bluuebunny/crossref_metadata_2025_split huggingface dataset:
Developing a DNAm Surrogate to Predict Cognitive Functioning among Older Adults
Authors: Farina Mateo , Klopack Eric , Crimmins Eileen M. 
Published: December 2023

AbstractBackgroundBlood‐based epigenetic measures are being developed and used to predict aging‐related health outcomes. Specifically, researchers have developed “epigenetic clocks” based on predictions of chronological age and age‐related health declines by DNA methylation. However, these markers are meant to predict aging per se and are not disease specific. Recently, scholars have developed “DNAm surrogates” to predict specific outcomes. This methodological technique has yet to be applied to cognitive functioning despite its potential to improve prediction of cognitive health in later life and provide insight into the role of biological aging.MethodThis study developed a novel DNAm surrogate measure for cognitive functioning (DNAmCogScore) based on an elastic net approach linking using 833,865 CpG sites predicting the Telephone Interview Cognitive Status score (TICS) available in the Health and Retirement Study (HRS), a nationally representative sample of older adults in the United States. Additionally, we evaluate the association of this DNAm surrogate and other neuropathology biomarkers. We used used ridge regression to create DNAmCogScore with 50% of the sample for training and 50% for testing (N = 2009 for each subsample). The Irish Longitudinal Study of Aging (TILDA) will be used for validation (results forthcoming).ResultWe find a positive association and modest predictive value between DNAmCogScore and TICS (see Figure 1, r = .4). Table 1 shows the strong associations with the DNAmCogScore and demographic characteristics. Overall, we find a strong positive coefficient between DNAmCogScore with attenuation after controlling for demographic characteristics, from 1.12 in Model 1 to .20 in Model 3, but remaining statistically significant throughout. Table 3 shows modest negative correlations between DNAmCogScore and NfL, pTau181, and GFAP (ranging from ‐.24 to ‐.36) and no correlation with AB42:40.ConclusionThis study is among the first to create a DNA methylation surrogate measure of cognitive functioning. Our measure is associated with cognitive functioning, even after adjusting for key demographic characteristics. And it has the expected association with other more neuropathology biomarkers. Overall, it suggests that changes in DNA methylation may be a molecular‐level mechanisms by which biological aging impacts cognitive health, and this measure may provide useful prediction of cognitive impairment before the onset of symptoms.
PROTAC tau degrader for the treatment of Alzheimer’s disease and primary tauopathies
Authors: Zhang Lili , Lai Yen‐Ting , Lin Yih‐Shyan , Lee Mi , Lin Shih‐Han , Hsu Mia , Chai Yuan , Wang Xiaojuan , Gu Xiang , Zhang Chenhua , Ma Haou‐Tzong , Jang Ming‐Kuei , Tempest Paul 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is characterized by progressive decline of memory and cognitive functions. Accumulation of hyperphosphorylated tau is a pathological hallmark of AD and also plays a pathogenic role in disease progression. Proteolysis Targeting Chimera (PROTAC) technology enables the selective removal of a target protein by cellular ubiquitin‐proteasome system. Here we describe the characterization of tau PROTAC degrader developed at APRINOIA as a novel disease modifying treatment.MethodsTau degrader was synthesized by linking a proprietary tau binder from Aprinoia tau PET tracer program with a ligand of E3 ligase. The PROTAC mediated tau degradation was first evaluated in HEK293 cells expressing P301L tau, which develops tau oligomer and aggregates upon incubation with “tau seeds” from brain lysates of rTg4510 mice. The reduction of tau aggregates was measured using a HTRF based immunoassay. A similar seeding induced tau aggregation assay was established in primary neurons to confirm the degrader activity. Efficacy was further evaluated in rTg4510 mice following treatment with IV injection.ResultsPROTAC tau degrader reduced tau oligomer/aggregates in cellular models as well as in therTg4510 mice. Preliminary data suggests degrader is more effective in degradation of soluble tau oligomers in early stage of pathological tau development.ConclusionTau PROTAC degrader generated from proprietary tau warhead can selectively decrease the oligomer/aggregated tau in both in vitro and in vivo models. Current effort is focused on optimization of ADME properties of tau degrader as a promising therapy for AD primary tauopathies.
Improving Early Recognition of Potentially Treatable Causes of Rapidly Progressive Dementia
Authors: Satyadev Nihal , Tipton Philip W , Dunham S Richard , Brier Matthew R , Geschwind Michael D , Morris John C , Graff‐Radford Neill R , Day Gregory S. 
Published: December 2023

AbstractBackgroundRapidly progressive dementia (RPD) includes patients with less than two years from the onset of cognitive impairment to incapacitation due to dementia. Although RPD is often associated with fatal neurodegenerative diseases, including early‐onset Alzheimer disease or Creutzfeldt‐Jakob disease, treatable forms of RPD are increasingly recognized. Early recognition of patients with potentially treatable causes of RPD is key to the timely provision of therapies required to achieve the best possible long‐term outcomes.Method155 patients with RPD were prospectively enrolled from February 2016 to August 2022 via two tertiary care centers. Etiologic diagnoses were independently assigned by two neurologists with good agreement (>90%). Causes of RPD were further classified as treatment‐responsive or nonresponsive, referencing the extant literature. Demographic, clinical, and paraclinical features associated with treatable causes of RPD were identified using stepwise multivariate logistic regression and validated with 5‐fold cross validation.Result87/155 patients (56.1%) had a potentially treatable cause of RPD, including autoimmune/inflammatory disease (n = 52, 59.8%), vasculitis (n = 13, 14.9%), primary psychiatric disease (n = 4, 4.6%), or nutritional deficiency (n = 4, 4.6%). Multivariable analyses identified seven features that were independently associated with treatment‐responsiveness: age‐at‐symptom onset (OR: 0.62 per decade, 95%CI: 0.42‐0.93), seizures (OR: 9.81, 95%CI: 2.84‐33.89), MRI suggestive of autoimmune encephalitis (OR: 23.08, 95%CI: 2.28‐233.40), CSF white blood cell count ≥10 cells/mm3 (OR: 32.24, 95%CI:5.80‐179.21), movement abnormalities (OR: 4.99, 95%CI: 1.76‐14.10), presence of disease‐associated tumor (OR: 13.82, 95%CI: 2.25‐85.11), and mania (OR: 18.47, 95%CI: 1.76‐193.61). Model performance was excellent (c‐statistic = 0.88, 95%CI: 0.82‐0.94; p<0.001): 71 patients (81.6%) with potentially treatable causes of RPD and 56 patients (82.4%) with non‐treatable causes of RPD were correctly classified (PPV = 85.5%; NPV = 77.8%).ConclusionTreatment‐responsive causes of RPD were common in our series. Younger age, seizures, movement abnormalities, or mania at presentation, and paraclinical tests suggesting inflammation (MRI or CSF) or tumor in patients with RPD should prompt consideration of treatable causes of RPD and initiation of treatment when indicated.
Abnormalities of hippocampal shape in idiopathic normal‐pressure hydrocephalus patients
Authors: Kang Kyunghun , Kim Jaeil , Yoon Uicheul , Park Ki‐Su , Jeong Shin Young , Lee Sang‐Woo 
Published: December 2023

AbstractBackgroundWe utilized 3‐dimensional, surface‐based, morphometric analysis to investigate hippocampus shape between 2 groups: (1) idiopathic normal‐pressure hydrocephalus (INPH) patients who had a positive response to the cerebrospinal fluid tap test and (2) healthy controls. The aims were (1) to evaluate INPH‐related structural abnormalities of the hippocampi and (2) to investigate relationships between hippocampal shape changes and gait disturbance in INPH patients.MethodForty‐eight INPH patients and 25 healthy controls were imaged with MRI, including 3‐dimensional volumetric images, for vertex‐based 3‐dimensional hippocampal shape analysis.ResultVertex‐wise shape analysis revealed significant bilateral deformation in patients with INPH compared with healthy controls after FDR correction. Both the left and right hippocampi were more elongated and narrowed in INPH patients than in the healthy controls. In both hemispheres, INPH patients demonstrated an upward bending of the middle and posterior hippocampus reflecting a bilateral vertical displacement from body to tail. Significant correlations were found between local shape deformity and the timed up and go and 10 meter walking tests (to a greater degree on the right than on the left). Bilateral inward deformations at the superomedial hippocampal tail and inferior hippocampal body were consistently associated with inferior performance across tests. Inward deformations at the right medial and lateral hippocampal head and right superior hippocampal body were also consistently associated with worse performance across tests.ConclusionThese results suggest that patients with INPH have unique patterns of hippocampal shape changes. Our findings encourage future studies to elucidate the underlying mechanism of hippocampal morphometric abnormalities in INPH patients. Changes in overall shape may contribute to the distinctive gait abnormalities associated with INPH.
The Multidimensional Autonomy Scale: a new integrative tool for clinicians and preliminary results
Authors: Dethoor Anais , Hainselin Mathieu , Vaugeois Arthur , Duclos Harmony 
Published: December 2023

AbstractBackgroundAutonomy is the ability to perform daily living actions within the environment where we live in (Dos Santos & Makdessi, 2010). It is a multidimensional concept, including 5 dimensions: psychological, functional, professional, digital and social autonomy (Dethoor et al., 2021). However, most studies mainly focused on functional autonomy. In this study we focused on social autonomy (SA) within an integrative approach.MethodsWe built an integrative tool, the Multidimensional Autonomy Scale (MAS), to assess the 5 dimensions of autonomy. The MAS includes 26 questions, divided in 5 sub‐scales for each autonomy dimension, for which we ask frequency and impact on daily life.In this study, we focused on SA and its relation with empathy and theory of mind among young (18‐40 years), intermediate (40‐60 years), and elderly participants (60‐80 years). We assessed empathy and theory of mind with the Social‐SMAF and the Movie for the Assessment of Social Cognition (MASC).ResultsWe found a decrease of theory of mind through aging, but no social autonomy change nor correlation between theory of mind and social autonomy.ConclusionThe decrease of theory of mind might be correlated with other dimensions of social cognition or autonomy. Older participants seem to have less relationships, but not worse, even better sometimes. We encourage clinicians and researcher to assess autonomy within a multidimensional framework and go beyond functional autonomy only.
Transferable individual brain regional atrophy progression prediction model using structural connectome
Authors: Xiao Yu , Chong Joanna Su Xian , Kok Bing Cai , Ng Kwun Kei , Chen Christopher Li‐Hsian , Zhou Juan Helen 
Published: December 2023

AbstractBackgroundBrain microstructure, as measured by diffusion MR imaging (dMRI), is an early biomarker of Alzheimer’s disease (AD) and has been previously demonstrated to predict whole brain atrophy and cognition. The network‐based neurodegeneration hypothesis posits that the onset of AD occurs within key vulnerable regions, whose network connectivity guides the spread of atrophy into new regions. Graph convolutional network (GCN) models can mimic this spread through its convolution process. Here we present a GCN‐based model to predict future individual nodal atrophy and disease progression across the AD spectrum using structural connectome.MethodWe analyzed 371 participants with baseline dMRI scans (154 cognitively normal (CN), 161 mild cognitive impairment (MCI), 56 AD) and longitudinal T1 scans (2.7±1.2 years) from the ADNI study. To predict annual nodal atrophy rates (126 nodes) from baseline structural connectivity (SC), we constructed a two‐layer GCN followed by multilayer perceptron (GCN‐MLP). Five‐fold nested cross‐validation and Optuna were used for hyperparameter tuning. We applied the trained GCN‐MLP model to predict future disease progression via transfer learning. GNNExplainer was used to identify the predictive SC features for atrophy or cognition. The GCN‐MLP model was validated in another independent dataset from Singapore (MACC) with 226 participants (61 CN, 112 MCI, 53 AD, follow‐up period of T1 scans (3.1±1.3 years)) using transfer learning.ResultThe proposed GCN‐MLP model predicted the annual rate of regional atrophy at the individual level in the main (R = 0.5407±0.0480; MAE = 0.0013±0.0001; EV = 0.2930±0.0516) and validation (R = 0.5323±0.0564; MAE = 0.0009±0.0001; EV = 0.2808±0.0559) datasets (Table 1; Figure 1). Graph edge SC of the target network contributed most to the atrophy prediction of its own network (Figure 2A&C). Nodal feature SC in hippocampus, striatum, and temporal network were major predictors of atrophy progression across all 10 networks (Figure 2B&D).Moreover, the trained atrophy prediction model predicted changes of CDR‐Sum‐of‐Boxes (main: R = 0.8035±0.0492; validation: R = 0.5555±0.0404), ADAS13 (main: R = 0.7475±0.0725), MMSE (main: R = 0.7124±0.0509; validation: R = 0.6377±0.0616), and MOCA (validation: R = 0.6764±0.0314).ConclusionWe developed an accurate and interpretable individualized longitudinal nodal atrophy and disease progression prediction model in the AD spectrum by leveraging the comprehensive properties of whole‐brain structural connectome. The approach was validated in both Caucasian and Asian datasets, highlighting its generalizability and interpretability.
Alzheimer’s disease risk gene BIN1 modulates neural network activity through the regulation of L‐type calcium channel expression in human induced neurons
Authors: Costa Marcos R 
Published: December 2023

AbstractBackgroundBridging Integrator 1 (BIN1) is the second most important Alzheimer’s disease (AD) risk gene after APOE, but its physiological roles and contribution to brain pathology are largely elusive. In this work, we tackled the short‐ and long‐term effects of BIN1 deletion in human induced neurons (hiNs).MethodWe generated isogenic BIN1 WT, KO and HET human induced pluripotent stem cells (hiPSCs), which were differentiated into hiNs grown in 2D and 3D (cerebral organoids) cultures. We also developed a novel protocol for the generation of highly pure glutamatergic neuron cultures, allowing the study of cell‐autonomous roles of BIN1. Using these three different systems, we probed neuronal electrical activity using MEA electrophysiology and gene expression alterations in individual cell types using snRNA‐seq.ResultWe show that BIN1 depletion leads to specific transcriptional alterations in glutamatergic neurons involving mainly genes associated with calcium homeostasis, ion transport and synapse function. We also show that BIN1 regulates calcium transients and neuronal electrical activity through interaction with the L‐type voltage‐gated calcium channel Cav1.2 and regulation of activity‐dependent internalization of this channel. Treatment with the Cav1.2 antagonist nifedipine partly rescues neuronal electrical and gene expression alterations in BIN1 knockout hiNs.ConclusionOur results indicate that BIN1 loss‐of‐function impairs calcium homeostasis at least in glutamatergic neurons, potentially contributing to the transcriptional changes and neural network dysfunctions observed in AD.
Amyloid β‐specific T cell response is enhanced in individuals with mild cognitive impairment
Authors: Chiu Yen‐Ling , Hung Ruo‐Wei , Fang Chuang Yi‐ 
Published: December 2023

AbstractBackgroundNeuroinflammation is a key process in initiating and propagating Alzheimer’s disease (AD). Even though it is widely known that the deposit of amyloid plaques and CSF levels of amyloid distinguishes patients with AD or mild cognitive impairment (MCI) from cognitively normal (CN) individuals, little is known about the role of amyloid‐specific immune response in cognitive decline.MethodUsing a polyfunctionality assay typically used for detecting virus‐specific T cell responses, we tested participants from the Epidemiology of Mild Cognitive Impairment in Taiwan study (EMCIT) and the Taiwan Precision Medicine Initiative of Cognitive impairment and dementia (TPMIC) study to compare the amyloid‐specific T cell responses between CN and MCI individuals. The abilities of T cell response parameters and plasma p‐Tau181 to distinguish MCI from CN were tested.ResultResults from both cohorts showed an enhanced amyloid‐specific T‐cell response in individuals with MCI. In the EMCIT cohort, the individual’s amyloid‐specific CD4+ response frequency of total CD4+ cells was significantly larger in MCI (n = 69, 0.93%) than in CN (n = 69, 0.51%, p < 0.001). CD4+ T cell response discriminated MCI versus CN (area under curve [AUC], 0.72 [0.64‐0.81]) with significantly higher accuracy than p‐Tau181 (AUC: 0.59 [0.5‐0.69], p < 0.01). In the TPMIC cohort, both CD4+ and CD8+ response frequencies were higher in MCI individuals (n = 21, CD4: 1.2%, CD8: 2.02%) than in CN (n = 30, CD4: 0.14%, CD8:0.27%; both p < 0.001). CD4+ T cell response frequency and CD8+ response frequency also outperform p‐Tau181 in their discriminative accuracy of MCI versus NC (CD4+ AUC, 0.97, [0.94‐1.01]; CD8+ AUC, 0.96, [0.92‐1.01]; p‐Tau181 AUC, 0.83, [0.69‐0.96]; both p < 0.05).ConclusionOur study validates the amyloid hypothesis by showing that amyloid‐associated neuroinflammation is involved in the process of neurodegeneration and demonstrated the accuracy of using amyloid‐specific T cell response to discriminate MCI from CN individuals. The TPMIC cohort is an ongoing longitudinal study that includes amyloid PET results and thus we will investigate the prognostic value of amyloid‐T cell response in the future.
Immunohistochemical study of synaptophysin expression in rat hippocampus during aging
Authors: Ekova Maria , Smirnov Alexey Vladimirovich , Tyurenkov Ivan Nikolaevich , Grigoryeva Natalya Vladimirovna 
Published: December 2023

AbstractBackgroundIn the process of aging, there is a general decrease in the physiological functions of the body, including cognitive ones. Cognitive abilities are a decisive factor in determining the quality of life of older people.Method2 groups were formed: group 1 ‐ rats at the age of 12 months (n = 10), group 2 ‐ rats at the age of 24 months (n = 10). The degree of expression of synaptophysin and the relative area of the immunoreactive material in the dorsal and ventral hippocampus were determined.ResultImmunohistochemical study using antibodies against synaptophysin in 12‐ and 24‐month‐old animals revealed a crescent‐shaped distribution of immunoreactive material in the neuropil of the pyramidal layer CA1‐CA4 of the dorsal hippocampus, most pronounced in old animals. In 24‐month‐old animals, an increase in the degree of expression of the immunoreactive material in the neuropil of the pyramidal, radial and molecular layers CA1 and CA3 of the dorsal hippocampus was revealed. In 12‐month‐old animals, in the neuropil of the pyramidal layer in CA1 and CA3 of the ventral hippocampus, a high degree of orderliness was found in the arrangement of dendrites in the radial layer and the distribution of immunoreactive material over the surface of the dendrites in the pyramidal and radial layers of the hippocampus, the most pronounced in CA1. At the same time, no age‐dependent increase in the degree of expression of the immunoreactive material was found in the ventral hippocampus. We also did not reveal a significant increase or decrease in the relative area of the immunoreactive material in either the dorsal or ventral hippocampus.ConclusionDuring aging in rats at the age of 24 months, an increase in the degree of expression of synaptophysin‐immunoreactive material in the neuropil of the pyramidal, radial and molecular layers CA1 and CA3 of the dorsal hippocampus was revealed, which may be associated with the redistribution of synaptic vesicles in the presynaptic part of the synapses with their predominant localization in the presynaptic membranes, which determines the increase in the degree of expression of synaptophysin.
Female Brain and Endocrinological Research Veteran Study: Identifying endocrinological, lifestyle and psychosocial determinants of female brain health outcomes for future intervention success
Authors: Watermeyer Tamlyn J , Ansdell Paul , Atkinson Elliott J , McGill Gill , Dodds Christina , Howatson Glyn , Udeh‐Momoh Chi T. 
Published: December 2023

AbstractBackgroundRecent studies have demonstrated a greater risk for dementia in female veterans compared to civilians; with highest prevalence noted for female veterans with a diagnosis of psychiatric (trauma, alcoholism, depression), and/or a physical health condition (brain injury, insomnia, diabetes). Such findings highlight the need for increased and early screening of medical and psychiatric conditions, and indeed dementia, in the female veteran population. Further, they call for better understanding of the underlying psychobiological mechanisms that might confer heightened risk for female veterans to prepare tailored preventative and interventional strategies that support brain health across the lifespan.MethodOur feasibility study will create an innovative highly‐phenotyped readiness cohort of female veterans to assess the impacts of, and risks associated with, military service on brain health, using state‐of‐the‐art non‐invasive cognitive, physiological and biomarker capture techniques.ResultFEMBER‐Vet will include 90 participants across study groups (30 female veterans, 30 male veterans, 30 female civilians) to delineate the precise biological, socio‐demographic, health, lifestyle, military‐related, and lifetime determinants of brain health outcomes (psychosocial, cognitive, neurophysiological, and other biomarkers).ConclusionThis work addresses the poorly understood biopsychosocial outcomes that female veterans suffer compared to male counterparts and the general female population. Ultimately, it will promote tailored interventions for an emerging health priority that currently lacks sufficient evidence for screening and therapeutic intervention.
Neuroprotective Effect of Perillyl Alcohol in Experimental Sporadic Alzheimer’s Disease
Authors: Kapoor Satyan 
Published: December 2023

AbstractBackgroundAlzheimer’s is most common neurodegenerative disorder characterized by memory loss due to accumulation of amyloid‐ β fibrils. There are different pathologies that count for AD like neuroinflammation. This study highlights the role of oxidative stress and inflammation in progression of AD whereas Perillyl alcohol (POH) shows antioxidative & antiinflammatory properties.Method‐Sprague Dawley ICV‐STZ (3mg/kg) rats (250‐300g, 7‐8 weeks) were treated with Perillyl alcohol treated with three different doses of (25, 50 and 100mg/kg p.o.) for 13 days from 15th to 27th day.ResultPerillyl alcohol treatment significantly attenuates declined body weight in ICV‐STZ induced dementia in rats, showed significant increase in crossing number, and active time. Dementia induced rats were unable to discriminate familiar and novel objects, which is improved by POH. POH attenuates STZ induced acquisition deficits and retention time, increased MDA and nitrite levels. POH attenuated depleted levels of GSH, Catalase, SOD comparable to standard drug donepezil, POH decreased AChE levels in cortex and hippocampus.ConclusionIn summary, present study has shown that Perillyl Alcohol is effective in amelorating i.c.v. STZ induced behavioral alterations, cholinergic dysfunctions and oxidative‐ nitrative stress.