bluuebunny/crossref_metadata_2025_split huggingface dataset:
The pTau interactome in sporadic Alzheimer’s disease across APOE genotypes
Authors: Thierry Manon , Ponce Jackeline , Ariza Mitchell Marta , Askenazi Manor , Faustin Arline , Leitner Dominique , Pires Geoffrey , Kanshin Evgeny , Drummond Eleanor , Ueberheide Beatrix , Wisniewski Thomas 
Published: December 2023

AbstractBackgroundAPOE polymorphism is the major genetic risk factor for sporadic Alzheimer’s disease (AD), characterized by the abnormal accumulation of β‐amyloid (Aβ) and phosphorylated Tau (pTau). Although the various ApoE isoforms are known mostly to differentially modulate Aβ aggregation and clearance, recent data support an influence of APOE genotype on pTau accumulation, which correlates better with AD symptom progression. The exact effects of ApoE isoforms on pTau metabolism, however, remain unclear.MethodThe localized proteomic methods developed in our laboratory, on post‐mortem human brain, are an ideal strategy to elucidate these aspects de novo. Co‐immunopurifications (IP) against pTau pSer396/pSer404 (PHF1) from frozen frontal cortex were combined with mass spectrometry to map out, for the first time, the pTau interactome across APOE genotypes in 10 sporadic AD cases (n = 5 APOEε3/ε3 and n = 5 APOEε4/ε4).ResultA total of 1130 and 1330 proteins were enriched in the IPPHF1 samples of the APOEε3/ε3 and APOEε4/ε4 groups (FC ≥ 1.50, IPPHF1 vs. IPIgG ctrl) and represented respectively 62% and 70% of the proteins previously identified as bona fide pTau interactors, validating our approach (Drummond et al., 2020). We identified 184 and 176 proteins as bona fide pTau interactors in the APOEε3/ε3 and APOEε4/ε4 groups (SAINT scores ≥ 0.65). Only 79 pTau interactors were common to both APOE groups and were mostly involved in proteostasis pathways (ubiquitin‐proteasome system, RNA metabolism, endo‐lysosomal trafficking). The pTau interactome of the APOEε3/ε3 group contained 17 proteins upregulated in APOEε3/ε3 cases (FC ≥ 1.50, IPPHF1 (APOEε3/ε3) vs. IPPHF1 (APOEε4/ε4))), a large majority of which being involved in RNA binding, processing or splicing (13/17 proteins, STRING analysis). The pTau interactome of the APOEε4/ε4 group contained 33 proteins upregulated in APOEε4/ε4 cases (FC ≥ 1.50, IPPHF1 (APOEε4/ε4) vs. IPPHF1 (APOEε3/ε3))), most of them being involved in synaptic transmission pathways (16/33 proteins, STRING analysis).ConclusionOur proteomic data highlighted an influence of the APOE polymorphism on pTau metabolism. These results will be validated in the human brain using histological and biochemical methods, paving the way to the identification of new therapeutic targets for AD.
Acetylcholine Receptor Agonists Exerted Neuroprotection Against Doxorubicin‐Induced Chemobrain
Authors: Ongnok Benjamin , Prathumsap Nanthip , Chunchai Titikorn , Arunsak Busarin , Pantiya Patcharapong , Chattipakorn Nipon , Chattipakorn Siriporn C 
Published: December 2023

AbstractBackgroundAlthough doxorubicin has been broadly used in treating a wide range of cancers, it frequently causes a serious neurological consequences referred to as chemobrain in cancer patients. Chemobrain shares several key pathological features with Alzheimer’s disease (AD) including neuroinflammation and Tau pathology. In addition to the inhibition of acetylcholinesterase, the activation of a7nicotinic and muscarinic acetylcholine receptors (a7nAChR and mAChR) using their agonists has been considered an effective therapeutic target against dementia. However, the benefit of intervention with nAChR and mAChR agonists in DOX‐induced chemobrain has never been investigated.MethodTwenty‐five male Wistar rats were assigned to received either (0.9% NSS) or doxorubicin (3 mg/kg; 6 doses) via intraperitoneal injection. Then, doxorubicin‐treated rats were divided into 4 intervention groups to treat with either vehicle, an a7nAChR agonist (PNU‐282987; 3 mg/kg), a mAChR agonist (bethanechol; 12 mg/kg), or a combined treatment of PNU‐282987 and bethanechol via intraperitoneal injection as a concomitant treatment with doxorubicin for a period of 30 days. After completion of the treatment paradigm, cognitive function was evaluated using the novel object location task (NOLT). The hippocampal tissues were dissected to enable further investigation.ResultSystemic administration of doxorubicin impaired long‐term cognitive function in rats as shown by a decreased preference index in the NOLT (Figure A). Furthermore, doxorubicin‐treated rats exhibited neuroinflammation in the hippocampus as demonstrated by an increase in TNF‐a protein expression (Figure B) and an alteration in microglial morphology to a pro‐inflammatory amoeboid‐liked phenotype (Figure C). Notably, injection of doxorubicin markedly reduced the phosphorylation of GSK3b at Ser9 (Figure D) and upregulated the phosphorylation of Tau at Thr181 (Figure E). Also, a decline in the dendritic spine density in the CA1 region was observed in doxorubicin‐treated rats compared with the controls (Figure F). Interestingly, all AChR agonists restored cognitive function in rats in a similar manner by attenuating neuroinflammation and Tau phosphorylation while preserving dendritic spine density (Figure A‐F).ConclusionTogether, activation of AChRs by their agonists protected against the neuropathology of doxorubicin‐induced chemobrain, indicating their potential role as a novel strategy to prevent chemobrain in patients receiving chemotherapy.
Differential cognitive and functional performance in racial and ethnic groups when stratified by consensus diagnosis: Findings from the NACC dataset
Authors: Pilonieta Giovanna , Geldmacher David S. 
Published: December 2023

AbstractBackgroundRecent studies comparing non‐Hispanic Whites (NHW) to non‐Hispanic Blacks (NHB) with cognitive impairment found differences in associations between neuropsychological performance and ratings of daily function. Evaluating differences in these relationships by race and ethnicity may be important to interpreting disparities in clinical research outcomes for people with Alzheimer’s disease and related disorders.MethodWe compared demographic and performance variables across consensus diagnostic groups (CN, impaired‐not‐MCI, MCI, or dementia) at baseline in NHB (N = 1,609; 15.62%), Hispanic (N = 706, 6.86%) and NHW (N = 7,984,77.52%) adults in the NACC cohort, using data from Version 3.0 of the UDS, collected at the 37 NIA‐ADRCs from March 2015 to June 2022 (alz.washington.edu). Spearman’s rank correlation examined the associations between CDR‐GS, MoCA, and FAS scores by race and ethnicity within consensus diagnostic groups.ResultAmong 10,299 participants, 5,964 (57.91%) were women, mean age at baseline was 69.34 (±9.80), and mean education was 16.02 (±2.81) years. Significant differences in gender proportions between race and ethnic groups were observed. NHB had a higher proportion of female participants (χ2 = 233.39 <.0001); and reported the lowest FAS scores (Z = 200.67, P < .001). Hispanic participants had completed fewer years of education (Z = 3999.92, p = <.0001); and reported higher depressive symptoms (Z = 39.81, p = <.0001). Significant correlations were observed between all assessments by race and ethnic groups. When stratified by consensus group, in the NHW and NHB subsamples, CDR and MoCA scores associations were significant except in the “Impaired not MCI” groups. In the Hispanic subsample, significant correlations were only observed in the dementia group. After adjusting for the effects of GDS scores, correlations retained significance except in the NHB MCI group. Significant correlations between CDR and FAS scores were observed except in the “Impaired not MCI” group in the Hispanic subsample. These associations were retained after controlling for depressive symptoms except in the Hispanic MCI group.ConclusionAssociations between cognitive and functional performance measures varied by racial and ethnic group when stratified by consensus groups in the NACC dataset. Specific ethnic, racial and socio‐cultural factors, as well as implicit/explicit examiner bias that may drive differences in performance warrant further study.
World Alzheimer Report 2022 ‐ How strong are global health systems: Lessons learned and case studies from across the globe
Authors: Weidner Wendy S 
Published: December 2023

AbstractBackgroundEach year Alzheimer’s Disease International (ADI) publishes a World Alzheimer Report, a comprehensive source of global health and socioeconomic information on dementia. The theme of ADI’s 2022 World Alzheimer Report was post‐diagnostic support ‐ aiming to provide a global perspective on treatment, care and support models, barriers to access and areas of best practice, and the role of policy in strengthening health systems.MethodWe conducted 3 global surveys; with people living with dementia in 41 countries, informal carers across 68 countries, and health & long‐term care professionals in 69 countries. 215 global experts contributed 119 expert essay and case studies. We also highlighted commentary and perspectives from people living with dementia and carers.ResultKey themes include a lack of access to post‐diagnostic support which impacted well‐being and health outcomes of families and professionals. 45% of people with dementia in lower‐ and middle‐income countries (LMICs) and 37% in high‐income countries (HICs) said they had not been offered support after their diagnosis. 66% of people with dementia did not have a personalised care plan. 54% of informal carers and 37% of professionals reported being stressed often or all the time. Case studies indicated stigma remains a major barrier and that care pathways are not clear or integrated – and often not culturally appropriate to ensure proper access to treatment and care. Carers and professionals expressed the need for better education and training. There were also areas of best practice to share.ConclusionHealth and long‐term care systems must be strengthened in order to provide treatment, care and support of people living with dementia and their carers. National dementia plans provide a framework, but don’t always guarantee access. Stigma must be challenged and person‐centred care that is culturally appropriate, gender inclusive, coordinated and accessible must become the norm. Support for carers must be prioritised and education and training must be improved and expanded. There are radical differences both between and within countries in education, acculturation, access to services, family responsibilities, and ability to mobilise resources. Understanding how these differences shape dementia care practice is crucial for developing appropriate dementia care policies.
The Availability and Use of Anti‐Dementia Drugs: An International Survey
Authors: Tang Eugene Yee Hing , Weidner Wendy S , Robinson Louise 
Published: December 2023

AbstractBackgroundThere is currently no cure for dementia and few medications to help with the symptoms of dementia. However, there are acetylcholinesterase inhibitors, such as Donepezil, Rivastigmine and Galantamine, which are available to people with dementia but there is potential for inequality in their availability globally. A potential reason for this is that there is no anti dementia medication included in the World Health Organisation’s Essential Medicine List which potentially creates inequalities of access to evidence based care.MethodIn collaboration with Alzheimer’s Disease International, a global electronic survey was sent to explore the international use of cholinesterase inhibitors. Here we focus on donepezil as the most commonly prescribed first line anti‐dementia medicationResultIn total we received 73 responses from 39 different countries with all continents represented. Respondents included psychiatrists (n = 21), neurologists (n = 18), physicians (n = 8), geriatricians (n = 7), nurses (n = 4), general practitioners (n = 2), a psychologist (n = 1) and a pharmacist (n = 1). Respondents from all levels of income were included. The majority of participants (n = 66, 90.4%) did prescribe anti‐dementia medications and for the majority of these respondents (n = 50, 68.5%), Donepezil was the first line anti‐dementia medication. Nearly half of all participants (n = 31, 42.5%) reported that they would prescribe anti‐psychotic medication for dementia if they could not access anti‐dementia medication. The efficacy of anti‐dementia drugs was mainly determined by family or carer reports (n = 64, 87.7%) followed by cognitive assessment (n = 54, 74%) and then the patient’s subjective account (n = 50, 68.5%). Participants when asked about their criteria for stopping anti‐dementia medications mainly reported that it was side/adverse effects and how globally/holistically effective the medication was rather than cognitive assessment alone.ConclusionThere are concerns that without access to commonly prescribed anti‐dementia drugs, this may introduce harms to people with dementia as they could be prescribed antipsychotics instead. Emphasis should be given to find ways for all people living with dementia, regardless of geographic or socioeconomic status, to access effective and safe anti‐dementia drugs such as donepezil.
Association between lipopolysaccharide, immune biomarkers and cerebral amyloid‐beta deposition in older adults with mild cognitive impairment & major depressive disorder
Authors: Feng Vivian , Lanctôt Krista L. , Herrmann Nathan , Kiss Alex , Fischer Corinne E. , Flint Alastair , Mah Linda , Mulsant Benoit H. , Pollock Bruce G. , Rajji Tarek K. , Tumati Shankar , Verhoeff Nicolaas Paul L.G. , Graff‐Guerrero Ariel , Gallagher Damien 
Published: December 2023

AbstractBackgroundInflammatory activation and increased immune response to lipopolysaccharide (LPS, a cell wall component of gut bacteria) is observed in both depression and cognitive decline. Depression is associated with accelerated cognitive decline, and persistent inflammatory activation may link depression and cognitive decline in later life. We determined if LPS is associated with inflammatory activation and cerebral deposition of amyloid‐beta (Abeta) in older adults with Mild Cognitive Impairment (MCI) and/or remitted Major Depressive Disorder (rMDD).MethodSerum samples of LPS, LPS‐binding protein (LBP, which enhances the inflammatory response to LPS), and inflammatory markers (Interleukin 6 [Il‐6], C‐reactive protein [CRP], Monocyte Chemoattractant Protein 1 [MCP‐1]) were measured using ELISA. Abeta deposition was measured using PET neuroimaging using [11C]‐PIB radiotracer. Global amyloid burden was calculated using a composite Standardized Uptake Value Ratio (SUVR) score with the cerebellar cortex as the reference region. Multivariable linear regression analyses, adjusting for significant demographic and genetic variables, were conducted to determine if LPS, LBP, inflammatory biomarkers, MCI and rMDD were independently associated with global cerebral deposition of Abeta.ResultAmong 155 study participants (79 with MCI only, 54 with both MCI and rMDD, 22 with rMDD only) we found a median Abeta SUVR of 1.41 (IQR 0.57). There was no significant association between LPS (beta ‐1.28, 95% CI ‐11.69, 9.13, p = 0.8) or LBP (beta ‐0.02, 95% CI ‐0.05, 0.006, p = 0.12) and global deposition of Abeta, following adjustment for age, sex, and APOE genotype. LBP was positively correlated with inflammatory biomarkers: CRP (r = 0.49, p < 0.001) and IL‐6 (r = 0.21, p = 0.01) but no inflammatory biomarker was significantly associated with Abeta deposition. Having a history of rMDD (beta ‐0.09, 95% CI ‐0.26, 0.08, p = 0.28) or MCI alone (beta ‐0.11, 95% CI ‐0.47, 0.049, p = 0.11) was not associated with deposition of Abeta.ConclusionIn this cross‐sectional analysis, we did not find an association between LPS/LBP, immune biomarkers, remitted MDD and global deposition of Abeta. Future analyses should examine the longitudinal relationships between peripheral and central biomarkers of immune activation with cerebral Abeta deposition in patients and controls.
MRI of Neuroinflammation Using a Folate Receptor β‐Targeted Nanoparticle Contrast Agent
Authors: Badachhape Andrew A , Parekh Parag A , Bhandari Prajwal , Menon Renuka , Bhavane Rohan , Srivastava Mayank , Tanifum Eric , Annapragada Ananth , Ghaghada Ketan 
Published: December 2023

AbstractBackgroundNeuroinflammation plays an important role in Alzheimer’s disease (AD) pathogenesis and disease progression leading to cognitive decline. Current efforts for non‐invasive imaging of neuroinflammation are based on using PET radiotracers. An MRI‐based contrast agent for imaging of neuroinflammation would be highly desirable due to widespread use of MRI in imaging of neurological disorders. Folate receptor β, a marker of pro‐inflammatory phenotype, is expressed in microglia. In this work, we investigated a folate‐targeted liposomal‐Gd contrast agent for molecular MRI of neuroinflammation in mouse models of AD.Method
In vivo studies were performed in APP/PSEN1 mice, a model of amyloid pathology, and P301S mice, a model of tau pathology. Transgenic mice and wild‐type (WT) littermates (n = 6/genotype, 24 total) underwent pre‐contrast MRI using T1‐weighted spin echo sequences with 160 µm in‐plane resolution and 1.2 mm slice thickness. Delayed MRI was performed 4 days after systemic administration of a high T1 relaxivity liposomal‐Gd contrast agent bearing folic acid molecules. Animals were euthanized after the final imaging session for microscopic analysis of brain. Signal changes between pre‐contrast and post‐contrast MRI were determined in target regions of the brain.ResultTransgenic APP/PSEN1 and P301S mice demonstrated signal enhancement in post‐contrast T1w‐MRI compared to pre‐contrast MRI. In comparison, WT control mice did not show signal enhancement in post‐contrast MRI. APP/PSEN1 transgenic mice exhibited greater relative enhancement (+5.9%, p<0.005) and lower inter‐subject variance than P301S mice (3.9%, p<0.05). Immunofluorescence analysis demonstrated higher burden of activated microglia in brains of transgenic mice compared to WT control mice.ConclusionA folate receptor β‐targeted liposomal‐Gd contrast agent enables in vivo MRI of neuroinflammation in mouse models of Alzheimer’s disease. Such imaging agents could play an important role in monitoring of Alzheimer’s disease progression leading to cognitive decline and evaluation of therapies that target neuroinflammation.
Multilayer network analysis of Alzheimer disease links multiscale paths to the phenotype
Authors: Lara‐Simon Elena , Garcia‐Ojalvo Jordi , Villoslada Pablo 
Published: December 2023

AbstractBackgroundAlzheimer Disease (AD) cover a wide range of biological scales, from genes and proteins to cells and tissues, up to behavior. However, how these scales, the endotype, interact with one another to define the clinical phenotype remains poorly understood.MethodsHere we conducted a systems biology study of AD, based on multilayer network analysis and deep phenotyping that integrates genomics, CSF biomarkers, tau and amyloid‐beta PET, brain MRI, risk factors and clinical data, obtained from the ADNI collaboration. Multilayer networks were constructed using mutual information, a nonlinear measure of correlation, at each layer and between layers. Boolean simulations identified paths within and among all layers through which dynamic information is transmitted. Multiple linear regression was then used to predict the phenotype (clinical or imaging variables) from paths within the genetic, molecular and imaging layers.Resultsthe most prominent paths that significantly predicted the phenotype included hippocampus atrophy and tau levels from CSF and PET. Our results thus show that integrating the flow of information across biological scales reveals relevant paths for AD.Conclusionpaths identified by multilayer networks can be pursued as biomarkers or new therapeutic targets.
Cognitive rehabilitation protocol for people with Parkinson’s disease and cognitive symptoms
Authors: Alves Larissa Scoralich , Shigaeff Nadia ,   Interdisciplinary Group for Research in Neuropsychology and Gerontology
Published: December 2023

AbstractBackgroundParkinson’s disease is the second most common neurodegenerative disease and affects the lives of people around the world. Approximately 30% to 40% of people with Parkinson’s disease also develop cognitive symptoms. Most notably impairments are observed in executive function, visuospatial abilities and memory are observed. An effective alternative to treat these symptoms is cognitive rehabilitation, but there are still too few publications presenting cognitive rehabilitation protocols for this population. The aim of the present study was to develop a rehabilitation protocol focused on cognitive symptoms in people with Parkinson’s disease.MethodsA free search was conducted for publications on the topic of cognitive rehabilitation for people with Parkinson’s disease and cognitive symptoms. From the reading of these studies, a set of exercises aimed at training executive functions, visuospatial skills and memory was then developed.ResultThe elaborated protocol includes nine sessions of 60 minutes each. It should be used by appropriately trained healthcare professionals. The protocol consists of activities using paper and pencil, as essential materials, which means low application costs. The protocol includes activities aimed at training visuospatial skills (Figure 1), memory (Figure 2) and executive functions (working memory, reasoning, mental flexibility, problem solving and planning) (Figure 3) with an increasing level of difficulty.ConclusionThis study presents the formulation and scientific dissemination of a protocol that is easy to use, inexpensive and effective in the rehabilitation of these individuals.References: Aarsland, D., Batzu, L., Halliday, G. M., Geurtsen, G. J., Ballard, C., Ray Chaudhuri, K., & Weintraub, D. (2021). Parkinson disease‐associated cognitive impairment. Nature Reviews. Disease Primers, 7(1), 47. https://doi.org/10.1038/s41572‐021‐00280‐3
Balestrino, R., & Schapira, A. H. V. (2020). Parkinson disease. European Journal of Neurology, 27(1), 27‐42. https://doi.org/10.1111/ene.14108