bluuebunny/crossref_metadata_2025_split huggingface dataset:
Objects of hope: using object elicitation to open up conversations about hope for people affected by rarer forms of dementia
Authors: Harding Emma , Camic Paul , Harrison Charles R , Akthar Nasifah , Wilson James , Stott Joshua , Rice Helen , Herron Daniel , Mummery Catherine J , Crutch Sebastian J ,   RDS Impact Study team
Published: December 2023

AbstractBackgroundHope is an essential component of the human experience and can play a critical role in sustaining wellbeing and a good quality of life. It can seem somewhat at odds however with the dominant societal discourses around dementia, which, stemming from a biomedical perspective, are often (naturally) focused on deficits and decline. With recent promising developments in the field of therapeutic interventions, it is of timely importance to explore the concept of hope for those affected by rarer forms of dementia, charactersised by atypical symptoms and associated with unique challenges, for whom emerging treatments may be too late. Here, we explored the use of an innovative methodology – object elicitation – to facilitate conversations on this complex and sensitive topic with these underrepresented groups.Method17 people affected by dementia and primary caregivers took part in 3 facilitated discussions using object elicitation to explore the concept of hope within the context of rarer forms of dementia, including: familial Alzheimer’s disease, behavioural variant frontotemporal dementia, and posterior cortical atrophy. Transcripts of the discussions were analysed thematically.ResultFindings were organised into 4 themes: (i) Reframing and reconceptualising hope in the context of dementia; (ii) Temporality: from hopes for the future to finding hope in the moment; (iii) Hope for the individual and hope for the collective; and (iv) The other side of the coin: lost hope, false hope and barriers to hope.ConclusionThe findings of this study shed light on some of the challenges to sustaining hope for people affected by lesser known forms of dementia and importantly, their resilience and resourcefulness in finding ways to continue to cultivate a sense of hope during difficult times within their everyday lives. These findings have implications for others living with these conditions and the unpaid carers and health and social care professionals supporting them, and are of particular relevance in the context of current treatment developments. This study has also demonstrated the utility and accessibility of the object elicitation method for opening up and facilitating conversations about emotionally charged topics for people living with and supporting people with different diagnoses of dementia.
EEG‐guided anesthetic titration and perioperative neurocognitive disorders
Authors: Evered Lisbeth A 
Published: December 2023

AbstractBackgroundPostoperative delirium (POD) is a serious complication of surgery associated with prolonged hospitalisation, long‐term cognitive decline, dementia and mortality. There is increasing evidence that electroencephalography (EEG) monitoring may reduce the incidence of POD, however, the best method for achieving this is unclear.MethodThis presentation will present the results of a multicentre randomised clinical trial of 515 at‐risk patients undergoing major surgery from 8 centres in 3 countries who were assessed for POD for 5 days postoperatively. They also underwent cognitive screening at baseline, discharge, 30 days and one year postoperatively. Patients were assigned to light or deep anaesthesia. Additionally, this presentation will consider a meta‐analysis of available studies investigating EEG monitoring to prevent delirium and outline the importance of EEG spectrogram interpretation as part of EEG monitoring and consequent anesthetic titration when using this technique to reduce or prevent POD.ResultThe incidence of POD was lower (19%) in the light anesthesia group compared with the deep anesthesia group (28%) (OR 0.58 (95% CI 0.38 to 0.88), P = 0.010). Meta‐analysis results were fragile and depended on inclusion criteria of studies. Interpretation of EEG spectrograms is a developing field, but adds significant, critical information.ConclusionEEG monitoring looks to be a possible method for preventing POD and long‐term complications. EEG spectrogram interpretation will likely add critical information to enhance this technique.
Working Memory related Frontal Brainwaves are Associated with pTau181Plasma Biomarkers in Healthy Older Adults
Authors: Jiang Yang , Katsumata Yuriko , Foley Kate E , Neal Jennifer A , Sudduth Tiffany L , Norris Christopher M. , Jicha Gregory A , Wilcock Donna M. 
Published: December 2023

AbstractBackgroundWe have previously reported distinct frontal signature of working memory related potentials (WMRP) in older adults with Normal Cognition (NC) versus age‐matched older adults with Mild Cognitive Impairment (MCI) (Li et al., 2017; Fig 1A). Our Kentucky cohort demonstrates that asymptomatic older individuals with MCI‐like frontal brainwave patterns convert to MCI within a short 5‐year period, as opposed to individuals with NC‐like patterns that remain normal 10 years later (Jiang et al., 2021; Fig 1B). Leveraging blood‐based Vascular/AD biomarkers, we test the hypothesis that WMPR is associated with preclinical AD/ADRD pathologies.Method33 (19 women) cognitively intact older volunteers, average age 79 (SD 8.53) years old, from a longitudinal cohort followed by University of Kentucky ADRC participated. Each participant was assessed by electroencephalogram (EEG) recording (64‐ or 14‐channels headset) during a visual working memory task and vascular/AD plasma markers (Wilcock et al., 2022). Multiple linear regression analyses adjusting for age and sex were applied for examining several frontal WMRP difference waves (Target items held in working memory – Nontargets) and multiple vascular/AD plasma biomarkers Aβ 42/40, pTau181, and GFAP (astrocyte reactivity).ResultsWe examined the association between WMRP and the percentage changes of Aβ 42/40, pTau181, GFAP levels from plasma Vascular/AD biomarkers. The decrease of WMRP levels (MCI‐like) was significantly associated with increased level of pTau181 at the left frontal F7 site after adjusting for age and sex (b = ‐0.035 and p = 0.043) (Fig. 2). Aβ42/40 and GFAP levels were not significantly associated with working memory related brainwaves.ConclusionOur results indicate that predictive WMRP are associated with tau pathologies. Working memory‐related EEG neuromarkers and plasma AD biomarkers are sensitive and affordable screening tools to predict continuous cognitive decline risk in healthy normal older adults.
References
Jiang, Y. et al. (2021). Memory‐Related Frontal Brainwaves Predict Transition to Mild Cognitive Impairment in Healthy Older Individuals Five Years Before Diagnosis. J. Alzheimer’s Dis. 79, 531‐541.Li, J et al. (2017). A cognitive electrophysiological signature differentiates amnestic mild cognitive impairment from normal aging. Alzheimer’s Res & Therapy, 9, 3.Wilcock D, et. al… (2021). MarkVCID cerebral small vessel consortium: I.Alzheimers Dement. 17:704‐715.
Reprogramming to alleviate Alzheimer’s disease through ameliorating microglial inflammation and neuronal damage
Authors: Shen Lu , Wan Meidan , Liu Xixi , Jiao Bin , Wang Zhenxing , Xie Hui 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disease, characterized by glial cell dysfunction and progressive neuron loss, leading to varying degrees of neuropathology and cognition impairment. Aging and epigenetic alterations accompany the progression of AD and disrupt cellular functions; therefore, whether reprogramming could restore epigenetic information while maintaining cellular identity remains unclear.MethodThe polycistronic expression cassette contained multiple transcription factors of the Oct4, Sox2, and Klf4 genes (OSK) that were cloned into a coexpression vector (Ad‐OSK). The effects of OSK on cognitive function and neuropathology were explored in 4‐month‐old and 6‐month‐old APP/PS1 transgenic AD model mice via stereotaxic injection into the bilateral hippocampus.ResultAd‐OSK maintained microglial and neuronal cellular identities while attenuating microglia‐induced neuroinflammation and neuronal apoptosis. Ectopic expression of OSK in mouse brain tissue alleviates and restores cognitive function, youthful neuronal pathogenesis, Aβ plaque deposition, microglial activation, and myelin damage in early stage and later stage AD mice, respectively. The DNA demethylation process is required for the beneficial effects of OSK induced reprogramming in brain health.ConclusionThese results suggest that brain tissues preserve youthful epigenetic information, which is primarily stored by DNA demethylation during OSK reprogramming and can be accessed to improve brain health in AD mice. Our findings provide the foundation for the future use of OSK adenovirus or mRNA medicine to treat AD.
Two novel beta synuclein specific assays for the detection of Alzheimer’s disease
Authors: Bayoumy Sherif , Goossens Julie , De Rocker Charlotte , Verberk Inge M.W. , Teunissen Charlotte E. , Vanmechelen Eugeen 
Published: December 2023

AbstractBackgroundRecent studies reported the potential use of elevated CSF β‐synuclein levels as an AD‐specific synaptic biomarker. These results were obtained with a sandwich ELISA where one of the antibodies recognizes both alpha‐and β‐synuclein1. Blood contamination can affect alpha‐synuclein concentrations in CSF, which is not observed for β‐synuclein2. Therefore, we aimed to develop a β‐synuclein‐specific assay to avoid possible interference with alpha‐synuclein.MethodsTwo novel sandwich CSF ELISA assays were established using only β‐specific synuclein monoclonal antibodies: a mid‐region and C‐terminal assay. Both assays use a monoclonal capture antibody that maps to C‐terminal. The mid‐region assay involves a detection antibody mapping to an epitope that overlaps with the SRM peptide used for CSF mass‐spectrometry quantification3. The C‐terminal assay includes a detection antibody targeting a less well‐defined C‐terminal epitope. Forty‐four remnant routine CSF samples were analyzed in duplicate (22 individuals with AD biomarker profile based on pTau181 and amyloid‐beta(1‐42), age70±7 years, 38%F and 22 control profiles, age70±7, 38%F).ResultsThe mid‐region assay showed a precision of 4%CV in clinical samples and a sensitivity of 1.25 pg/ml compared to 10%CV and 4.22 pg/ml with the C‐terminal assay (Fig. 1). CSF β‐synuclein levels were significantly elevated in patients with an AD CSF‐profile compared to individuals with negative‐AD CSF‐profiles, with AUCs of 0.77 [95%CI: 0.62‐0.90] for the C‐terminal assay and 0.71 [0.55‐0.87] for the mid‐region assay (Fig. 2). The assays showed comparable (Delong’s P = 0.53) clinical performance and their results correlated (r = 0.61, P = <0.001)(Fig. 2). Both C‐terminal and mid‐region β‐synuclein associated with CSF pTau181 (Spearman’s rho = 0.58 (p<0.001), rho = 0.51 (P = <0.001), respectively), and did not correlate with CSF Abeta(1‐42) (Fig. 3). Both assays are specific for recombinant beta‐synuclein, but the C‐terminal assay showed higher selectivity for β‐synuclein compared to the mid‐region assay, as increasing signals were observed with the latter with increasing concentrations of spiked recombinant alpha/gamma‐synuclein.ConclusionThe two novel β‐synuclein assays show clinically relevant changes in relation to AD CSF biomarker positivity. Both assays are specific to β‐synuclein. The assays will be transferred to SIMOA, which provides a wider dynamic range, and thus we will further assess the selectivity in plasma/serum.
Cerebral amyloid angiopathy‐related inflammation presented with posterior reversible encephalopathy syndrome
Authors: Chung Ji Yeon , Lee Chang Ju , Kim Ju Hye , Moon Hyeo Seo , Lim Da‐Hye , Kim Hoowon 
Published: December 2023

AbstractBackgroundCerebral amyloid angiopathy (CAA) is characterized by the deposition of amyloid beta protein deposits within the media and adventitia of small and medium‐sized leptomeningeal and cortical blood vessels of the brain. CAA‐related inflammation (CAA‐ri) is a relatively rare and aggressive subtype of CAA with diverse neurologic deficits and characteristic radiological findings. Posterior reversible encephalopathy syndrome (PRES) is a neurological disorder of acute or subacute onset characterized by various neurological symptoms and reversible entity both radiologically and clinically. We report a case of CAA‐ri presented with PRES.MethodA 80‐year‐old man with a history of hypertension presented to the Emergency department with sudden onset of drowsy mentation and disorientation. At admission arterial blood pressure was 210/100mmHg. Brain computed tomography revealed hypodense lesion in both parieto‐occipito‐temporal lobes with the predominance on the left side. Brain MRI susceptibility weighted imaging (SWI) presented multiple microbleeds with diffuse cerebral edema in both parieto‐occipital and left temporal cortex and subcortex as can be seen in cerebral amyloid angiopathy (CAA). Obtained images suggested CAA coexisting with posterior reversible encephalopathy syndrome (PRES). Electroencephalopgraphy (EEG) revealed regionalized sharp wave in the right parieto‐occipital area. There was no evidence of venous thrombosis. CSF analysis showed no pleocytosis with protein elevation of 105 mg/dl. PRES was considered due to neurologic deficit of acute onset, elevated arterial blood pressure and vasogenic edema on MRI. 18F‐Florbetaben PET CT showed amyloid positivity.ResultA diagnosis of CAA‐ri was considered, and the patient was started on intravenous steroid for 5 days and valproic acid with clinical improvement. Arterial blood pressure showed gradual normalization within 5 days of hospitalization. After 2 weeks of hospitalization, the patient was able to walk without assistance. MMSE score was 17 with normal orientation of place, acalculia and memory impairment. The modified Rankin Scale was 1 and Barthel index score was 20 at the time of discharge.ConclusionCAA‐ri may present with PRES‐like features. Early detection and appropriate management of trigger factors of PRES which may caused by CAA‐ri would facilitate acute phase recovery and long term prognosis.
Telomere length in the superager sample of the Vallecas Project cohort
Authors: Pascual Marta Garo , Zhang Linda , Calero Miguel , Medina Miguel , Defelipe Javier , Strange Bryan A 
Published: December 2023

AbstractBackgroundSuperagers are individuals aged 80 and over with youthful episodic memory that can provide insights into protective mechanisms against age‐related memory loss and dementia. We aim to study telomere length in human superagers since telomere attrition is considered a hallmark of ageing and can explain some structural and functional changes occurring in an ageing organism. We therefore tested whether telomere length is associated with successful episodic memory of superagers.MethodTelomere length was measured in peripheral blood cells from 57 superagers (mean age 81.9 years ± 2.0 std, 61.4% women) and 48 age‐matched typical older adults with normal memory for age (mean age 82.4 years ± 1.9 std, 64.6% women) selected from the Vallecas Project cohort. A high‐throughput quantitative fluorescence in situ hybridization technique (HT Q‐FISH) (Life length, Spain) was used. This technology has a low detection limit of < 100 bp, enabling the quantification of short telomeres that can be more informative of telomere dysfunction than centrality measures.ResultSuperagers have significantly shorter median telomere lengths than typical older adults (p = 0.0009, t = ‐3.4) and show a higher proportion of short telomeres (<6 Kbp) (p = 0.0005, t = 3.6) and extremely short telomeres (<3 Kbp) (p = 9. 4×10−5; t = 4.1) than typical older adults. Thus, superagers have shorter average telomere lengths and a higher proportion of short telomeres, which are most associated with genome instability.ConclusionThe successful episodic memory of our superager population is not associated with long telomere length or the presence of fewer short telomeres measured in a cross‐sectional setting. Further analysis exploring telomere attrition rate of these two groups over time may help to interpret the current findings.
Dissociations between APP pathology and metabolic signalling in the neuron‐specific hBACE1 knock‐in PLB4 mouse
Authors: Franklin Zara J , Delibegovic Mirela , Platt Bettina 
Published: December 2023

AbstractBackgroundPatients with Alzheimer’s Disease (AD) frequently suffer comorbidities such as type 2 diabetes mellitus (T2DM) alongside shared common pathologies e.g. increased inflammation, endoplasmic reticulum (ER) stress, and impaired energy homeostasis (Plucinska et al., 2016, https://doi.org/10.1007/s00125-016-3960-1). The complexity of neurodegenerative and metabolic diseases requires a systems‐based approach that examines the interplay between brain pathology and metabolic regulation. Emerging evidence points towards abnormal cellular energy regulation as a common denominator, investigated here in hBACE1 associated pathologies (Findlay et al., 2015, https://doi.org/10.3389/fncel.2015.00382).MethodGlucose tolerance tests were performed in male PLB4 and PLB‐WT controls (3 – 8 months) to determine diabetic status (Plucinska et al., 2014, https://doi.org/10.1523/JNEUROSCI.0433-14.2014). Protein analysis was employed to characterise beta‐amyloid/APP processing, ER stress, glucose regulatory signalling, and bioenergetic metabolites in brain, liver, muscle or plasma, and gene expression analysis examined hypothalamic alterations in energy regulation.ResultNeuronal hBACE1 expression caused early pathological cleavage of APP, in parallel with increased brain ER stress (p‐eIF2α) and the chaperone binding immunoglobulin protein (BIP). APP processing declined over time, alongside increased ER stress (IRE1α) in brain and liver. Systemic glucose intolerance was evident from 3 months, varied between tissues and ages, and was confined to the periphery. All key markers normalised to control levels at 8 months. Evidence for altered bioenergetics metabolites (LDH‐A and BCKDH) in brain and liver, also affected by ageing, were detected in PLB4 mice. Furthermore, hypothalamus‐specific changes in energy and appetite regulators (NPY and GLP‐1 receptor) were uncovered in the hBACE1 mice.ConclusionhBACE1 resulted in early APP misprocessing alongside ER stress but not post‐insulin receptor signalling changes. Peripheral metabolic and bioenergetic alterations were age‐ and tissue‐specific but did not correlate with APP processing. Further tissue analyses are ongoing to determine cellular consequences of hBACE1 expression on systemic bioenergetics.
A novel function of CD44 in the pathogenesis of Alzheimer’s disease
Authors: Lee Yeongyeong , Lee Jeongmi , Jo Dong‐Gyu 
Published: December 2023

AbstractBackgroundAlzheimer’s disease is the main cause of dementia, which is believed to progress with Aβ, neurofibrillary tangle (NFT) and neuroinflammation. CD44 is a transmembrane glycoprotein acts as a receptor for extracellular matrix (ECM). It was firstly found as a receptor for hyaluronic acid (HA). CD44 is cleaved by α‐ or γ‐secretase, becoming soluble form. This fragment activates and modulates several genes related with cell survival. The binding of low molecular weight of HA and CD44, activates NLRP3 inflammasome, and inflammatory cytokines boosts cohesion of HA and CD44. Previous reports indicated that CD44 upregulation was shown in early stage of AD, and amyloid increases CD44 expression. Other researchers illustrated that applying siRNA of CD44 reduced Aβ toxicity, indicating that CD44 participates in Aβ metabolism.MethodA total of 38 mice were randomly divided into 4 groups according to their genotype; WT (Control group), CD44−/−, 5xFAD (AD model), and 5xFAD;CD44−/−. Behavioural tests were conducted during the age of 8.5 months. We performed Morris Water Maze (MWM) to analyze cognition level. After 7 days of behaviour test, brain tissue was collected by PBS perfusion and analyzed through quantitative real‐time‐PCR(RT‐qPCR), western blot, and immunofluorescence.ResultIn MWM, 5xFAD;CD44−/− male mice showed restored cognition level through probe day result. In molecular analysis, Aβ plaque significantly reduced in both cortex and hippocampus of 5xFAD;CD44−/− mice compared to 5xFAD mice. Inflammatory factors, such as nlrp3, il‐1b, also reduced in the cortex of 5xFAD;CD44−/− mice.ConclusionOur data indicated that CD44 plays a pivotal role in Aβ plaque formation, leading to cognition impairment. Significant changes in amyloid plaque level were shown, as well as an reduction of inflammatory factors in the brains of 5xFAD;CD44−/‐ mice. With these results, drugs blocking CD44 would be a strong candidate for the treatment of Alzheimer’s disease. Further studies are needed to clear the mechanism of AD pathology associated with CD44.
APOE genotypes and oxidized lipids in Alzheimer’s Disease
Authors: Diaz‐Sanchez Lorena , Hill Eric J , Griffiths Helen R , Dias Irundika 
Published: December 2023

AbstractBackgroundThe APOE4 allele is a strong risk factor for late‐onset and early‐onset forms but APOE4 is neither a prerequisite for, nor sufficient to cause, AD. Despite decades of research, the exact mechanisms underlying how ApoE4 contributes to AD pathogenesis remain incompletely defined. Astrocytes are homeostatic cells of the central nervous system and play a pivotal role in maintaining neuronal health and survival. Brain metabolic enzyme activity is altered in ApoE4 carriers where mitochondrial oxidative phosphorylation is disrupted and is accompanied by increased oxidative stress. In this study, we aim to investigate the hypothesis that the astrocytic oxidised phospholipids and oxysterol profile is affected by ApoE genotype influencing mitochondrial bioenergetics and altering redox state.MethodHuman iPSC lines for APOE3/3, APOE 4/4 and APOE knockout were maintained in mTeSRTM1 culture medium and transformed to neural precursor cells. Neural precursor cells were then transformed to pure astrocyte cultures using published protocols. Cells were collected and lipids were extracted using methyl‐tert‐butyl ether (MTBE). Oxidised phosphatidylcholines and oxysterols were measured using liquid chromatography mass spectrometry (ABSciex 5500). Mitochondrial bioenergetics were measured by Seahorse technology.ResultCompared to APOE3/3 astrocytes, a slower growth rate was observed for APOE4/4 cells. APOE4/4 cells showed increased levels of oxysterols (24‐hydroxycholesterol (24‐OHC), 27‐hydroxycholesterol (27‐OHC), 7β‐hydroxycholesterol (7β‐OHC) and 7‐ketocholesterol (7KC) and increased levels of short‐chain, oxidised phosphatidylcholines (POVPC; 1‐palmitoyl‐2‐(5‐oxovaleroyl)‐sn‐glycero‐3‐phosphorylcholine, PONPC; 1‐palmitoyl‐2‐(9‐oxo‐nonanoyl)‐sn‐glycero‐3‐phosphocholine and PGPC; 1‐palmitoyl‐2‐glutaryl‐sn‐glycero‐3‐phosphocholine).ConclusionThis study shows that the potential to investigate discrete oxidised lipids in APOE genotypes. By studying the profile of oxylipids and mitochondrial bioenergetics, this work will inform future studies into mitochondrial metabolism and targeting oxylipids in mitochondria to improve brain cell health and in AD.