bluuebunny/crossref_metadata_2025_split huggingface dataset:
Advanced machine learning approach to increase diagnostic accuracy in atypical Alzheimer’s disease cases
Authors: Temtam Ahmed , Cruz Erica J , Okhravi Hamid , Strock Daniel , Sternick Molly , Iftekharuddin Khan M 
Published: June 2023

AbstractBackgroundThe early diagnosis of Alzheimer’s disease (AD) and other types of dementia is essential in clinical practice. Up to 50% of patients with any form of dementia may remain undiagnosed during their lifetime and the diagnosis of AD may often be inaccurate. In assessing patients, accurate diagnosis based on only clinical data and structural (MRI or CT) imaging is suboptimal in a subset of patients with atypical presentation. Although amyloid PET imaging and CSF biomarkers can provide incremental benefits, numerous obstacles preclude their wider use in clinical practice. In this work, a parametric study was performed to create a machine learning (ML) model to accurately diagnose hard‐to‐detect cases of AD, to mitigate the need for more expensive or invasive testing such as amyloid imaging or spinal tap.MethodData from 173 participants (MCI and mild dementia), including 105 patients (60%) with AD and 68 (40%) Non‐AD patients, were included from our memory clinic. The dataset for each participant included pertinent history, AD risk factors, scores on a neuropsychological testing battery, functional status, and MRI volumetric studies. Participants were divided into two groups: Group I (easy‐to‐detect) with a high probability of AD diagnosis based on clinical data (subjective and objective amnestic presentation) and volumetric studies (hippocampal and medial temporal lobe atrophy). Group II (hard‐to‐detect), who did not fit into the first group and the diagnosis was confirmed with either amyloid imaging or CSF analysis. The distribution of diagnosis by group: 1‐ Easy to detect (43 AD, 29 Non‐AD),2‐ Hard to detect (62 AD, 39 Non‐AD), a total of three experiments with different combinations of groups were conducted, 1‐ All Groups (Exp.1.), 2‐ Hard to detect (Exp.2.), 3‐ Easy to detect (Exp.3.). In all experiments, Leave‐One‐Out cross‐validation technique was performed.ResultA total number of 132 features utilized, by employing feature selection approach, 13 features were selected. Our model attains the highest accuracy of 87.27% on classification of Exp.1., 83.28% on Exp.2. and 95.80% on Exp.3.ConclusionWe investigated discrimination of AD from Non‐AD on hard‐to‐detect cases using ML. The proposed method obtains competitive performance and achieves improved accuracy results.
Regulatory T cells decrease A1‐like C3‐positive reactive astrocytes in Alzheimer‐like pathology
Authors: Stym‐Popper Grégoire , Matta Karen , Chaigneau Thomas , Rupra Roshan , Fouquet Stéphane , Dansokho Cira , Toly‐Ndour Cecile , Dorothee Guillaume 
Published: June 2023

AbstractBackgroundIncreasing evidence support a key role of peripheral immune processes in the pathophysiology of Alzheimer’s disease (AD), highlighting an intricate interplay between brain resident glial cells and both innate and adaptive peripheral immune effectors. We previously showed that regulatory T cells (Tregs) have a beneficial impact on disease progression in AD‐like pathology, notably by modulating the microglial response associated with Ab deposits in a mouse model of amyloid pathology. Besides microglia, reactive astrocytes also play a critical role in neuroinflammatory processes associated with AD. Different phenotypes of reactive astrocytes have recently been characterized, including A1 neurotoxic and A2 neuroprotective subtypes. However, the precise impact of Tregs on astrocyte reactivity and phenotypes in AD still remains poorly defined.MethodsWe assessed the impact of Treg immunomodulation on astrocyte reactivity in a mouse model of AD‐like amyloid pathology. Using 3D imaging we carried out extensive morphological analyses of astrocytes following either depletion or amplification of Tregs. We further assessed the expression of several A1‐ and A2‐like markers by immunofluorescence and RT‐qPCR.ResultsModulation of Tregs did not significantly impact the magnitude of global astrocyte reactivity in the brain nor in the close vicinity of cortical amyloid deposits. We did not observe changes in the number, morphology, or branching complexity of astrocytes according to immunomodulation of Tregs. However, early transient depletion of Tregs modulated the balance of reactive astrocyte subtypes, resulting in increased C3‐positive A1‐like phenotypes associated with amyloid deposits. Conversely, early depletion of Tregs decreased A2‐like phenotypes of reactive astrocytes associated with larger amyloid deposits. Intriguingly, modulation of Tregs also impacted the cerebral expression of several markers of A1‐like subsets in healthy mice.ConclusionsOur study suggests that Tregs contribute to modulate and fine tune the balance of reactive astrocyte subtypes in AD‐like amyloid pathology, by dampening A1‐like astrocytes in favor of A2‐like phenotypes. This effect of Tregs may partly relate to their capacity at modulating steady state astrocyte reactivity and homeostasis. Our data further highlight the need for refined markers of astrocytes subsets and strategy of analysis for better deciphering the complexity of astrocyte reactivity in neurodegeneration.
Head‐to‐head comparison of plasma biomarkers across the AD continuum in an Australian population
Authors: Chatterjee Pratishtha , Pedrini Steve , Doecke James D , Thota Rohith N , Villemagne Victor L , Dore Vincent , Singh Abhay K , Wang Penghao , Rainey‐Smith Stephanie , Fowler Christopher J , Taddei Kevin , Sohrabi Hamid R , Molloy Mark P , Ames David , Maruff Paul , Rowe Christopher C. , Masters Colin L. , Martins Ralph N ,   the AIBL research Group
Published: June 2023

AbstractBackgroundPlasma amyloid‐β (Aβ) 1‐42/Aβ1‐40 ratio, phosphorylated‐tau181 (p‐tau181), glial fibrillary acidic protein (GFAP) and neurofilament light (NFL) are putative blood‐based biomarkers for Alzheimer’s disease (AD). However, head‐to‐head comparisons of the afore‐mentioned biomarkers across the AD continuum are lacking.MethodPlasma Aβ1‐42, Aβ1‐40, p‐tau181, GFAP and NFL were measured using the Single Molecule Array platform and compared cross‐sectionally in models with and without AD risk factors (age, sex and APOE ε4 status) across the AD continuum in Aβ PET positive confirmed participants (CU Aβ+, n = 39; MCI Aβ+, n = 33; AD Aβ+, n = 46) and Aβ PET negative confirmed participants (CU Aβ‐, n = 81; MCI Aβ‐, n = 26) from the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL) cohort. Area under the receiver operating characteristic curves (AUCs) for predicting Aβ PET‐/+ status were compared using DeLong test. Associations between plasma biomarker levels at baseline and prospective cognitive decline (CDR‐SOB) and brain Aβ load were also assessed.ResultLower plasma Aβ1‐42/Aβ1‐40 ratio and higher p‐tau181 and GFAP were observed in preclinical AD (Aβ1‐42/Aβ1‐40 ratio: ∼19%; p‐tau181: ∼70%; GFAP: ∼52%), prodromal AD (Aβ1‐42/Aβ1‐40 ratio: ∼14%; p‐tau181: ∼69%; GFAP: ∼45%) and AD (Aβ1‐42/Aβ1‐40 ratio: ∼16%; p‐tau181: ∼91%; GFAP: ∼85%), and higher plasma NFL was observed in prodromal AD (∼27%) and AD (∼45%) (Figure 1). Based on the AUCs, p‐tau181 performed equivalent to or better than (≥) other biomarkers, in predicting Aβ PET‐/+ status across the AD continuum (p‐tau AUCs for CU Aβ‐ vs CU Aβ+ ∼81%/ MCI Aβ+ ∼86%/ AD ∼92%). A biomarker panel of Aβ1‐42/Aβ1‐40 ratio, p‐tau181 and GFAP performed ≥ the biomarkers alone in predicting Aβ PET‐/+ status across the AD continuum (biomarker panel AUCs for CU Aβ‐ vs CU Aβ+ 90%/ MCI Aβ+ 89%/ AD 96%). Higher p‐tau181 (β = 0.531, p = 3.18E‐08), GFAP (β = 0.530, p = 5.07E‐08) and NFL (β = 0.487, p = 4.76E‐06) were associated with cognitive decline prospectively and lower plasma Aβ1‐42/Aβ1‐40 ratio (β = ‐6.035, p = 1.56E‐04) and higher p‐tau181 (β = 2.823, p = 4.72E‐05) and GFAP (β = 2.075, p = 0.003) were associated with increased Aβ PET load prospectively.ConclusionThese findings suggest that plasma biomarkers are altered across the AD continuum and are associated with cognitive decline and increased brain Aβ load prospectively.
Degradation of CNTNAP2 is mediated by both macroautophagy‐lysosome pathway and ubiquitin‐proteasome pathway
Authors: Zhang Qing , Sterling Keenan , Song Weihong 
Published: June 2023

AbstractBackgroundRecent studies suggested Contactin‐associated protein‐like 2 (CNTNAP2) as a novel risk gene for Alzheimer’s disease (AD). Reduced expression levels of CNTNAP2 were found in the brains of AD patients. However, the mechanisms underlying CNTNAP2 protein degradation remain elusive.MethodHEK and N2a cells transfected with human CNTNAP2 plasmid were treated with cycloheximide, lysosome inhibitors, and proteasome inhibitors. Immunoprecipitation was performed to study the interaction between CNTNAP2 and ubiquitin. Immunofluorescent staining was performed to investigate colocalization.ResultHuman CNTNAP2 protein has a half‐life of approximately 4 hours. CNTNAP2 protein has a glycosylated mature form on the cell membrane and an intracellular immature form. Mature CNTNAP2 was increased by lysosome inhibitors in a dose‐ and time‐dependent manner, while immature CNTNAP2 was increased by proteasome inhibitors dose‐ and time‐dependently. In addition, CNTNAP2 was co‐immunoprecipitated with ubiquitin and was increased by macroautophagy inhibitor 3‐MA. Immunofluorescent staining further showed the co‐localization of CNTNAP2 with ubiquitin and lysosome marker LAMP1.ConclusionHuman CNTNAP2 is degraded via both lysosome and proteasome pathways. Dysregulation of lysosome and ubiquitin‐proteasome pathways have been implicated in AD. Therefore, the present degradation study of a risk gene may deepen the current understanding of AD pathogenesis.
Melody memory project: Increasing dementia awareness through traditional gamelan music
Authors: Setiadi Tania M , Kharismayekti Manik , Utomo Amalia Fonk , Wortmann Marc 
Published: June 2023

AbstractBackgroundGamelan, a traditional music ensemble has become the most popular traditional music played by Balinese people for decades, both as leisure and religious activities. Musical activity can enhance cognitive function. However, there are limited activities for retired musicians.AimAlzheimer Indonesia Nederland Foundation (ALZI Ned) initiated the “Melody Memory Project” which aimed to increase the quality of life and dementia awareness of the retired Balinese elderly musician through gamelan practice.MethodsA weekly gamelan practice was conducted at the Pinda village community center, Gianyar, Bali Indonesia. Each session is preceded with dementia awareness session (e.g. sharing the 10 early signs of Alzheimer’s, brain gym) by ALZI Ned volunteers. There were health screenings once every two weeks (i.e. blood pressure/ blood sugar check, hearing problem). Cognitive assessment was conducted using Mini Mental State Examination (MMSE) before and after 6 months.Thirty participants (age 58‐77 yo) were registered in this program. From July to October 2021, 6 practice sessions (each for 2 hrs), 2 performances and 3 health screening sessions were conducted in cooperation with the local government authorities. Due to Covid‐19 local lockdown, the program has been halted and will resume in February 2022. This activity has recently been approved as part of the village program and further continuity will be supported by the government. We expect to obtain more data by the time of the conference.
Neurofilament L dynamics description in the model of tauopathy
Authors: Pchelintseva Polina , Karelina Tatiana 
Published: June 2023

AbstractBackgroundNeurofilament proteins are important constituents of neuronal cytoskeleton along with microtubules. Increased concentration of neurofilament light protein in cerebrospinal fluid(CSF) and plasma is considered as a potential biomarker of axonal degeneration [1]. Together with tau, neurofilaments are contained in the neurofibrillary tangles (NFT), the biomarker of Alzheimer’s disease and other tauopathies [2]. The goal of this study was to develop a quantitative systems pharmacology (QSP) model to describe neurofilament dynamics during progression of tauopathies both in human patients and in transgenic P301L Tau mice.MethodThe quantitative model correctly describes the dynamics of neurofilament proteins during neurodegeneration processes, which include cytoskeletal degradation by calpain, proteasome, autophagy and caspase, formation of pathological aggregates, release of neurofilament proteins from degenerated axons to cerebrospinal fluid and plasma. These processes are dependent on pathological processes in tauopathy models, such as changes in protein degradation, axonal transport deficits, pathological hyperphosphorylated tau accumulation. To calibrate the model, the literature data on neurofilament concentration in brain, cerebrospinal fluid and plasma, phosphorylation and degradation level were used. Description of the processes is partially based on neuron homeostasis model developed earlier [3]. The model was validated on taupathy P301L transgenic mice, amyloid APP/PS1 mice and on Alzheimer’s disease patients’ data.ResultThe described model correctly predicts the increase of neurofilament light protein concentration in CSF and plasma both in P301L transgenic mice model of tauopathy and in human patients versus controls. Pathological changes of microtubule dynamics and cytoskeleton breakdown are also described. Model predicts the reduction of NfL concentration in CSF during potential tau targeting therapy in P301L transgenic mice and humans.ConclusionThe developed model can be helpful in simulating potential effects of therapeutics used in neurodegeneration diseases treatment.
The association among plasma p‐tau181, cognitive progression and structural brain change in early Alzheimer’s disease
Authors: Lin Yung‐Shuan 
Published: June 2023

AbstractBackgroundPlasma levels of phosphorylated tau 181 (p‐tau181) is one of the potential blood‐based biomarkers for the diagnosis of Alzheimer’s disease (AD). However, the association among plasma p‐tau181 and cognitive progression and structural brain change still needs to be investigated.MethodAD and mild cognitive impairment (MCI) patients diagnosed with a multidisciplinary consensus meeting were recruited. Cognitive function was assessed at baseline and at annual follow‐ups. Plasma p‐tau181 levels at baseline were measured using Quanterix SIMOA kits. The regional cortical thickness and volumes of baseline brain MRI were measured using the FreeSurfer image analysis suite. T‐tests and multiple regression were used for analyses. FDR tests were performed for multiple comparisons.ResultA total of 162 AD and 19 MCI patients were recruited (mean age = 77.4 ± 7.3 years, 42% male, 37% APOE ɛ4 carrier, and mean MMSE = 20 ± 5.4). There were 137 patients (75.7%) having at least two annual follow‐up and the mean follow‐up time was 2.1 ± 0.4 years. The baseline plasma p‐tau181 levels were correlated with the rates of MMSE decline per year (r = 0.284, p < 0.001). After adjusting for age, gender, education, APOE ɛ4 status and baseline MMSE, the baseline plasma p‐tau181 levels were still correlated with the yearly MMSE decline (β = 0.292, p = 0.001) and was able to predict MMSE decline>3 per year (OR = 4.03, 95% CI 1.47–11.05). There were 152 patients (135 AD and 17 MCI) with valid brain MRI. The cross‐sectional analyses with adjustments of age, gender, education and APOE ɛ4 status showed significant association between plasma p‐tau181 levels and left hippocampus volume (β = ‐0.205, p = 0.010), right hippocampus volume (β = ‐0.213, p = 0.009) and right middle temporal thickness (β = ‐0.292, p < 0.001).ConclusionHigher plasma p‐tau181 levels were associated with the faster rate of MMSE decline in AD and MCI patients as well as the decreased volume and cortical thickness of several AD‐specific brain areas. Our study suggested that the plasma p‐tau181 could be a potential biomarker for tracking cognitive decline and reflecting structural brain changes in AD and MCI patients.
Associations between modifiable and non‐modifiable risk factors and domain‐specific cognitive decline over a 17‐year period
Authors: Glans Isabelle , Nägga Katarina , Gustavsson Anna‐Märta , Stomrud Erik , Sonestedt Emily , Nilsson Peter M , Melander Olle , Hansson Oskar , Palmqvist Sebastian 
Published: June 2023

AbstractBackgroundModifiable risk factors account for 40% of worldwide dementias. However, to what extent different risk factors are associated with different types of cognitive decline remains unclear. The aim of this study was to investigate how different risk factors contribute to future decline in memory and attention/executive function, respectively.MethodBaseline examination of individuals without dementia in the prospective Swedish population‐based Malmö Diet and Cancer Study (MDCS) took place in 1991‐1996. In 2007‐2012, a randomly selected subsample was invited to a re‐examination using cognitive assessments (the Mini‐Mental State Examination [MMSE], A Quick Test of cognitive speed (AQT) and, for a sub‐population, The Montreal Cognitive Assessment (MoCA). Participants with complete data on cognitive assessments, body measurements, education and APOE genotype were included in the study (n = 2,881; n = 720 with MoCA). Linear regression models were used to examine the modifiable risk factors (hypertension, body mass index [BMI], long‐term glucose levels [HbA1c], lipid levels, physical activity and alcohol consumption) and non‐modifiable risk factor (APOE‐genotype). Follow‐up outcomes were 1) AQT‐color/form (processing speed and executive function, higher scores indicating worse function), 2) delayed recall and orientation scores from MMSE (memory function), and 3) subscores from MoCA. All models were adjusted for age, sex, education and time between baseline and cognitive assessments.ResultMedian follow‐up time was 17.3 (inter‐quartile range [IQR] 2.2) years. APOE‐e4 and higher HbA1c levels were independently associated with worse future memory function in a multivariable model (Table 1). Mean arterial blood pressure, obesity, lower HDL‐C, and higher HbA1c levels were independently associated with worse future processing speed/executive function (Table 2). Higher alcohol consumption was associated better performance in executive function (Table 2). Similar results were found using corresponding MoCA subscores (delayed recall and orientation subscores; visuospatial/executive and attention subscores).ConclusionIn this prospective, population‐based, 17‐years follow‐up study, cardiovascular risk factors in mid‐life were associated with future decline in processing speed and executive functions, while an APOE‐e4 genotype was associated with worse memory function. Alcohol consumption in mid‐life was associated with better performance in both cognitive domains. These results suggest that targeting cardiovascular risk factors in interventions may have a greater effect on future executive function than memory.
Should oral medication dose be adjusted in Alzheimer’s disease?
Authors: Pan Yijun , Sun Jiaqi , Jin Liang , Kagawa Yoshiteru , Owada Yuji , Nicolazzo Joseph 
Published: June 2023

AbstractBackgroundLittle is known about the absorption, distribution, metabolism and excretion (ADME) of both AD and non‐AD medicines currently used in people with AD. If drug disposition processes are altered in AD, individuals with AD may be at a greater risk of additional drug‐induced adverse effects, toxicity, or lack of effectiveness. Senescence Accelerated Mouse (SAMP8) is a naturally‐occurring mouse line that displays many characteristics identified in AD patients, and it is considered as a model of sporadic AD. The current study aims to assess if ADME is affected in SAMP8 mice.MethodWe utilized a proteomics approach to assess drug transporter and metabolising enzyme expression in the small intestine, liver, and kidney in SAMP8 mice. In addition, plasma concentrations of valsartan, digoxin, quetiapine (three model drugs selected based on proteome data) following oral administration in SAMP8 mice were assessed using LC‐MS. The morphological changes of small intestine, liver and kidney was evaluated using H&E staining. The intestine permeability to these drugs was studied using Ussing chamber.ResultFollowing proteomic analysis, PCA plot indicated a clear separation between SAMP8 and SAMR1 intestine, liver and kidney tissue, with global functional analysis indicated altered drug metabolism in the small intestine and liver of SAMP8 mice. The oral pharmacokinetic study revealed a significant elevation in plasma exposure (i.e. AUC) to valsartan and digoxin but reduction to quetiapine in SAMP8 mice compared to their non‐AD control mice. When interpreted together with H&E staining, ex vivo drug permeation study, and proteome data, the increase AUC to valsartan and digoxin is likely due to increased intestine leakiness. For digoxin, despite P‐glycoprotein expression was significantly increased in the small intestine, it failed to compensate the leaky gut. For quetiapine, the reduction in AUC in SAMP8 was due to increased hepatic metabolism, as increased levels of metabolites of quetiapine was detected in the plasma.ConclusionConsistent with our previous observation in APP/PS1 mice, drug disposition following oral administration was also noted in a mouse model of sporadic AD (SAMP8). Clinical study to evaluate altered ADME in people with AD should be considered to achieve precise medication use in people with AD.
Application of quantitative systems pharmacology model of Alzheimer’s disease for simulation of efficacy of tyrosine kinase inhibitors
Authors: Karelina Tatiana 
Published: June 2023

AbstractBackgroundRepurposing of tyrosine kinase inhibitors (TKI), such as nilotinib, imatinib etc. for the treatment of neurodegenerative disease is considered actively. Some tyrosine kinases which are targeted by these drugs (c‐Abl, DDR) are upregulated in neurodegenerative diseases (AD and PD). Thus, discoidin domain receptors (DDRs) are important regulators of microglial state, while c‐Abl‐kinase is a key regulator of cell stress response. TKI have been shown to boost autophagy through the interaction with these targets and to allow for the clearance of toxic tau and amyloid protein aggregates. The aim of this work was to apply the quantitative systems pharmacology (QSP) model of AD amyloid and tau pathology to translate the preclinical results for prediction of potential efficacy in humans.MethodInteraction of cell metabolism with amyloid ant tau accumulation was described earlier in QSP translational model [1]. It described dynamics of multiple biomarkers in brain, CSF and plasma. Amyloid and tau exert toxic influence on protein degradation by autophagy and proteasome and transport. In this work, c‐Abl was added as one of the drivers of AD pathology through p53 regulation, tau phosphorylation and autophagy inhibition. Data for nilotinib [2] and other TKI were used for model validation. PK data for nilotinib and other TKI were used to estimate brain concentration of the drug.ResultModel describes boosting of autophagy by about 40% [3] after c‐Abl inhibition. This leads to the reduction of amyloid and tau pathology, in correspondence to the data observed in vitro. However, for amyloid and tau transgenic mice, efficacy of c‐Abl inhibition was significantly lower assuming brain concentrations of about 1 nM, and contribution of microglial processes due to DDR1 inhibition was added. Human data on SUVR and CSF p‐tau reduction after 1 year of nilotinib treatment were described satisfactorily.ConclusionThe model can be applied to simulations of the efficacy of tyrosine kinase inhibitors in neurodegeneration diseases.[1] Karelina, T. et al, (2021). CPT: PSP, 10, 545.[2] Fowler, et al, (2019). Drugs in R and D, 19(2), 149.[3] Lonskaya, I. et al, (2013). PLoS ONE, 8(12), e83914.