ConclusionAs there are numerous PSEN2 mutations still incompletely characterized, there remains a need to systematically report patients either with familial or sporadic presentation and very early age of onset and classify their pathogenicity accordingly. Providing information about the genetic bases of AD can help allay the stress of patients and families about their diagnosis, individual risks, and possible care planning.