bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasma melatonin night‐time peak levels and 24‐hour area under the curve profile seem higher in AD patients with epileptiform activity than in those without
Authors: Nous Amber , Seynaeve Laura , Feys Odile , Wens Vincent , De Ti Xavier , Smolders Ilse , Engelborghs Sebastiaan 
Published: December 2023

AbstractBackgroundPlasma melatonin levels drop in elderly, which might become more pronounced in Alzheimer’s disease (AD) as compared to controls.(1) Melatonin can serve as a potential biomarker for AD, given the inverse correlation between cerebrospinal fluid (CSF) melatonin levels and severity of neuropathology (Braak stages).(2) Due to suggested antiepileptic effects(6), melatonin can potentially slow down disease progression as epileptiform activity may contribute to AD disease progression.(3‐5). We here present a preliminary interim analysis of an ongoing study.Aims1. To evaluate melatonin’s potential as biomarker for AD by comparing blood melatonin levels between patients with mild cognitive impairment (MCI) and dementia due to AD and preclinical AD subjects.2. To study the link between melatonin levels and epileptiform activity in AD.MethodsAll subjects underwent a neuropsychological examination, and lumbar puncture for analysis of core AD CSF biomarkers or amyloid brain PET. Subjects belonging to the AD continuum (dementia [n = 7]; MCI [n = 4]; preclinical AD [n = 1]) were diagnosed according to the NIA‐AA research criteria. A subset of subjects (n = 6) underwent 50‐minute magnetoencephalography to detect epileptiform activity. Blood samples were taken multiple times during a 24‐hour period, in in‐hospital controlled circumstances, and were analysed by use of liquid chromatography‐mass spectrometry.ResultsAD patients with epileptiform activity (n = 2) tended to have a higher melatonin 24‐hour area under the curve (AUC) and peak concentration (AUC 517.9pg/ml.h [+/‐140.1pg/ml.h] versus 204.5pg/ml.h [+/‐115.5pg/ml.h]; peak 65.4pg/ml [+/‐14.6pg/ml] versus 25.8pg/ml [+/‐17.5pg/ml]) than AD patients without (n = 4) (p = 0.064 for both; MWU test). There was no statistical difference regarding the melatonin 24‐hour plasma AUC or peak levels between patients with dementia, MCI, preclinical AD subjects (p = 0.760 for both; Kruskall‐Wallis test). We have to interpret these data with caution since sample sizes are still small and more patients are being recruited.ConclusionOn the basis of very preliminary data, 24‐hour plasma melatonin profile and peak plasma melatonin concentration tended to be higher in AD patients with epileptiform activity than in those without. Whether this could be a potential compensatory mechanism against epileptiform activity in AD or whether melatonin could rather have pro‐epileptic effects, remains to be elucidated in future research.
Day‐to‐day Sleep Variability in Val66Met BDNF Carriers: A Potential Biological Pathway Between BDNF Activity and Alzheimer’s Disease Pathology?
Authors: Baril Andree‐Ann , Picard Cynthia , Labonte Anne , Sanchez Erlan , Mohammediyan Bery , Duclos Catherine , Breitner John C.S. , Villeneuve Sylvia , Poirier Judes ,   PREVENT‐AD Research Group
Published: December 2023

AbstractBackgroundWe previously showed that day‐to‐day sleep variability was associated with biomarkers of Alzheimer’s disease (AD) pathology. Given that brain‐derived neurotrophic factor (BDNF) activity has been involved in both AD and cognitive impacts of lifestyle risk factors, we sought to evaluate day‐to‐day sleep variability in those carrying the Met allele of the Val66Met BDNF polymorphism, which affects BDNF release. Additionally, we explored whether BDNF polymorphism modified the association between CSF AD pathology and day‐to‐day sleep variability.MethodThe PREVENT‐AD cohort enrolls dementia‐free persons with a parental history of sporadic AD. We characterized 203 dementia‐free participants from this cohort at the polymorphic BDNF locus, identifying 136 persons with genotype Val/Val (age 68.2±5.3y, 75%women), 67 Met heterozygotes/homozygotes (68.4±5.6y, 73% women, including six Met/Met homozygotes). After a week of actigraphy, we calculated these participants’ standard deviation of day‐to‐day sleep characteristics. We used t‐tests to compare day‐to‐day sleep variability in sleep characteristics between Val homozygotes and Met carriers. In a subsample of 101 participants, we assayed CSF Aβ42, t‐tau and p‐tau181, and used age‐ and sex‐adjusted linear regressions with an interaction term to test for moderation by BDNF genotype (36 Met carriers vs. 65 Val homozygotes) between sleep variability and CSF biomarker results.ResultAs compared to Val homozygotes, sleep was disturbed and unstable in BDNF Met carriers (heterozygotes/homozygotes). They had higher day‐to‐day variability in sleep fragmentation (activity counts, wake after sleep onset, fragmentation index), sleep onset latency, and sleep duration, resulting in weekly sleep patterns that were more fragmented and less efficient. Further, BDNF genotype moderated the association between CSF t‐tau and p‐tau181 with day‐to‐day sleep duration variability, such that only Met carriers showed an association between elevated tau concentration and sleep duration variability.ConclusionBDNF Met carriers had disturbed and unstable daily sleep patterns. Because the Met allele is known to decrease plasticity of neural mechanisms, the ability to achieve healthy and stable sleep may depend on such mechanisms. Thus, poorer sleep in Met carriers might be a biological mechanism by which altered BDNF activity affects tau pathology or, alternatively, accumulated AD pathology in Met carriers may disrupt sleep‐wake patterns.
Correction of mTORC1‐mediated brain protein synthesis rescues memory in mouse models of Alzheimer’s disease
Authors: Cozachenco Danielle , Ribeiro Felipe C. , Argyrousi Elentina K. , Staniszewski Agnieszka , De Felice Fernanda G. , Lourenco Mychael V. , Arancio Ottavio , Aguilar‐Valles Argel , Sonenberg Nahum , Ferreira Sergio T. 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disorder characterized by synapse failure and cognitive decline. Brain mRNA translation is central to synaptic plasticity and cognition, and converging evidence indicates it is impaired in AD. The mammalian target of rapamycin complex 1 (mTORC1) pathway plays a key role in regulating protein synthesis, and mTORC1 signaling has received considerable attention in AD research. In this current work, we investigated whether stimulating mTORC1‐mediated protein synthesis can alleviate the impairments in synaptic plasticity and memory in AD mice.MethodTo address this question, we used two different approaches: 1. genetic reduction of the translational repressors, Fragile X messenger ribonucleoprotein (FMRP) or eukaryotic initiation factor 4E (eIF4E)‐binding protein 2 (4E‐BP2); and 2. pharmacological treatment with (2R,6R)‐hydroxynorketamine (HNK), an active metabolite of the antidepressant ketamine that stimulates mTORC1 signaling.ResultOur results showed that genetic reduction of FMRP and 4E‐BP2 prevented the inhibition of hippocampal protein synthesis and memory impairment induced by amyloid‐β oligomers (AβOs) in mice. Reduction of 4E‐BP2 further rescued memory deficits in the APPswe/PS1dE9 (APP/PS1) transgenic mouse model of AD. Moreover, HNK treatment prevented deficits in long‐term potentiation (LTP) and fear memory in AbO‐infused and APP/PS1 mice.ConclusionTaken together, our findings indicate that strategies targeting mRNA translation correct hippocampal protein synthesis, synaptic plasticity and memory deficits in AD models, and raise the prospect that HNK could emerge as a therapeutic approach in AD.
HDAC3 inhibition increases the expression levels of the Amyloid Precursor Protein
Authors: Sastre Magdalena , Palmisano Ilaria , Taylor Ben , Davis Nicola 
Published: December 2023

AbstractBackgroundEpigenetic‐based interventions have recently garnered attention as potential therapies for Alzheimer’s disease (AD). Histone deacetylases (HDACs) represent an interesting target for neurodegenerative diseases therapies, since HDAC inhibitors have been shown to have the ability to reinstate memory even after neuronal loss. Particularly, HDAC3 inhibition has been shown to enhance long‐term memory and reduce amyloid‐β in AD models, although the molecular mechanisms behind these effects are unclear. The aim of this study was to characterise the effects of HDAC3 inhibition on the mechanisms of generation and degradation of Aβ using in vitro and in ex vivo models of ADMethodN2a mouse neuroblastoma cells overexpressing the Swedish mutation (N2asw) as well as organotypic brain cultures (OBCs) of 5XFAD mice were incubated with various concentrations of the HDAC3 selective inhibitor RGFP966 (0.1‐10 μM) for 24h.ResultTreatment with HDAC3 inhibitor RGFP966, led to a 4% increase on Aβ42 levels in N2a cells, associated with elevated levels carboxy‐terminus fragments (CTFs) and APP protein expressions as well as APP mRNA levels. In vitro chromatin immunoprecipitation (ChIP) analysis in N2a cells, revealed enriched HDAC3 binding at APP promoter regions. The increase in APP expression was also detected in OBCs from 5XFAD mice incubated with 1 μM RGFP966, without significant changes in Aβ secretion. In addition, mRNA sequencing in OBCs revealed that HDAC3 inhibition affects neuronal regenerative pathways, in particular linked to neurogenesis, neuronal differentiation, axonogenesis, resulting in an increase in dendritic spine density.ConclusionThese results suggest that the HDAC3 therapeutic role in AD involves the regulation of APP expression and regenerative pathways, leading to increased synaptic connectivity.
Evaluating dynamic autophagic responses to tau inclusions
Authors: Vontobel Davi , Rowe Lyla A , Goodwin Marshall S , Ryu Daniel H , McHutchon Andrew , Golde Todd E , Croft Cara L 
Published: December 2023

AbstractBackgroundAlzheimer’s disease and other tauopathies are characterised by the accumulation of misfolded microtubule‐associated protein tau in intracellular inclusions. We recently showed that newly formed tau inclusions are dynamic structures with a slower, but constant turnover of aggregated tau in murine organotypic brain slice cultures (BSCs) (Croft et al., 2021). Clearance by autophagy or the proteasomal machinery are indicated to be the key mechanisms involved in pathogenic protein clearance. However, the current tools to measure these processes have received mixed review, and in particular struggle to capture these processes in a continuous manner.MethodsTo dynamically assess autophagy in the presence of tau inclusions we have repurposed the autophagic flux sensor (GFP‐LC3‐RFP∆G‐LC3) to be delivered by rAAV to specific central nervous system (CNS) cell types in BSCs. This probe delivers a cytosolic internal control so autophagic flux can be estimated by calculating the GFP/RFP ratio. When utilized in conjunction with live imaging, the rate of autophagic flux can be measured over time in the same CNS cells expressing pathological or physiological tau. The rate of autophagic flux can also be measured in response to established/novel compounds or genetic manipulation.ResultsWe have successfully developed and characterized the use of rAAV‐GFP‐LC3‐RFP∆G‐LC3 specifically in neurons and astrocytes in BSCs and are expanding its use to other CNS cell types. We have validated its use to sense autophagic flux whilst pharmacologically enhancing and inhibiting autophagy in BSCs. We are now using this sensor to determine dynamic autophagic processes in the presence of soluble tau and aggregated tau and its response to other manipulations.ConclusionsMethods to understand autophagic processes have traditionally only provided snapshots over time. With this tool we can now dynamically assess autophagy in ex vivo BSCs and characterize changes in response to tau and other pathologies. Overall, understanding the mechanisms that enable tau turnover may guide therapies for Alzheimer’s disease and other neurodegenerative conditions where tau plays a role. Importantly, we will also begin to understand whether enhancing tau inclusion clearance may be beneficial or detrimental to cell health.
In vivo neuronal deficits and microglia structural dynamics in the course of tau pathology and during antibody treatment
Authors: Martin‐Avila Alejandro , Sigurdsson Einar M. 
Published: December 2023

AbstractBackgroundWe crossed mouse models Thy‐1GCaMP6, Cx3cr1CreER:tdTomatoflox and Cx3cr1GFP with PS19 P301S tauopathy mice to visualize neuronal calcium and microglia structural dynamics in vivo during the progression of tau pathology and after tau immunotherapy.MethodBy using two‐photon live imaging in head‐restrained mice attached to a custom‐made, free‐floating treadmill, we examined calcium activity in L2/3 pyramidal neurons and microglia structural dynamics in the motor cortex during tau pathology progression and after two intravenous antibody injections targeting the truncated Asp421 epitope of tau.ResultL2/3 pyramidal neurons from young Thy‐1GCaMP6:wild‐type mice (1‐6 months old) increased their somatic activity during running periods as expected, but their littermate Thy‐1GCaMP6:PS19+/− mice did not. Importantly, acute tau immunotherapy restored neuronal function after two intravenous antibody injections (100 µg each) in Thy‐1GCaMP6:PS19+/− mice (5‐6 months old), whereas control antibody had no effect. Although tau pathology is evident in the cortex and hippocampus in 2‐3 months old Cx3cr1GFP/+:PS19+/− mice and Cx3cr1CreER/+:tdTomatoflox:PS19+/− mice, their microglia morphology did not differ from control littermate Cx3cr1GFP/+:wild‐type mice.ConclusionOur current findings indicate that functional deficits in cortical neurons associated with tau pathology start early in PS19 mice and can be alleviated by two acute tau antibody injections. Also, those neuronal functional impairments can be detected without accompanying structural changes in microglia, which suggests that neuronal deficits linked to tau accumulation precede microglial activation. Studies on the potential influence of tau antibody treatment on microglia morphology in vivo are underway.
Functional connectivity moderates the impact of synaptic loss on behaviour in frontotemporal lobar degeneration syndromes
Authors: Whiteside David J , Holland Negin , Tsvetanov Kamen A , Malpetti Maura , Savulich George , Jones P Simon , Naessens Michelle , Fryer Tim D , Hong Young T , Aigbirhio Franklin I , Mulroy Eoin , Bhatia Kailash , Rittman Timothy , O'Brien John T , Rowe James B. 
Published: December 2023

AbstractBackgroundThere is growing evidence for early and extensive synaptic loss in frontotemporal lobar degeneration syndromes from in vivo and post‐mortem studies. We proposed that synaptic loss would affect behaviour, in relation to changes in functional connectivity.MethodWe recruited 29 participants with progressive supranuclear palsy, 16 participants with amyloid‐negative corticobasal syndrome, 8 participants with behavioural variant frontotemporal dementia and 24 similarly‐aged healthy volunteers. All participants underwent resting‐state functional 3T MRI and positron emission tomography with [11C]UCB‐J, that binds synaptic vesicle 2A. We compared the connectivity metrics of nodal weighted degree and voxelwise regional homogeneity with [11C]UCB‐J non‐displaceable binding potential (BPND), in associative and commonality analyses. We then used independent component analysis to extract [11C]UCB‐J BPND signal variance across participants, followed by derivation of participant‐specific scores of functional spatial covariance with the [11C]UCB‐J components. We applied model selection to assess whether connectivity scores would improve prediction of and moderate the effect of synaptic loss on clinical severity.ResultReduced [11C]UCB‐J BPND was associated with reduced connectivity, with synaptic density predicting both measures of connectivity over and above grey matter volume (Figure 1). The anatomical distribution of synaptic loss partially overlapped in PSP, bvFTD and CBS, but there were also disease‐specific effects (Figure 2). The effect of synaptic loss on functional connectivity was expressed local to the regions of severe synaptic loss, and in remote regions. Moreover, functional connectivity explained additional variance and moderated the relationship between synaptic density and clinical severity (Figure 3).ConclusionIn vivo synaptic loss is associated with reduced connectivity, and changes in behaviour, with implications for modelling disease pathogenesis and translational studies.
A Culturally Competent Approach to the Lived Experience of Dementia
Authors: Michael Mary Chi 
Published: December 2023

AbstractBackgroundIn 2021, the Global Council on Alzheimer’s Disease (GCAD) conducted research of the lived experience and care partner journey. In 2022 and 2023, GCAD expanded this research to focus on the experiences of individuals from historically underrepresented populations, specifically the LGBTQ+, Black, Latinx, and Asian communities."A Culturally Competent Approach to the Lived Experience of Dementia” seeks to explore the key differentiating factors in the journey for each population, how and when behavioral symptoms are identified and managed, and how the burden of care shifts among each community.MethodTo understand the experiences of each community living with dementia, we undertook qualitative primary research, complemented by secondary research. Primary research consisted of dozens of one‐on‐one interviews with people living with dementia and their care partners. Secondary research consisted of a review of existing literature on each community’s experiences with dementia.ResultResults account for the journey that each community experiences. It maps not only the challenges they face, but also the resources the community has built, and how they manage care along the disease progression.ConclusionThe research identifies several key differences in the dementia experience among each community. For instance, medical inequity includes a history of exploitation, discrimination, and distrust, which impacts how care is managed. Additionally we found that there is potential for a lack of a traditional family care structure, stigma surrounding dementia, and lack of resources and tools for living well with dementia.This research also highlights the ways in which the communities are responding to those challenges. For instance, advocating for fair treatment within medical systems, raising awareness around dementia within their community, and creating systems of support and practices of careFinally, it provides calls to action for how the broader dementia community can better support those from the underrepresented communities living with dementia. Addressing bias, discrimination, and inequity in healthcare settings, and creating resources that account for the specific needs and challenges of Black, LGBTQ+, Latinx, and Asian people living with dementia.
Can an online battery match in‐person cognitive testing in predicting age‐related cortical changes
Authors: Thienel Renate , Borne Léonie , Faucher Caroline , Robinson Gail , Fripp Jurgen , Giorgio Joseph , Martin Nicholas G , Breakspear Michael , Lupton Michelle K 
Published: December 2023

AbstractBackgroundStudies into cognitive changes typically employ detailed in person cognitive testing, which is not always feasible. Therefore, we compared the relationship between brain morphology (sulcal width) and cognitive functioning, using an online and an in‐person modality and disentangled the influence of age, sex, β‐Amyloid (Aβ) and APOE‐status.Method141 healthy participants (mean age 60, range 46‐71 years, 75% female) assessed with structural MRI; cognitive batteries both, face‐to‐face and online (Cambridge Brain Systems), Aβ status (Fluorine‐18 florbetaben‐PET scan) and APOE genotype (Lupton et al., 2021); Canonical Partial Least Square method to compare cognitive modalities and Sulcal width (SW; Morphologist pipeline‐BrainVISA toolbox; Borne et al., 2020). Age effects tested with two‐sided Wald Test. Analysis of covariance to test age and sex‐interactions, amyloid and APOE status, sex‐effects (controlling for age), Aβ, and APOE (controlling for age and sex).ResultThe single robust mode for brain (SW) ‐ behaviour (cognition) covariation loaded most strongly onto memory and executive functions for both the onsite (1st mode, p = 0.013, cov = 3.55, z‐cov = 2.93, R2 = 0.18, z‐R2 = 0.95; 2nd mode, p>0.99), and the online battery (1st mode, p<0.001, cov = 2.76, z‐cov = 4.71, R2 = 0.14, z‐R2 = 1.15; 2nd mode, p = 0.99) (Fig. 1).Cognition‐related SW showed a regional pattern similar for online and in person cognitive appraisal. Significant effect of sex on SW projections in both the online and onsite conditions with larger sulcal width for men (p<0.001) and a similar effect on onsite cognitive projections with lower performance for men (p<0.001) (Fig. 2a). Cognitive performance ‐ both online (p = 0.03) and in‐person (p<0.01) – showed a significantly steeper decline with age for Aβ‐positive participants (Fig. 2b). Variance explained for the online cognitive assay (R2 = 0.15) was only slightly less than for the in‐person testing (R2 = 0.18). Brain‐behaviour z‐transformed covariance was likewise comparable across modalities.ConclusionSimilar sulcal width brain projections for both cognitive modalities, with memory and executive domains showing the strongest loadings. Aβ‐aggregation associated with a steeper cognitive projection slope for both batteries, suggesting that in our preclinical sample the early stages of Aβ accumulation accelerate cognitive ageing potentially before translation into structural brain changes. Adequate sensitivity of online cognitive tests for studying age‐related neurobiology of cognition is suggested.
Amyloid‐β and monocytes in Alzheimer’s disease
Authors: Huang Xin , Fowler Christopher J , Li Qiao‐Xin , Perez Keyla , Lim Yen Ying , Drysdale Candace , Rumble Rebecca , Villemagne Victor L , Rowe Christopher C , Martins Ralph N , Maruff Paul , Doecke James D , Lin Yong , Barnham Kevin J , Masters Colin L , Gu Ben J ,   Aibl Research Group
Published: December 2023

AbstractBackgroundCompelling evidence suggests that failure of Aβ clearance is a major mechanism of late‐onset Alzheimer’s disease (LOAD). The molecular basis remains unclear, but genome‐wide association studies (GWAS) strongly point to altered phagocytosis/endocytosis in the CNS and peripheral. Previously, we have demonstrated perturbation of monocyte basal and stimulated innate phagocytosis in LOAD.MethodFlow cytometry immunophenotyping (FCIP) is used to investigate the relationship between peripheral blood leukocyte transport Aβ and disease stage in AD patients.ResultsIn this study, we identified a subset of circulating intermediate monocytes (CD14+CD16+) that carry high amounts of Aβ dimers and co‐express the cell migration receptors CX3CR1 and CCR2. We then performed a quantitative study involving 165 AIBL participants and found that the number of monocytes carrying Aβ was decreased by 26% in AD and was inversely correlated with the subjects’ brain Aβ load and accumulation rate. Curiously, our further investigations revealed that the predominant type of infiltrating monocytes in human CSF are intermediate monocytes (CD45+CD14+CD16+).ConclusionThe passage of those cells across blood‐brain barrier and their physiological significance are unknown. But it suggests a possible mechanism for the transport of brain Aβ to the periphery by monocytes.