bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional genomic studies in diverse populations to characterize risk loci for Alzheimer Disease
Authors: Nuytemans Karen ,   the Alzheimer’s Disease Sequencing Project Functional Genomics consortium
Published: December 2023

AbstractBackgroundAs part of the ADSP Functional Genomics consortium, we aim to unravel ancestry specific effects of genomic regulation of AD loci. African Americans (AA) and Hispanics (HI) are at higher risk for Alzheimer’s disease (AD) compared to non‐Hispanic whites (NHW). Even though AA, HI and other diverse groups make up 40% of the US population, over 90% of participants in large‐scale genomic research studies have been NHW, representing European (EU) ancestry. Recent AD research including diverse groups has shown that genes and variants contributing to disease can have different risk effect dependent on the ancestral background they reside on (i.e. APOE). Together these clearly indicate a need to expand genome‐wide and gene‐specific analyses of genomic organization and regulation for other ancestries contributing to diverse, admixed populations, such as African (AF) or Amerindian (AI) ancestries.MethodWe analyzed interaction of variants in the APOE region with AD risk in WGS of diverse populations to identify modifiers of the APOEɛ4 risk effect. Additionally, to assess overall differences in chromatin regulation genome‐wide across ancestries, we performed bulk and single cell chromatin accessibility (ATAC‐seq) and bulk chromatin interaction (Hi‐C) assays in brains from admixed individuals with high EU, AF (>95%) or AI (>75%) ancestry contribution.ResultWe identified both close‐by and distant modifier variants (in the downstream PSG gene family region) inferring protection against the APOEɛ4 risk on the AF ancestry. Single cell ATAC‐seq data in brain showed higher accessibility of the APOE region and large regions of chr19 in astrocytes, but not microglia, of EU versus AF ancestry. Lastly, bulk Hi‐C analyses in brain strongly supported the hypothesis of ancestry dependent regulation by genome‐wide detection of differential chromatin interactions comparing EU to AF ancestry.ConclusionOur analyses using complementary functional genomic assay methods show clear differences of genome regulation between EU and AF ancestry. Overall, these data support genome regulation to be strongly influenced by ancestral origin. The generated data on samples with high single ancestral contributions will help elucidate risk effects seen for AD related genes in different population groups, as we describe for the APOE region.
NEUROPROTECTIVE POTENTIAL OF ALOGLIPTIN IN LIPOPOLYSACCHARIDE INDUCED EXPERIMENTAL MODEL OF PARKINSON’S DISEASE
Authors: Dhureja Maanvi , Deshmukh Rahul Renukadas 
Published: December 2023

AbstractBackgroundParkinson’s disease is a hypokinetic movement disorder characterized by selective loss of dopaminergic neurons in the substantia nigra. Dopaminergic degeneration of neurons is considered to be due to oxidative stress, neuroinflammation, mitochondrial dysfunction etc. Thus therapies that could alter all the pathologies linked with the disease and produces less or minimal side effects may work as better therapeutic target than the existing one.MethodThe intranigral LPS (5µg/μl) administration was used to induce PD like symptoms in rats. LPS‐infused rats were treated with alogliptin (10, 20 and 40 mg/kg/day/p.o.) for 21 days. Behavioral parameters and body weight analysis were performed on weekly basis to examine the movement disabilities in rats. On 21st day, animals were sacrificed; biochemical and histological assessment was done to evaluate role of alogliptin in LPS‐infused rats.ResultIt has been observed that Alogliptin at significant dose level attenuates movement disabilities in LPS induced in PD rats. Alogliptin significantly reduces malondialdehyde, nitrites levels and raises glutathione levels. These suggest that neuroprotective action of alogliptin is due to its anti‐oxidant activity. Moreover, histomorphological assessment confirms the neuroprotective activity of alogliptin.ConclusionAlogliptin has neuroprotective potential and observed increment in the motor activity of LPS‐infused rats following alogliptin treatment may be due to its antioxidant potential and ability to prevent the morphological alterations in brain cells.
Methylomic‐based molecular subtyping of late onset Alzheimer’s Disease
Authors: Laroche Valentin , Reijnders Rick A , Smith Adam R. , Eijssen Lars M.T. , Cavill Rachel , Hove Daniel L.A. , Lunnon Katie , Pishva Ehsan 
Published: December 2023

AbstractBackgroundAccumulating evidence shows that the heterogeneity and temporal complexity of Alzheimer’s Disease contribute to the treatment failure. Advances in omics technologies along with development of efficient integrative analytical pipelines, provide a unique opportunity to investigate the drivers of heterogeneity at multiple molecular levels.MethodWe used genome‐wide DNA methylation data generated in postmortem prefrontal cortex samples from two independent biobanks of Brain for Dementia Research (BDR; n = 382) and the UK Brain Bank Network (UKBBN; n = 250). Multiple unsupervised clustering methods including network‐based, Bayesian and Ensemble approaches were applied on DNA methylation data quantified by the Illumina EPIC arrays in the discovery cohort (BDR). Following each clustering methods, distinct features related to the identified subtypes were captured using classification models such as sparse partial least square discriminant analysis and random forest. The most accurate models comprising the distinct features were used to classify the samples in the UKBBN cohort into the appropriate subtypes. Clinical and pathological evaluation of the identified subtypes have been performed for both discovery and replication cohortsResultWe identified well‐defined cluster of samples in the BDR cohort. We achieved acceptable prediction values in the test data to classify the subgroups using the distinct methylation features related to the identified subtypes (AUC: 0.86 – 0.96). The best performing classification model was applied on the other independent cohort and similarly labelled samples across different cohorts were extensively characterized using relevant clinical and pathological information.ConclusionWe used state‐of the‐art methods to undertake the first systematic, DNA methylomic‐based subtyping of AD. this is a vital step to unravel the heterogeneity of the disease
Establishing the contribution of genetic risk loci in the Lewy dody diseases
Authors: Imm Jennifer L , Harvey Joshua , Creese Byron , Chouliaras Leonidas , Dempster Emma , Ballard Clive G , O'Brien John T , Aarsland Dag , Mill Jonathan , Pishva Ehsan , Lunnon Katie 
Published: December 2023

AbstractBackgroundDementia with Lewy bodies (DLB), Parkinson’s disease (PD) and Parkinson’s disease dementia (PDD) are termed Lewy body diseases (LBDs). These neurodegenerative diseases are classified by the accumulation of alpha‐synuclein in neurons, forming Lewy bodies (LB). Whilst pathologically similar, symptomatic staging is different. Previous genome wide association studies (GWAS) have identified classic Alzheimer’s disease (AD) and PD loci as risk loci in DLB. Therefore, we have used polygenic risk score (PRS) analysis to investigate the contribution of AD and PD variants in the LBDs.MethodDNA was extracted from bulk brain tissue from 481 individuals (162 controls, 95 DLB, 156 PDD and 68 PD) and genotyped on the Illumina global screening array. After a strict quality control and imputation pipeline, PRSs for multiple relevant traits using reference GWAS summary statistics were calculated using PRSice2.ResultStudy groups have been sourced consisting of cases with PD, PDD and DLB based on LB deposition and clinical symptom staging. All groups, including controls are stratified for age and concomitant AD pathology. Assessing multiple PRSs for association with pathological development and clinical outcomes we have identified the contribution of genetic risk from related neurodegenerative and neuropsychiatric disorders in our cohort of PD, PDD and DLB samples.ConclusionWe have collated a well powered study cohort to interrogate the genetic basis of the Lewy body dementias and the relative contribution of AD and PD risk loci in the LBDs. We are currently generating methylation quantitative trait loci (mQTLs) for this dataset using previously generated matched DNA methylation data in the brain.
Cortical white matter hyperintensities are associated with locus coeruleus atrophy in elder subjects
Authors: Medel Vicente , Vidal Victor , Gonzalez‐Gomez Raul , Vergara Rodrigo , Wainstein Gabriel , Orellana Patricia , Ibanez Agustin , Shine James M , Delgado Carolina , Delano Paul H , Farías Gonzalo 
Published: December 2023

AbstractBackgroundWhite matter hyperintensities (WMHs) are frequently seen on FLAIR MRI images in aging and Dementia. It has been hypothesized that an imbalance in norepinephrine (NE) signaling could lead to a “hypometabolism” by decreasing astrocyte metabolism which has been proposed as an important cause leading to local demyelination.We hypothesize that structural atrophy in human Locus Coeruleus (LC) leading to NE deficiencies could contribute to the pathophysiology of WMHs by affecting astrocytic metabolism through astrocytic beta‐adrenergic 2 receptors.MethodFLAIR na T1‐MPRAGE images were obtained from healthy elder subjects (n = 108). LC atrophy was calculated using gray matter mask. WMHs were calculated through both manual segmentation done by an expert, as well as with automatic segmentation. Gene‐expression gradient of beta‐adrenergic 2 receptor was obtained from the Allen Human Brain Atlas.ResultWe found that LC atrophy is related to an increase of WMHs, mainly in frontal lobes. We replicated previous findings associating WMHs with Gait speed, where we found that this effect was significantly mediated by LC atrophy in structural correlation analysis. We developed Linear Mixed Model to account for Random Effects in the relation between WMHs local load and the expression of beta‐adrenergic 2 receptor, and found that subjects that had a higher random effect between these variables had significantly less LC atrophy.ConclusionWMHs are correlated with LC atrohy, and spatially overlaps with beta‐adrenergic receptor 2 expression. We theorize that LC atrophy and subsequent decreased NE release disrupt normal astrocyte function through the beta 2 adrenergic receptor, leading to defective axonal metabolism and ultimately to axonal degeneration observed through WMHs with neuroimaging techniques.
Ponatinib and dabrafenib reduce the accumulation of necroptosis‐related proteins and neuronal loss in APP23xTAU58 mice.
Authors: Koper Marta J , Moonen Sebastiaan , Ronisz Alicja , Ospitalieri Simona , Rabe Sabine , Staufenbiel Matthias , De Strooper Bart , Balusu Sriram , Thal Dietmar Rudolf 
Published: December 2023

AbstractBackgroundNeuronal death is the result of the neurodegenerative process in Alzheimer’s disease (AD). Both histopathological hallmark lesions of AD, i.e., amyloid plaques and neurofibrillary tangles, are associated with reduced numbers of neurons in the brain. To model AD‐like neuronal death, mouse models with transgenic overexpression of the amyloid precursor protein (APP) and the tau protein can be used. Recently, the necroptotic cell death pathway was found to be activated in the AD brain. In this context, the activated necrosome was found in granulovacuolar degeneration (GVD) lesions in neurons. Therefore, the question arises whether inhibition of the necroptosis pathway reduces neuron loss.MethodWe analyzed APP23xTAU58 double transgenic mice for the presence of the activated necrosome in GVD lesions in association with amyloid and tau pathology. APP23xTAU58 mice at 2, 6, and 12 months of age were studied (n = 5‐10 animals/group). Neuronal densities in the subiculum and the amygdala were compared with those of wildtype littermates. To clarify whether necroptosis inhibitors can interfere with neuron death in this model, we treated APP23xTAU58 mice from 2‐6 months either with dabrafenib or ponatinib (n = 5 animals/group) and compared neuronal densities with that of vehicle‐treated mice. Neuronal densities as well as the percentage of necroptosis markers exhibiting neurons in the subiculum and amygdala were assessed.ResultSix‐ and 12‐month‐old APP23xTAU58 mice showed significantly decreased neuronal densities in the subiculum and amygdala compared to wildtype mice (p < 0.005), as well as an increased number of neurons exhibiting the necroptosis executor pMLKL in GVD lesions (p < 0.0001). Treatment with the necroptosis inhibitors ponatinib and dabrafenib reduced neuronal loss in the subiculum and the amygdala compared to vehicle treatment (p ≤ 0.0002).ConclusionThese results show that neuron loss in the APP23xTAU58 model is associated with the accumulation of necroptosis‐related proteins. This neuron loss and the expression of necrosome components can be reduced by ponatinib or dabrafenib. Thus, it is tempting to speculate that necroptosis inhibition could be a promising strategy to prolong neuron survival and, by doing so, to slow down cognitive decline in AD patients.
Funding: FWO
Effects of meditation training and non‐native language training on cognition in older‐adults: A secondary analysis of the three‐arm Age‐Well randomized controlled trial
Authors: Demnitz‐King Harriet , Requier Florence , Whitfield Tim , Schlosser Marco , Gonneaud Julie , Ware Caitlin , Barnhofer Thorsten , Coll‐Padros Nina , Dautricourt Sophie , Delarue Marion , Klimecki Olga M , Paly Léo , Salmon Eric , Schild Ann‐Katrin , Wirth Miranka , Frison Eric , Lutz Antoine , Chetelat Gael , Collette Fabienne , Marchant Natalie L ,   Medit‐Ageing Research Group
Published: December 2023

AbstractBackgroundNon‐pharmacological interventions are a potential strategy to maintain or promote cognitive functioning in older adults. We investigated the effects of 18‐months meditation or non‐native language training versus no intervention on cognition in older adults.MethodAge‐Well was an observer‐blind, randomised, controlled clinical trial with three parallel arms. Cognitively healthy adults aged ≥ 65 years and were recruited in France. Participants were randomised (1:1:1) to a meditation training, non‐native language (English) training, or a no intervention group for 18 months. Cognition (a pre‐specified secondary outcome) was assessed pre‐ and post‐intervention via the Preclinical Alzheimer’s Cognitive Composite 5 (PACC5), and composites assessing episodic memory, executive function, and attention. Linear mixed models, adjusted for age, sex, and education, evaluated cognitive changes between arms. Baseline neocortical amyloid deposition was added as a fixed effect in a sensitivity analysis. Additional sensitivity analyses assessed intervention effects for participants who attended at least 20% of intervention classes or were classified as ‘responders’.Results137 participants were randomly assigned to meditation training (n = 45), non‐native language training (n = 46), or no intervention (n = 46). Two participants were excluded for not meeting eligibility criteria, and one died during follow‐up (Figure 1). A positive effect of non‐native language training was observed on episodic memory relative to the no intervention group (0·32 [95% CI: 0·04‐0·61], p = 0·025), and on PACC5 scores compared to meditation training (0·33 [95% CI: 0·01‐0·66], p = 0·045; Figure 2). In sensitivity analyses, neither the inclusion of amyloid as an additional covariate nor the exclusion of participants who attended <20% of intervention classes affected results. Following exclusion of ‘non‐responders’, evidence for beneficial effects (relative to the no intervention group) on episodic memory became significant for meditation training (0·33 [0·01, 0·66]), and was weakened for non‐native language training (0·30 [‐0·02, 0·62]). No other between‐group differences emerged.ConclusionAmong cognitively healthy older adults, there was limited evidence for positive effects of 18‐months meditation training on cognition. However, in addition to having real‐life utility, non‐native language learning in late life may have beneficial effects on cognitive domains affected early in Alzheimer’s disease. Studies investigating whether these effects are long‐lasting are warranted.
Olfactory Mucosal Cells of Individuals with Alzheimer’s Disease Display Alterations Similar to the Alzheimer Brain
Authors: Lampinen Riikka 
Published: December 2023

AbstractBackgroundA sense of smell is orchestrated in the first place by the cells of the olfactory mucosa (OM), located in the rooftop of the nasal cavity. Impairments in olfaction are implicated in aging but also in Alzheimer’s disease (AD). Here, we describe the observed alterations in cultures of OM cells derived from individuals with late‐onset AD or amnestic form of mild cognitive impairment (MCI) when compared to OM cells derived from their cognitively healthy control subjects.MethodPrimary cultures of OM cells were harvested from biopsies of OM derived from cognitively healthy individuals and individuals with late‐onset AD or amnestic MCI and cultured in vitro. First, the cell types present in cultures of OM cells and genes differentially expressed between the OM cells derived from control subjects and individuals AD or MCI OM were assessed by single cell RNA‐sequencing (scRNA‐seq). Next, a total RNA‐seq was applied to a larger cohort of samples. The results of total and scRNA‐seq were further validated with various functional in vitro assays including inductively coupled plasma mass spectrometry (ICP‐MS) and measurements of intracellular ATP levels.ResultThe scRNA‐seq unveiled a total of five distinct cell populations in OM cell cultures. A total of 240 previously AD‐related genes were found to be differentially expressed between the AD and control OM cell cultures. Similarly, the MCI OM cells harbored 224 differentially expressed genes when compared to OM cells derived from their control subjects. Common for both AD and MCI OM cells were the alterations in genes related to mitochondrial function when compared to controls. Additionally, the ICP‐MS revealed increased levels of zinc, calcium and sodium in the AD OM cells in comparison to the OM cells derived from cognitively healthy subjects.ConclusionThe results implicate the role of olfactory mucosa as a site displaying early alterations related to Alzheimer’s disease.
A feasibility study of a 6‐week online technology‐assisted compassion training (T‐ACTS) to improve mental health in older adults living in the UK during the COVID‐19 pandemic
Authors: Khan Zunera , Da Silva Miguel Vasconcelos , Longworth‐Krafft Miranda S , Kitas Florentia , Palmer Alice , Daly Jessica , Glorioso Danielle , Aarsland Dag 
Published: December 2023

AbstractBackgroundThe COVID‐19 pandemic led to serious health implications for older adults who may have already significant comorbidities. In addition to the risk related to COVID‐19, self‐isolation and limited social contact may have led to psychosocial impacts, such as increased boredom, frustration, depression and anxiety. These stressors may have had increased effects on other key health outcomes, including worse general well‐being, and diminished quality of life. Therefore, finding techniques to boost older adults’ ability to manage these stressors is vital for better planning of unsettled events of similar nature.MethodA feasibility study assessing a 6‐week online technology assisted compassion training (T‐ACTS) for older adults (Age 60+ without a diagnosis of dementia, access to internet) living in the UK during the COVID‐19 pandemic. T‐ACTS builds on the Raise Your Resilience intervention by Treichler et al., (2020) [1] with weekly one‐to‐one online sessions by research therapists on empathy, self‐compassion, social connections, acts of kindness, gratitude, self‐efficacy, and positive ageing. Key activities included relaxation, gratitude journaling, and positive social engagement. The data reported on feasibility, demographics and mental health using the Patient Health Questionnaire at pre‐ and post‐intervention. McNemar test reported the difference in depression pre‐and post‐intervention.ResultForty‐seven participants gave consent, 35 participants entered the intervention, 25 participants (100% Caucasians, 64% females with age 76/5.74 mean/SD) completed the 6 week intervention; and 10 participants withdrew at different timepoints. Reasons for withdrawals included eligibility (1), IT difficulties (1), intervention content (1), engagement (5) and availability (2). There was a significant difference in levels of depression; pre and post intervention (p = 0.014). Around 70% of the participants found the programme enjoyful very‐much so; 30% some‐what enjoyful. Forty‐three percent found the intervention very‐much useful for setting personal goals, with 57% some‐what useful. Activities that were useful included relaxation exercises, gratitude journaling and acts of kindness.ConclusionThe T‐ACTS intervention demonstrates feasibility of pragmatic online interventions to improve mental health in older adults, suggesting high potential for further evaluation in a larger sample and implementation for older adults. Future studies are warranted for assessing benefits to other key health outcomes such anxiety and general wellbeing.
ARIA‐E, ARIA‐H, and CAA‐related inflammation: time of reconsiderations?
Authors: Piazza Fabrizio 
Published: December 2023

AbstractBackgroundEvidence from published clinical trials suggests that high‐dose of monoclonal antibodies (mAbs) are needed to significantly remove parenchymal‐deposited Aβ plaques. However, high‐dosing mAbs resulted in a 25‐35% increased risk of amyloid‐related imaging abnormalities‐edema (ARIA‐E) and ARIA‐hemorrhage (ARIA‐H) side events. Although most ARIA‐E are incidentally recognized as clinically silent during pre‐planned safety monitoring MRI scans and suggested to be managed by dose reduction or suspension, it is noticeable that half of ARIA‐E progressed to symptomatic at continued dosing and to associate with late occurrence of ARIA‐H. Of particular importance, a few of them aggravated to potentially severe brain injury or death due to fatal CAA‐related events. Increased evidence from natural history studies suggests that ARIA‐E is the iatrogenic manifestation of cerebral amyloid angiopathy‐related inflammation (CAA‐ri), a rare autoimmune encephalopathy due to raised anti‐Aß autoAbs levels in the cerebrospinal fluid (CSF).MethodNatural history study of CAA‐ri demonstrated that immunotherapy‐related ARIA‐E share several commonalities with the spontaneous occurrence of autoAbs‐related ARIA‐E, including fluid, MRI, and PET biomarker changes and the potential response to treatment outcomes.ResultThe prospective longitudinal monitoring of patients with CAA‐ri provide evidence for a regional and temporal association of ARIA‐E on MRI with focal peaks of neuroinflammation on microglial‐PET imaging. This association was strong in patients with positive CSF markers of AD (ATN positive) and comorbid CAA pathology on MRI, while it was negligible in patients with CAA disease w/o AD (ATN negative). Raised CSF concentrations of anti‐Aß autoAbs were found in all patients at (sub)acute presentation, and reduced within 5 months from the ARIA‐E index event, in parallel with evidence of radiographic resolution of ARIA‐E. At follow‐up MRI scan, the occurrence of new hemorrhagic markers (aka ARIA‐H in trials) were found only in patients with coexisting CAA and AD comorbid pathology. The MRI scales for ARIA commonly used in clinical trials only partially paralleled the clinical, biological, and MRI findings.ConclusionThis suggests that to mitigate and monitor the risk of ARIA, more sensitive, specific, cost‐effective and easy to interpret diagnostic tools and biomarkers than MRI alone will be needed for precision drug‐dose tailoring.