bluuebunny/crossref_metadata_2025_split huggingface dataset:
The impact of young controls in the detection of tau load in cognitively impaired and asymptomatic elderly
Authors: Macedo Arthur C. , Tissot Cécile , Therriault Joseph , Rahmouni Nesrine , Servaes Stijn , Arias Jaime Fernandez , Wang Yi‐Ting , Aumont Etienne , Socualaya Kely Quispialaya , Lussier Firoza Z , Stevenson Jenna , Nazneen Tahnia , Hosseini Seyyed Ali , Karikari Thomas K , Benedet Andrea Lessa , Ashton Nicholas J. , Zetterberg Henrik , Blennow Kaj , Pascoal Tharick A. , Rosa‐Neto Pedro 
Published: December 2023

AbstractBackgroundNeuropathological observations report incipient tau accumulation in the human brain starting in the third decade of life, with the proportion of individuals with some degree of tau deposition increasing with age. Given the high prevalence of tau positive cases among cognitively unimpaired (CU) older adults, one may question whether these individuals constitute an ideal reference group when assessing tau load in symptomatic population. Here, we compare tau biomarker levels of participants with Alzheimer’s disease (AD) and CU of different ages.MethodWe evaluated 35 CU young individuals (aged <26 years) and 124 amyloid‐beta (Aβ)‐ elderly, considered the two control groups. We also assessed 42 Aβ+ CU and 122 Aβ+ cognitively impaired (CI) individuals, diagnosed with either mild cognitive impairment or AD dementia. Participants were assessed with 18F‐MK6240 positron emission tomography (PET) and CSF and plasma pTau181, 217, 231 and 235. We used linear regression to perform voxel‐wise comparisons of tau‐PET signal between groups. We compared the standardized uptake value ratio (SUVR) in medial‐temporal and Braak‐like regions‐of‐interest (ROI) and fluid biomarkers levels using the Wilcoxon rank sum test.ResultIn the voxel‐wise comparisons (Figure 1A‐E), CI participants presented more widespread cortical signal than control groups. Less signal in the parietal cortex was observed in the comparison with CU young. Higher t‐values were observed in Aβ+ CU individuals in the medial temporal region, compared to both control groups, and adjacent neocortex, especially compared to CU young. Temporal and Braak V‐VI SUVR were higher in CI but not in Aβ+ CU individuals compared to controls. Moreover, Braak I‐II and III‐IV SUVR and the fluid biomarkers levels were higher in both Aβ+ groups compared to controls (Figures 2A‐D; 3A‐G). Importantly, Braak I‐II SUVR and the CSF biomarkers levels were higher in CU old Aβ‐ versus young.ConclusionHere, we provide in vivo evidence that tau‐load in age‐matched Aβ‐ controls constitutes a bias for identifying tau pathology, particularly in individuals at early stages of AD pathophysiology. Age‐related tau load should be considered when selecting control groups to assess tau in symptomatic populations, especially those with early AD, and when defining criteria for tau abnormality.
The German S2k guideline: Informed consent of people with dementia to medical treatment
Authors: Pantel Johannes , Tesky Valentina Antonia , Haberstroh Julia 
Published: December 2023

AbstractDue to demographic change, the medical care system will be confronted with a growing number of people with dementia (PwD). PwD are usually multimorbid, frequently suffer from other diseases in addition to dementia and are therefore regularly confronted with decisions on medical diagnostics, treatment, or palliative care measures. Since the ability of PwD to give informed consent is often called into question, representative decisions are frequently made. In many cases, PwD are even categorically judged incapable to consent based on their diagnosis. This deprives them of their right to autonomous decisionmaking which is, however, not in line with the demands oft the United Nations Convention on the Rights of Persons with Disabilities/UN‐CRPD. To make sure that legally effective informed consent has been given, the ability to consent must be assessed. Furthermore, PwD have to receive adequate information, and they have to be adequately supported by the application of suitable measures (e.g. enhanced consent procedures). Aim of the German S2k‐ guideline “Informed Consent of people with dementia to medical measures” is to provide assistance for medical professionals with respect to the above mentioned challenges, whereby S2k defines a standard of higher quality guidelines which use formalized methodological techniques for the consensus process. The guideline was developed under the auspice of the Deutsche Gesellschaft für Psychiatrie, Psychotherapie und Nervenheilkunde (DGPPN), the Deutsche Gesellschaft für Neurologie (DGN) and the Arbeitsgemeinschaft Wissenschaftlicher Medizinischer Fachgesellschaften (AWMF) in Germany. Two of the authors (JP and JH) served as chairpersons for the guideline development. The guideline contains 33 recommendations and 31 legal requirements that were consented by 24 participating medical societies and institutions, including legal and bioehtical expertise. The patient perspective was provided by the German Alzheimers Associtaion (Deutsche Alzheimer Gesellschaft). The guideline is intended to provide a structured approach to ensure that people with dementia are able to act in terms of self‐determination when making decisions about medical measures. Structure and content oft the guideline that may serve as a template for the development of similar guidelines in other countries are presented at the congress.
ApoE variant associated with cognitive resilience alters AD associated hyperexcitability in dentate granule neurons
Authors: Berchulski Mariah R , Singh Surjeet , Martin Sophie L.A. , O'Connell Kristen MS , Kaczorowski Catherine C. 
Published: December 2023

AbstractBackgroundCognitive decline in Alzheimer’s disease (AD) differs based on background genetics even with similar pathology. Using genetic linkage analysis, we identified a coding variant in the receptor binding domain of ApoE that leads to changes in cognitive performance across a genetically diverse population harboring familial (FAD) mutations known as the AD‐BXDs (Neuner et al., 2019). Using CRISPR‐based gene editing, we developed a C57BL/6J (B6) mouse carrying the ApoE allele from the DBA/2J (D2) strain (ApoEE163D) and determined that ApoEE163D mice with 5XFAD transgene (ApoEE163D‐5XFAD) are susceptible to cognitive decline compared to B6‐5XFAD mice (Kaczorowski, et al., 2022).Analysis of hippocampal RNA sequencing profiles from the hippocampus indicates robust transcriptomic changes in dentate gyrus (DG) granule cells associated with cognitive resilience to FAD mutations in the presence of the B6 ApoE genotype. Here we aim to evaluate the functional implications.MethodWe adapted the Patch‐Seq method (Cadwell et al., 2017) to investigate transcriptional and electrophysiological changes within the DG associated with both FAD mutations and ApoE genotype. Whole‐cell patch clamp was used to evaluate intrinsic excitability of granule cells from 14month old B6 mice carrying FAD mutations and ApoEE163D, compared to age matched controls. The cellular contents, including the nucleus, were collected after each recording to characterize the transcriptome, and the cells were filled and stained for downstream analysis of neuronal morphology.ResultWe observed a significant interaction of the 5XFAD and ApoE genotypes on DG granule cell excitability. Specifically, cells from ApoEE163D‐5XFAD required less current stimulus to both elicit a single action potential, and to fire in response to a current ramp (rheobase). Although input resistance was comparable across all 4 groups, the sag ratio of ApoEE163D‐5XFAD was also reduced.ConclusionEnhancement of DG excitability of ApoEE163D‐5XFAD mice may underlie increased seizure susceptibility that has been reported previously in FAD animal models on D2 genetic background and associated with increased risk of seizures in AD patients. Ongoing work will integrate DG excitability with single‐cell RNAseq, morphology, and behavior to dissect mechanisms underlying the modifier effect of ApoE genotype on susceptibility and resilience to cognitive deficits in FAD mutation carriers.
Assessing the Effects of Burden on Alzheimer’s Patients’ Caregivers: A Comprehensive Review
Authors: Karur Prasanna , Shah Anjali , Marivada Snigdha , Patel Saajan , Khanna Deepesh 
Published: December 2023

AbstractBackgroundAlthough Alzheimer’s disease (AD) care is a heavily researched subject, caregiver burden is often overlooked. Caregiver burden may hinder care for those with AD. The objective is to assess caregiver burden in respect to sleep patterns, depression, and gender identity.MethodA comprehensive review of effects of caregiver burden for AD patients was conducted using databases such as PubMed and Google Scholar. PRISMA guidelines were followed. Keywords “caregiver burden,” “Alzheimer’s,” and “dementia” were paired with “sleep disturbance,” “depression,” and “gender” to find relevant articles. All searches were performed by the authors and re‐assessed for accuracy. Searches were restricted to publications from 2008‐2022. Eligible studies were excluded if caregiver burden was associated with diseases other than AD. Inclusion criteria consisted of AD caregivers from homes, nursing homes, and hospitals. Papers in the review were not restricted to the US population.ResultAccording to literature, AD caregivers reported sleep disturbances, with 58% reporting poor sleep quality, ⅔ being disturbed in the middle of their sleep, and 47% being woken up several times throughout the night1. Studies indicated that those caregivers with worse sleep quality had more depressive symptoms. Most studies showed a positive association between depression and AD caregivers. One article indicated that caregivers demonstrated the following depressive attributes: poor ability to take care of themselves, ignorance of basic physical and emotional needs, and low self‐care2. Findings show that female caregivers experienced a higher level of burden compared to male caregivers, specifically in regard to time dependence, development, physical, and social burdens.ConclusionFindings suggest that the quality of sleep is decreased, depressive and other neuropsychiatric symptoms were associated with caregiver burden, and females were more affected by caregiver burden than males. We recommend raising awareness and providing resources that may reduce this burden for AD caregivers.1. Creese, J., Bédard, M., Brazil, K., & Chambers, L. (2008). Sleep disturbances in spousal caregivers of individuals with Alzheimer’s disease. International Psychogeriatrics, 20(1), 149‐161. https://doi.org/10.1017/S10416102070053392. Vespa, A., Spatuzzi, R., Fabbietti, P., Penna, M., & Giulietti, M. V. (2021). Association between care burden, depression and personality traits in Alzheimer’s caregiver: A pilot study. PloS One, 16(9), e0251813. https://doi.org/10.1371/journal.pone.0251813
Cardiometabolic disease, cognitive decline, and structural brain differences in mid‐ and late‐life: a large population‐based cohort study
Authors: Dove Abigail , Guo Jie , Wang Jiao , Sakakibara Sakura , Xu Weili 
Published: December 2023

AbstractBackgroundThe impact of cardiometabolic diseases (CMDs; including type 2 diabetes [T2D], heart disease [HD], and stroke) on cognitive trajectories and brain structural changes across the life course is unclear. We aimed to explore the association of patterns of co‐morbid CMDs with cognitive decline and structural brain MRI measures in mid‐ vs. late‐ life.MethodWithin the UK Biobank, 46,562 dementia‐free participants aged 40‐70 were followed for 9 years. Baseline CMDs were ascertained medical records. A battery of 5 cognitive tests was administered at baseline and follow‐up and used to derive global and domain‐specific cognitive function scores. A subsample (n = 39,353) underwent brain magnetic resonance imaging (MRI) scans at the follow‐up examination. Volumes of total brain, white matter, grey matter, hippocampus, and white matter hyperintensities (TBV, WMV, GMV, HV, and WMHV) were assessed. Data were analyzed using multivariate adjusted mixed‐effects models and linear regression.ResultAt baseline, 3,437 (7.4%) participants had 1 CMD and 297 (0.6%) had ≥2. In mixed‐effects models, the presence of any CMD was related to a steeper decline in global cognitive function (β [95% confidence interval]: ‐0.005 [‐0.008, ‐0.003]) as well as working memory (‐0.024 [‐0.033, ‐0.014]), visual declarative memory (‐0.004 [‐0.007, ‐0.001]), and processing speed (‐0.002 [‐0.002, ‐0.001]), especially for those with CMD profiles involving T2D and/or HD. In stratified analysis by age (mid‐ [<60] vs. late‐ [≥60] life), CMDs were related to a decline in only processing speed in mid‐life, while in late‐life, CMDs were additionally related to a decline in verbal/numeric reasoning. In linear regression, people with CMDs had significantly lower TBV (‐0.15 [‐0.18, ‐0.12]), GMV (‐0.17 [‐0.20, ‐0.14]), WMV (‐0.11 [‐0.14, ‐0.08]), HV (‐0.14 [‐0.18, ‐0.11]) and significantly higher WMH (0.05 [0.02, 0.09]), and this was exacerbated among people with ≥2 CMDs compared to 1 CMD. Similar results were observed in both mid‐ and late‐life.ConclusionThe presence of CMDs is associated global/domain‐specific cognitive decline and brain MRI measures involving neurodegenerative and vascular markers in both mid‐ and late‐ life. Our findings highlight the need for the effective management of CMDs in mid‐life for the prevention of dementing disorders in late‐life.
The feasibility and preliminary efficacy of a novel, online culturally tailored psychoeducation course for Black dementia caregivers
Authors: Alexander Karah L , Cave Nkosi , Oliver Sloan , Epps Fayron 
Published: December 2023

AbstractBackgroundMany psychoeducation interventions utilizing different distant learning modalities to engage caregivers have been effective in enhancing caregiving mastery, but few programs have been specifically adapted to develop mastery in Black caregivers (Gallagher‐Thompson & Coon, 2007; Pinquart & Sörensen, 2006). The purpose of this study was to assess the feasibility and preliminary efficacy of the novel Caregiving while Black psychoeducation course (CWB). CWB was co‐produced by Black caregivers, persons living with dementia, and healthcare professionals. Caregivers from across the United States participated in the pilot study and engaged in ∼10 hours of asynchronous, online content related to healthcare system navigation, managing home life, and caregiver self‐care topics.MethodUsing quantitative and qualitative methods, caregivers were allotted 10‐weeks to complete the course and were quantitatively assessed on burden, depression, anxiety, and mastery at baseline, midpoint, and end of study. Caregivers then participated in an optional qualitative assessment (semi‐structured interview) of their experiences with course engagement. Descriptive statistics and t‐tests were used for quantitative data analysis and qualitative data were thematically analyzed.ResultOf the 75 caregivers enrolled, 31 were withdrawn to reasons including personal illness, death of care recipient, and reporting being too busy. Sixty‐four caregivers attempted the course with 32 completing the course within the timeframe. Quantitative data revealed significant improvement in caregiver depression, burden, and role strain. Caregiver mastery from baseline to completion increased 0.42 points. Twenty‐nine caregivers participated in a qualitative assessment which produced 5 overarching themes: Comfortability with a Culturally Tailored Course, Experiences Navigating the Course Platform; Utility of Course Resources; Time as a Barrier and Facilitator; Familial and Community Engagement.ConclusionFindings confirmed CWB’s ability to improve Black caregivers’ emotional well‐being and sense of confidence and mastery in their caregiving role. Caregivers expressed their appreciation of a culturally tailored course to address their needs and greatly utilized the external resources the course offered. However, time and complexities with the course’s online platform served as a barrier for many, to optimize engagement with and even finishing the course. Study findings will help inform and fuel the success of the next iteration of the Caregiving while Black Course.
UPREGULATING ABCA1‐MEDIATED CHOLESTEROL TRANSPORTATION BY CS6253 – OPPORTUNITY FOR CONVENIENT SC ROUTE OF ADMINISTRATION
Authors: Johansson Jan O. , Winblad Bengt , Michaelson Daniel M , Zetterberg Henrik , Cummings Jeffrey L. , Yassine Hussein N. 
Published: December 2023

AbstractBackgroundThe ATP‐binding cassette transporter A1 (ABCA1) is a validated target for AD and upregulation has therapeutic potential in APOE4‐associated AD. The apoE4 protein compared to E2/E3 has impaired interaction with the ABCA1 transporter protein, affecting cholesterol homeostasis in the brain, causing dementia and hemorrhage. CS6253 is an ABCA1‐agonist that in monkey’s has shown safety and increase in Ab42/40‐ratio. A phase 1 SAD‐MAD with CS6253 administered IV was initiated. Here we describe translational efforts for transitioning from IV to SC route‐of‐administration.MethodThe Phase 1 is initiated with SAD:In 4‐6 cohorts of 8 subjects (6 active: 2 placebo) CS6253 starting with 1 mg/kg will be administered IV and plasma and CSF collected simultaneously over 24 hours to assess PK and response markers, and, MAD: In 3‐4 cohorts of 8 subjects (6 active: 2 placebo) CS6253 will be administered to elderly stratified for sex and APOE4 status.Using the identical CS6253 drug product, a GLP local‐tolerance study in rats was conducted to support up to 30 days SC administration in humans. Rat groups of n = 12 received PBS‐control and 7.5, 25 and 75 mg/kg CS6253 SC every other day, 7 times. PK is analyzed by LC‐MS following first and 7th/last dose.ResultBodyweight: Treated animals gained weight throughout the study at a comparable rate to control; no Test Article(TA)‐related variations identified.Clinical Signs: No TA‐related observations were noted, all animals remained in good condition until the end of dosing and end of recovery.Food consumption: No TA‐related effects on food consumption, all means were comparable to controls.Gross Pathology: No gross lesions were observed for terminal and recovery animals.Human Phase 1 SAD results are expected late summer of 2023 and human MAD data late fall of 2023 and with clearing local‐tolerance toxicology the CS6253 program can transition from IV to SC route‐of‐administration.ConclusionThe ABCA1 agonist CS6253 has therapeutic potential for APOE4‐associated AD. Safety, PK and biomarker efficacy is being assessed in a Phase 1 study. The SC local tolerance study opens up the potential to self‐administer CS6253 SC for optimal convenience and compliance.
Tunneling nanotubes at the microglia‐neuron interface in neuroinflammation and Alzheimer’s disease
Authors: Zaccard Colleen R , Parnell Euan , Gippo Isabel , Geula Changiz , Penzes Peter 
Published: December 2023

AbstractBackgroundBrain‐resident innate immune cells termed microglia can mediate synapse formation and plasticity, but become dysregulated in Alzheimer’s disease (AD), contributing to chronic neuroinflammation and synapse loss (Wu, Dissing‐Olesen et al. 2015, Hong, Beja‐Glasser et al. 2016). Yet, the mechanisms underlying direct microglia‐neuron interactions are poorly defined. Pro‐inflammatory signals can induce extremely long, thin, membranous connections, i.e., tunneling nanotubes (TNTs), in peripheral innate immune cells (Zaccard, Rinaldo et al. 2016). TNTs have been observed in various cell types and can support high‐speed, cell‐cell trafficking of diverse cytoplasmic and membrane‐bound cargoes. Herein, we explore the role of TNTs in microglia‐neuron communication during neuroinflammation and AD.MethodWe established a co‐culture model of human induced excitatory neurons (iENs) and postmortem elderly adult human microglia. Microglia‐tropic adeno‐associated virus vectors encoding plasma membrane‐targeted tdTomato fluorophores were utilized to label microglia and emerging TNTs. We treated co‐cultures with pro‐inflammatory factors, i.e., oligomeric amyloid β (Aβ) and interferon‐gamma, or anti‐inflammatory factors for 24 hours, and utilized our recently developed enhanced resolution confocal microscopy technique to assess TNTs.ResultThe number of TNT‐positive microglia and number of TNTs per microglia were increased in live human iEN‐microglia co‐cultures under AD‐relevant pro‐inflammatory conditions compared to anti‐inflammatory or control conditions. Additionally, TNT length and the percentage of TNTs contacting neuronal axons or dendrites were significantly increased under pro‐inflammatory conditions. We used time‐lapse enhanced resolution imaging to capture microglial TNTs interacting with spine‐like dendritic protrusions, which extended finer spinule‐like protrusions. Finally, we visualized direct, rapid, cell‐cell transfer of oligomeric Aβ and enhanced localization of oligomeric Aβ to TNTs under pro‐inflammatory conditions in microglia mono‐cultures.ConclusionOur results in human iEN‐microglia co‐cultures indicate that an AD‐relevant, pro‐inflammatory micro‐environment increases microglial TNT formation and TNT‐driven interactions with neuronal axons, dendrites, and dendritic protrusions. TNTs can provide additional contact points and extend the reach of microglia, facilitating communication with distant target microglia or sub‐neuronal elements. During chronic neuroinflammation in aging and AD, TNT over‐expression likely increases microglia‐synapse interactions and supports rapid, cell‐cell spread of Aβ. Hence, TNTs may contribute to AD progression and could represent a new target for therapeutic intervention in neurodegenerative disorders.
Which Mild Behavioral Impairment‐Checklist (MBI‐C) items discriminate between cognitive diagnoses at baseline and follow‐up? Results from the Compostela Ageing Study (CompAS)
Authors: Mallo Sabela Carme , Real‐Deus Eulogio , Pérez‐Blanco Lucía , Felpete Alba , Campos‐Magdaleno Maria , Facal David , Nieto‐Vieites Ana , Pereiro Arturo X 
Published: December 2023

AbstractBackgroundThe Mild Behavioral Impairment Checklist (MBI‐C) is a 34 Neuropsychiatric Symptoms (NPS) checklist for the evaluation of pre‐dementia states. Our aim was to analyze which MBI‐C symptoms could best discriminate between participants with different cognitive outcomes both at baseline and at diagnosis time (after 50‐75 months).MethodA total of 179 participants from the Compostela Aging Study (CompAS) were included in the analyses, 108 identified as Subjective Cognitive Complainers (SCC), 47 diagnosed as Mild Cognitive Impairment (MCI) and 24 diagnosed as dementia. NPS were assessed using the validated Spanish version of the MBI‐C (Mallo et al., 2018) at baseline and 50‐75 months follow‐up. Discriminant analyses were carried out at baseline and follow‐up, being the dependent variable the diagnosis at the follow‐up and the independent variable the MBI‐C scores.ResultThe results of the discriminant analysis at baseline indicated a poor adjustment of the model to the data (Wilk’s lambda = .821; p<.001). At baseline, three items (item 9 “discouraged”, 22 “hoard objects”, and 19 “stubborn/rigid”) discriminate 65% of cases, mostly SCCs (97.2%) (Table 1).The results of the discriminant analysis at follow‐up indicated a much better adjustment of the model to the data (Wilk’s lambda = .468; p<.001) (Table 1).The variance was explained almost exclusively by the first function obtained (53%) while the second only reached 7%. At follow‐up, seven items discriminate between groups (item 4 “unmotivated”, 25 “less sensible”, 26 “talk to strangers”, 21 “food no tasty”, 24 “control difficulties”, 5 “less emotional”, 28 “no social judgement”). These items correctly discriminated the SCC (99%) and the 66.7% of dementia patients, but only 6.8% of the MCI (Figure 1).ConclusionModel fit at baseline was poor, and almost exclusively discriminate SCC. The discrimination power increased as the MBI‐C measure were close to the diagnosis, especially for dementia.Distal prediction of dementia nor predementia states using NPS was not successful though some MBI‐C items showed slight better performance at baseline than in follow‐up.