bluuebunny/crossref_metadata_2025_split huggingface dataset:
Probabilistic computer‐aided diagnosis of Alzheimer’s disease and frontotemporal dementia based on MRI and biochemical markers
Authors: Pérez‐Millan Agnès , Thirion Bertrand , Borrego‐Écija Sergi , Contador José , Juncà‐Parella Jordi , Bosch Beatriz , Falgàs Neus , Antonell Anna , Ruiz‐García Raquel , Naranjo Laura , Balasa Mircea , Lladó Albert , Sanchez‐Valle Raquel , Sala‐Llonch Roser 
Published: December 2023

AbstractBackgroundOne of the clinical problems for biomarkers' clinical use is the ability to differentiate between Alzheimer’s disease (AD), frontotemporal dementia (FTD), and healthy subjects (CTR). This clearly challenges diagnosis and prognosis. We implemented a ML algorithm that provides individual probabilistic diagnoses for these dementias based on magnetic resonance imaging (MRI) and we correlated the results with biochemical markers.MethodWe studied 3T‐T1w MRI of 432 subjects. A subset of these participants had cerebrospinal fluid (CSF) and plasma biomarkers (Table 1). We obtained regional subcortical gray matter volumes and cortical thickness measures using Freesurfer. We implemented a calibrated classifier with a Support Vector Machine with only the MRI data. We tested paired‐wise classification and classification across the 3 groups. We obtained individual probabilities associated with group correspondence. We studied the correlation between these probabilities and CSF and plasma biomarkers. For this, we subdivided the groups into true‐group (subjects with classification according to clinical diagnosis) and false‐group (subjects which did not coincide with clinical diagnosis). Finally, we implemented a permutation test to find the importance of each region in the classification.ResultWe obtained accuracies of 90.7 ± 6.7% in the CTR vs AD classification, 88.6 ± 4.5% for CTR vs FTD, 79.3 ± 8.8% for AD vs FTD, and 79.9 ± 5.1% when discriminating the 3 groups. We obtained a significant positive correlation for plasma p‐tau181 for the false‐AD in the comparison AD vs CTR (Figure 1). The correlation of the false‐CTR was significantly positive for the CSF and plasma NfL. Finally, in the AD vs FTD, the true‐FTD had a significant negative correlation with CSF NfL. The other biochemical biomarkers did not provide additional information. The most important regions for classification are shown in Figure 2.ConclusionThe ML algorithm gave high accuracies. Within wrongly classified AD patients, probabilities correlated positively with plasma p‐tau181, suggesting hidden pathological processes associated with subjects clinically classified as CTR. Finally, the group probability within well‐classified FTD patients in comparison with AD negatively correlated with CSF NfL. We suggest that this approach can be used as a tool to try to develop personalized diagnoses.
The need for a tailored National Dementia Plan in Ethiopia: a call for action
Authors: Ayele Biniyam A. 
Published: December 2023

AbstractBackgroundGlobally, a rapid demographic transition is occurring with a significant increment in the proportion of older individuals. For the first time in history, individuals aged 65 and above outnumber that of children under five years of age.MethodA mini review was conducted to assess the burden and types of dementia risk factors in Ethiopia.ResultsIn Ethiopia, the life expectancy has shown dramatic improvements in the past few decades and is expected to reach 74 years by mid‐century. Older age is considered the most important non‐modifiable risk factor for dementia. Likewise, other modifiable diseases such as infectious diseases, non‐communicable diseases, particularly cardiovascular diseases, and traumatic brain injuries are associated with dementia. Despite, the high prevalence of dementia risk factors and impending economic and health impact from dementia, no country in the sub‐Saharan Africa (SSA), including Ethiopia, has developed a standalone national dementia strategic plan to guide the overall effort to improve dementia care in the country. It is vital to design and develop a national dementia plan in line with a framework outlined by the 2017 World Health Organization (WHO) global action plan. The health, social, & economic burden from dementia is expected to be high to the developing countries such as Ethiopia unless clear prevention and management strategies are designed at a national level to cascade the care to the primary care level. The planned strategic policy may focus on improving the knowledge and skills of health care professionals. Translation and cultural adaptation of cognitive, functional, and behavioral assessment batteries is of paramount importance in improving the diagnostic accuracy along with availability of advanced imaging, biomarkers, and dementia treatment.ConclusionIn summary, this call for action paper recommends developing a tailored stand‐alone or an integrated national dementia prevention and care plan which is in congruent with the seven WHO global action plan.
African star apple leaf extract attenuates hyperglycemic mediated cognitive impairment and neurodegeneration in Streptozotocin induced diabetic rats
Authors: Idaguko Chika Anna , Memudu Adejoke Elizabeth , Unit Neuroscience Research , Uzairue Anatomy Department Edo State University 
Published: December 2023

AbstractBackgroundDiabetes is a chronic disease affecting millions of people. It is associated dementia. Over the years the use of natural product such African star apple (Chrysophyllum albidum) with strong antioxidant activities has been study for treating of diabetes. This study is carried out to evaluate African star apple possible anti‐diabetic, neuroprotective and effects on neuro‐ cognition in streptozotocin (STZ)‐induced diabetic rats model using Morris water maze to evaluate spatial working memory, Malondialdehyde (MDA) as biomarker for tissue damage while superoxide dismutase (SOD) and catalase (CAT) as antioxidant enzyme markers assayed using spectrophotometer.MethodsThirty male Sprague‐Dawley (S‐D) rats used were divided into six groups (n = 5) viz: A‐ control, B‐ Diabetic model (50mg/kg bw STZ), C‐ Diabetic model +2mg/kg bw glibenclamide, D‐Diabetic model +125mg/kg bw African star apple leaf extract, STZ+250mg/kg bw African star apple leaf extract and STZ+500mg/kg bw African star apple leaf extract. Treatment was for 21 days via oral administration. The prefrontal cortices excised were processed for histological examination.ResultsDiabetic model was characterized by a decline in final body weight, spatial memory, antioxidants enzymes (SOD and CAT) with an elevation in MDA and blood glucose levels in addition to marked disruption of the neurons in the prefrontal cortex (PFC) characterized by presence of pkynotic and necrotic pyramidal neurons of the PFC. Furthermore, African star apple leaf extract significantly increased superoxide dismutase (SOD), catalase (CAT), and cognitive functions in a dose‐dependent manner (P>0.05) as compared to the diabetic model.ConclusionDiabetes can result in cognitive impairment via hyperglycemic mediated neurodegeneration which is attenuated by African star apple leaf extract ability to increase antioxidant enzymes, reduce neuro‐inflammation thereby improving neuronal function for memory and cognition.
Investigating Selective Neuronal Vulnerability in Alzheimer’s and Parkinson’s Disease with Induced Pluripotent Stem Cells and Pre‐formed Fibrils
Authors: Abey Ajantha S , Ng Bryan , Heon‐Roberts Rachel , Carlyle Becky C. , Bengoa‐Vergniory Nora , Wade‐Martins Richard 
Published: December 2023

AbstractBackgroundAlzheimer’s and Parkinson’s disease feature progressive neurodegeneration associated with the accumulation of protein aggregates in a remarkably regionally selective manner. The cortical neurons that are relatively vulnerable in Alzheimer’s Disease (AD) are only affected late in Parkinson’s Disease (PD), whereas midbrain dopaminergic neurons exhibit striking vulnerability in PD, but are relatively spared in AD. Rodent and human post mortem studies have posited a role for cell autonomous mechanisms such as autophagy or calcium buffering deficits driving this, but having a live human cell model that can replicate the phenomenon of selective neuronal vulnerability can help to better determine common and contrasting disease mechanisms and identify therapeutic targets.MethodHere, we used induced pluripotent stem cell (iPSC) derived neurons as they offer a rare opportunity to examine cell autonomous vulnerability in live human cells. iPSCs from patients with AD‐related presenilin‐1 mutations (n = 3), PD‐related leucine rich repeat kinase 2 mutations (G2019S n = 3, R1441C n = 3), and isogenic corrected (n = 3) and healthy controls (n = 4) have been differentiated into both cortical neurons and midbrain dopaminergic neurons to enable comparison of vulnerability phenotypes in different neuronal subtypes from the same patient.ResultAD cortical neurons insulted with alpha‐synuclein pre‐formed fibrils (PFFs) have impaired neurite outgrowth, reduced synaptic density, and extensive aggregate formation. Meanwhile, PFF insulted PD cortical neurons exhibit normal neurite outgrowth and relatively little aggregation, whereas PD dopamine neurons readily produce aggregates.ConclusionThese preliminary results show relative vulnerability of AD and resilience of PD cortical neurons to alpha synuclein aggregates for the first time. This suggests the selective vulnerability to proteinopathy exhibited in these diseases may be replicated by the iPSC neuronal model, and additionally supports the notion that cell intrinsic factors may partly determine this vulnerability.
From diagnosis to end of life: Evolving training and support needs of caregivers of seniors living with Alzheimer’s disease
Authors: Dubé Véronique , Gaied Nouha Ben , Caron Laurence , Thorn Karine 
Published: December 2023

AbstractBackgroundNo one is prepared for a diagnosis of Alzheimer’s disease, either the person diagnosed or the caregiver. In order to cope with the disease and support their loved ones, caregivers express numerous needs for training and support. But what are these needs at each stage of the disease?MethodAs part of an action‐research project, 8 focus groups and 28 individual interviews held on the Zoom platform were used to collect the training and support needs of caregivers of seniors living with Alzheimer’s disease in the province of Quebec, Canada. A content analysis inspired by the approach proposed by Miles and Huberman was conducted.ResultA total of 52 caregivers, aged between 33 and 85 years old (mean = 61,88; SD = 12,42), identified training and support needs: a) surrounding the diagnosis; b) during the assistance of the loved one at home, with and without cohabitation; c) during accommodation in a long‐term care facility and; d) following the death of the person being cared for.ConclusionCaregivers have training and support needs that evolve according to the trajectory of their loved one’s Alzheimer’s disease. Interventions tailored and personalized to their pathway are necessary to support them in this long trajectory of caregiving.
Evaluation of the major pathological hallmarks in the humanized APPSAA knock‐in mouse model, in response to drug treatment
Authors: Carmans Sofie , Dejonckheere Wannes , Cornelissen Tom 
Published: December 2023

AbstractBackgroundTo improve clinical translatability of non‐clinical in‐vivo Alzheimer’s disease (AD) models, a humanized APP knock‐in mouse model (APPSAA) was recently created (Xia, D. et al., 2022). This homozygous APP knock‐in model carries a humanized Aβ1‐42 sequence and 3 disease causing mutations (Swedish, Arctic, and Austrian). These modifications lead to increased Aβ42/40 ratios in AD relevant tissues, resulting in an age‐dependent amyloid deposition in the brain. The highest plaque density is found in cortical and hippocampal regions. APPSAA mice also display clear neuroinflammation and an increase in fluid biomarkers of neurodegeneration (NF‐L and total Tau in CSF). Here we assess the value of this model as a tool for non‐clinical efficacy studies of experimental drugs with diverse mechanisms of action to facilitate the development of novel AD therapeutics.MethodAPPSAA mice and WT controls were aged and sacrificed at various time points. In addition, APPSAA mice were treated with drug or vehicle, on a daily basis for 3 months from the age of 3 months onward. The major pathological hallmarks of this model and the treatment effect will be investigated with biochemical and immunohistological assays. Monthly blood sampling will allow the follow up of pathology progression in individual mice by assessing plasma‐based biomarkers. Since APPSAA mice lack an obvious behavioral phenotype, synaptic plasticity will be investigated to serve as a functional readout.ResultThe treatment is well tolerated by the mice in study. Body weights were not altered between compound and vehicle dosing during the first 2 months of the treatment. Data on pathological outcomes and synaptic plasticity are not yet available but will be shared during the presentation.ConclusionA humanized knock‐in model for AD is hypothesized to be a broadly applicable tool to investigate disease‐modifying drugs with diverse modes of actions.
Brain structural changes associated with Apoe2 in 3041 subjects from the UK Biobank
Authors: Rajagopalan Priya 
Published: December 2023

AbstractBackgroundCommon variants in the apolipoprotein E gene are the greatest known source of genetic risk for late‐onset Alzheimer’s disease (AD). Carriers of one or more copies of the ε4 allele are more likely to develop AD, but carriers of the ε2 allele have a lower incidence of AD (1,2,3). Mechanisms underlying this effect are not fully understood, motivating comparisons of brain imaging data in people carrying different APOE genotypes. Prior voxel‐based morphometry (VBM) studies have reported gray matter alterations in medial temporal and precuneal regions in people with AD (4) and in healthy APOE ε4 carriers (5) but less is known about the effect of APOE ε2 compared to ε4 carrier status on gray matter volume in elderly adults.MethodThe ENIGMA voxel based morphometry (VBM; https://sites.google.com/view/enigmavbm; 6) pipeline was used to perform a large‐scale analysis of 3D T1‐weighted brain MRI data from 3,041 older adult participants (45.5% female; 72.0 (6.2SD) years old) from the UK Biobank (UKBB). Subject demographics are outlined in Table 1. The statistical relationship between voxel‐wise brain gray and white matter volumes and APOE2 genotype was assessed using linear mixed models, adjusting for age, sex, intracranial volume, population structure, and scan site. All associations were corrected for multiple comparisons using the standard false discovery rate method.ResultSignificantly larger volumes were detected in subcortical gray and deep white matter regions of the brain for the APOE ε2 genotype, while smaller volumes were noted in the peripheral cortex and juxtacortical white matter, when controlling for FDR at q = 0.05 (gray matter critical P‐value 0.008 and white matter critical P‐value 0.01). Significance values and brain maps for the APOE ε2 genotype are outlined in Figure 1 and Figure 2.ConclusionWe identified alterations in gray and white matter volumes related to presence of at least one APOE2 allele. These results support prior reports that elderly adult carriers of the APOE2 haplotype have, on average, neurostructural alterations in gray matter architecture, even after adjusting for the effects of ancestry and age.
Repurposing anti‐diabetic drugs for neuroprotection
Authors: Harding Edward C 
Published: December 2023

AbstractBackgroundMidlife obesity and diabetes are dramatically increasing in prevalence and are significant risk factors for dementia, but the mechanism linking these diseases is largely unknown. We believe that targeting this shared mechanism may represent an untapped therapeutic strategy to slow neurodegenerationMethodTo test this hypothesis, we are utilising a mouse model of prion disease (RML scrapie) that faithfully recapitulates many aspects of the neurodegenerative process common to multiple forms of dementia, including endoplasmic reticulum stress, synaptic loss, and cell death but without disease‐specific overexpression or introducing familial mutations. In these mice, worsening behavioural and motor signs can be quantified using machine learning based pose‐estimation and memory phenotyping. This also forms the basis of a new automated pipeline for screening potential neuroprotective compounds from the pool of previously approved drugs. We aim to understand the potential for repurposing anti‐diabetic and other compounds for dementia risk reduction.ResultIn preliminary experiments, treatment with the commonly used anti‐diabetic drug Metformin reduced the severity of motor disruption in prion‐inoculated mice fed either a control or a high‐fat diet, with evidence of prolonged survival. Furthermore, an unbiased query of the Connectivity Map database predicted numerous related drugs classes, used to treat metabolic disease, that reverse transcriptional signatures observed in the brains of prion‐inoculated mice.ConclusionTogether these suggest a possible mechanistic convergence of anti‐diabetic compounds on a neuroprotective mechanism. To gain insight into the molecular mechanisms that might be shared in the brain between metabolic and neurodegenerative disease, we are now using multi‐omics approaches to characterise the signatures of drugs that delay prion signs. We aim to improve the prediction and validation of compounds for repurposing in dementia and identify the patient groups most likely to benefit from early intervention.
The role of Kir6.2‐KATP channels in modulating sleep, brain metabolism, and neuronal excitability in AD
Authors: Constnantino Nicholas J , Carroll Caitlin M , Irmen Riley E , Snipes James A , Gould Robert W , Macauley Shannon L 
Published: December 2023

AbstractBackgroundATP sensitive potassium (KATP) channels act as metabolic sensors to regulate cellular excitability. We recently demonstrated that neuronal KATP channels are composed of Kir6.2 subunits, are highly expressed on excitatory and inhibitory neurons, and are differentially expressed in the Alzheimer’s brain (Grizzanti et al. 2022). Mechanistically, we demonstrated that KATP channels couple changes in cerebral metabolism with neuronal activity and amyloid‐beta (Aβ) release, suggesting a role for KATP channels in Alzheimer’s disease. Here, we extend these studies to explore how KATP channels contribute to excitatory/inhibitory (E/I) balance in the brain to impact sleep and Alzheimer’s pathology. How KATP channels coordinate sleep, metabolism, and neuronal activity was examined using the Kir6.2‐/‐ mice, a mouse model lacking neuronal KATP channel activity.MethodIntracranial biosensors measuring interstitial fluid (ISF) glucose and ISF lactate concurrent with EEG/EMGs were implanted into the hippocampus of wild type (WT) and Kir6.2‐/‐ mice. Diurnal rhythms of ISF glucose, ISF lactate, and EEG/EMG were recorded for 72 hours. Mice were injected with saline, glucose, or glibenclamide to determine effects of metabolic challenges on ISF glucose, ISF lactate, and sleep/wake cycles. Quantitative EEG analysis and sleep staging was performed and correlated with ISF glucose and lactate over the 24 hour light/dark period.ResultWildtype mice have diurnal fluctuations in ISF glucose and lactate, with increases during the dark cycle when mice are awake and decreases in the light cycle when mice are asleep. In Kir6.2‐/‐ mice lacking neuronal KATP channel activity, diurnal fluctuations in ISF glucose and lactate are lost. Kir6.2‐/‐ mice spent more time in NREM sleep and less time awake than WT mice. Furthermore, reductions in absolute EEG power suggest changes in the brain’s E/I balance. Lastly, Kir6.2‐/‐ mice were unresponsive to metabolic challenges, demonstrating that ISF lactate, a metabolic trigger for wakefulness, is controlled by KATP channels.ConclusionWe describe the role of neuronal KATP channels as metabolic sensors in coordinating sleep/wake architecture in mice. Ongoing studies are exploring the impact of KATP channels on sleep and brain excitability in AD.
PET Imaging of Rho‐Associated Protein Kinase 2 in A Mouse Model of Alzheimer’s Disease
Authors: Zheng Chao , Nicholson LaShae , Chen Baosheng , Toyonaga Takuya , Liu Michael , Strittmatter Stephen M , Carson Richard E. , Huang Yiyun , Cai Zhengxin 
Published: December 2023

AbstractBackgroundRho‐associated protein kinase 2 (ROCK2) activity is implicated in Alzheimer’s disease (AD) and other central nervous system (CNS) disorders 1. In this study, we investigated the relative expression levels of ROCK2 in APP/PS1 transgenic AD mice and age‐matched wild‐type (WT) C57BL/6J mice using the ROCK2‐specific PET radioligand, [11C]ROCK201.MethodsThe ROCK2 tracer [11C]ROCK201 was synthesized according to the previously published procedure 2. PET scans were performed in a Focus‐220 scanner on 12‐month‐old APP/PS1 transgenic mice (n = 8) and WT controls (n = 5). Self‐blocking scans were performed 10 min post injection (p.i.) of the unlabeled ROCK201 (i.v., 3.3 mg/kg). Regions of interest (ROIs) were extracted from the Ma‐Benveniste‐Mirrione mouse brain atlas and regional time‐activity curves (TACs) were obtained by applying template ROIs to the averaged PET images (0 to 60 min p.i.). Distribution volume ratio (DVR) values were generated using the simplified reference tissue model 2 (SRTM2) on the 60‐min dynamic PET imaging data, with cerebellum (CB) as the reference region. ROCK2 protein expression levels were assessed immunohistochemically in brain tissues of 12‐month‐old APP/PS1 (N = 3) and WT (N = 3) mice.ResultsUptake of [11C]ROCK201 was observed throughout the mouse brain, with peak SUV of 2.6. TACs were consistently higher in the hippocampus of APP/PS1 mice than controls, within 20 min p.i. (Fig. 1a). Reduced uptake was observed in self‐blocking studies, indicating specific binding of [11C]ROCK201 in the rodent brain (Fig. 1a). TACs were well fitted with SRTM2. Compared with age‐matched WT controls, the DVR(CB) in the hippocampus of APP/PS1 mice was 9.3% higher than that of WT mice (p = 0.03) (Fig. 1b). Consistent with PET imaging results, ROCK2 protein expression is elevated by 49±2% in the CA1 of APP/PS1 mice compared to that of WT mice (Fig. 1c).ConclusionsWe demonstrated the uptake and detection sensitivity of the radioligand [11C]ROCK201 in the mouse brain, with higher tracer uptake in the hippocampi of APP/PS1 mice as compared to WT mice, supporting the use of [11C]ROCK201 in preclinical AD drug discovery and development.