bluuebunny/crossref_metadata_2025_split huggingface dataset:
Imaging markers in dementia with Lewy bodies
Authors: Ferreira Daniel 
Published: December 2023

AbstractBackgroundImaging markers are central to diagnose and monitor disease progression in dementia with Lewy bodies (DLB). This presentation provides an up‐to‐date overview of the contributions of positron emission tomography (PET) and magnetic resonance imaging (MRI) to the field of DLB.MethodsExpert opinion and road‐map for the future based on the current state‐of‐the‐art.ResultsPET for Lewy pathology is an active area of research but a reliable tracer is still lacking. Tracers for glucose metabolism and dopaminergic deficits have merited inclusion in diagnostic criteria for DLB. Alzheimer’s disease (AD) co‐pathology is common in DLB. Amyloid PET has been used in DLB for a long time and most studies show an elevated frequency of a positive amyloid scan in DLB. Tau PET has recently attracted attention, with studies suggesting an atypical pattern of tau PET uptake in DLB, different from the pattern seen in AD. Newest advances include PET tracers for synaptic activity, microglial activation, and neuromelanin. MRI findings in DLB traditionally include preservation of hippocampal volume, as compared with AD. More recent findings encourage the inclusion of a pattern of cortical neurodegeneration, mostly affecting posterior cortical areas, with sparing of the hippocampus. This finding is consistent across MRI markers (volume, thickness, functional MRI, diffusion, perfusion, and connectivity). Advanced techniques for cholinergic system have shown vulnerability of cholinergic basal forebrain and its white matter projections.ConclusionsNeuroimaging is central for DLB diagnosis and for advancing mechanistic knowledge about the disease. Biomarkers of Lewy pathology are emerging and will revolutionize the field, but in the absence of topographical markers, the reviewed techniques will have an important role in precision medicine, for example, helping to identify subgroups with different disease trajectories or treatment response.
Apolipoprotein E Receptor 2 is associated with Alzheimer’s disease pathogenesis
Authors: Belaidi Abdel Ali , Bush Ashley I , Ayton Scott 
Published: December 2023

AbstractBackgroundGenetic variations to apolipoprotein E (apoE) underlie the strongest risk for Alzheimer´s disease (AD) after aging but it is not yet known how apoE confers risk for AD. While most research is focusing on dysregulations associated with the presence of the risk allele of apoE, several aspects of apoE biology remain poorly understood. In particular, the physiological relevance of apoE interaction with members of the low‐density lipoprotein (LDL) receptor gene family is not well understood.MethodFerroptosis was induced in the N27 neuronal cell model of ferroptosis using multiple agents (erastin, RSL3, iron, cysteine depletion). Genetic variants of apolipoprotein E receptor 2 (apoER2) were generated via site‐directed mutagenesis and expressed in N27 neurons. The severity of ferroptosis was measured by several toxicity assays (MTT, LDH) and lipid peroxide probe (C11BODIPY). The association between apoER2 polymorphism and cognition were investigated in two longitudinal studies: the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the Australian Imaging Biomarkers and Lifestyle Study of Ageing (AIBL).ResultWe recently reported that apoE is a potent inhibitor of ferroptosis in neuronal cells in a mechanism that involves a receptor‐mediated activation of the PI3K/AKT signaling pathway. In this study, we identified genetic variants of apoER2 (also known as LRP8, a member of the LDL receptor family) that were associated with slower cognitive decline in clinical cohorts of AD. In preliminary work, we show that one apoER2 variant was associated with an increased protection from ferroptosis in an apoE‐dependent process.ConclusionWe present evidence for a biological role of apoER2 and its genetic variation on pathologies associated with Alzheimer’s disease, which may help develop new diagnostic and therapeutic approaches towards the disease.
Age‐related alterations in meningeal immunity drive impaired central nervous system waste removal
Authors: Rustenhoven Justin 
Published: December 2023

AbstractBackgroundThe meningeal lymphatic network enables the drainage of cerebrospinal fluid (CSF) and facilitates the removal of central nervous system (CNS) waste. During aging and in Alzheimer’s disease, impaired meningeal lymphatic drainage promotes the buildup of toxic misfolded proteins in the CNS. Reversing this age‐related dysfunction represents a promising strategy to augment CNS waste clearance, however, the mechanisms underlying this decline remain elusive.MethodYoung (2‐3 month old) and aged (20‐24 month old) C57BL/6J mice were used to study age‐related meningeal phenotypes by single‐cell RNA‐sequencing (scRNA‐seq), high dimensional flow cytometry, and immunohistochemistry. Lymphatic drainage to deep cervical lymph nodes was determined by CSF‐delivery of ovalbumin‐A594. CSF‐delivery of AAVs or antibodies were used to model age‐related deficits in young mice. Peripheral chronic neutralizing antibody administration was utilized to attenuate age‐related alterations in aged mice. 3D in vitro microfluidic devices of human lymphatic endothelial cells were used to model physiological flow parameters.ResultscRNA‐seq of meningeal lymphatic endothelial cells from aged mice revealed a response signature to the inflammatory cytokine IFNγ, which was increased in the aged meninges due to T cell accumulation. Chronic elevation of meningeal IFNγ in young mice via AAV‐mediated over‐expression attenuated CSF drainage—comparable to the deficits observed in aged mice. Mechanistically, this occurred through disruption of lymphatic adherans junctions which was confirmed in 3D in vitro microfluidic systems, and through antibody‐mediated VE‐Cadherin disruption. Therapeutically, IFNγ neutralization alleviated age‐related impairments in meningeal lymphatic function.ConclusionHere we demonstrate that alterations in meningeal immunity underlie the age‐related lymphatic impairment and impaired CNS waste removal. These data suggest manipulation of meningeal immunity as a viable approach to normalize CSF drainage and alleviate the neurological deficits associated with impaired waste removal in neurodegenerative disease.
Microglia‐mediated T cell Infiltration Drives Neurodegeneration in Tauopathy
Authors: Chen Xiaoying , Firulyova Maria , Manis Melissa , Herz Jasmin , Smirnov Igor , Aladyeva Ekaterina , Wang Chanung , Bao Xin , Finn Mary Beth , Hu Hao , Shchukina Irina , Kim Min Woo , Yuede Carla M , Kipnis Jonathan , Artyomov Maxim N , Ulrich Jason D , Holtzman David M. 
Published: December 2023

AbstractBackgroundExtracellular amyloid‐β (Aβ) deposition as neuritic plaques and intracellular accumulation of hyperphosphorylated, aggregated tau as neurofibrillary tangles (NFT) are two of the characteristic hallmarks in Alzheimer’s disease (AD). The regional progression of brain atrophy in AD highly correlates with tau accumulation but not amyloid deposition and the mechanisms of tau‐mediated neurodegeneration are not clear. Innate immune responses represent a common pathway for the initiation and progression of some neurodegenerative diseases. To date, little is known about the extent or role of the adaptive immune response in the presence of Aβ or tau pathology.MethodWe utilized transgenic mice that develop Aβ deposition or tau pathology and neurodegeneration. We isolated all immune cells in the brain followed by single cell RNA sequencing and systematically compared the immunological milieus in the brain of mice with amyloid deposition or tau aggregation and neurodegeneration. Histological, biochemical, and behavioral analyses were also performed to assess the immune response and brain damage in the different mice with or without different treatments.ResultWe found that mice with tauopathy but not amyloid, developed a unique innate and adaptive immune response and that depletion of microglia or T‐cells blocked tau‐mediated neurodegeneration. T cells, especially cytotoxic T cells, were markedly increased in areas with tau pathology in mice with tauopathy and in the AD brain. T cell numbers correlated with the extent of neuronal loss, and dynamically transformed their cellular characteristics from activated to exhausted states along with unique TCR clonal expansion. Inhibition of IFN‐γ and PD‐1 signaling both significantly ameliorated brain atrophy.ConclusionOur results thus reveal a tauopathy and neurodegeneration‐related immune hub involving activated microglia and T cell responses, which could serve as therapeutic targets for preventing neurodegeneration in AD and primary tauopathies.
Haploinsufficiency of progranulin causes mitochondrial dysfunction
Authors: Bautista Javier S. , Falabella Micol , Lu Shanti , Rohrer Jonathan D. , Plun‐Favreau Helene , Wray Selina , Taanman Jan‐Willam , Pitceathly Robert D. S. , Pitceathly Robert D.S. 
Published: December 2023

AbstractBackgroundFrontotemporal dementia (FTD) is the second most common cause of young‐onset dementia, caused by nerve loss in the frontal and temporal lobes. Mutations in the progranulin (GRN) gene are one of the leading causes of FTD, resulting in a happloinsufficiency of the soluble protein progranulin (PGRN). However, the effect of PGRN happloinsufficiency on mitochondrial activity has not been explored in FTD.MethodA stable GRN knockdown was generated in H4 neuroglioma cells using a lentiviral shRNA vector. Mitochondrial DNA and RNA transcripts were measured by quantitative polymerase chain reaction (qPCR), protein expression by Western Blot analysis, and bioenergetics profile by Seahorse analysis and Native PAGE.ResultIn the H4 model, PGRN deficiency induced a bioenergetic impairment, indicating a mitochondrial defect. The activity of the complexes of the electron transport chain was decreased. In addition, we observed impaired mitochondrial genomics.ConclusionThese results suggest that PGRN happloinsufficiency may play a role in mitochondrial homeostasis, which may be contributing to the development of FTD. Future work will involve characterising the mitochondrial mechanism, and further validating these findings in FTD patient samples.
Improvement of cognitive skills in elderly undergoing vestibular rehabilitation
Authors: Ribeiro Marlon Bruno Nunes , Mancini Patricia Cotta , Bicalho Maria Aparecida Camargo 
Published: December 2023

AbstractBackgroundstudies that used vestibular rehabilitation (VR) found improvement in cognitive abilities of spatial memory, visuospatial function, executive functions, attention and a decrease in psychological distress. However, these studies only used cognitive screening tests or did not include comprehensive neuropsychological assessment.Methodlongitudinal, observational, analytical and quasi‐experimental study. The sample consisted of 50 elderly people of both sexes, aged between 60 and 86 years. Elderly people with vestibular dysfunction confirmed by the Vestibular Evoked Myogenic Potential (VEMP) and Video Head Impulse Test (v‐HIT) tests were included. The Geriatric Depression Scale ‐ short version (GDS‐15) was used to assess psychological distress and cognition was assessed using the Brief Neuropsychological Battery (Neupsilin). Psychological distress and cognition were assessed before and after eight sessions of vestibular rehabilitation according to the Cawthorne and Cooksey method (customized). Pre and post VR variables were detected using the Wilcoxon test. A significance level of 5% was adopted (p< 0.05).Resultafter vestibular rehabilitation, there was improvement in general cognition ‐ Neupsilin (142/145) and its subscales orientation (8/8), attention (12/20), memory (24/26), arithmetic skills (5/7), oral language (20/21), written language (28/29), praxis (12/14.5), executive functions (5/6) and decrease in psychological distress ‐ GDS‐15 (5/3).Conclusionafter vestibular rehabilitation, the elderly showed improvement in general cognition, orientation skills, memory, arithmetic skills, oral and written language, praxis and executive functions. Also note the decrease in psychic suffering.
Perspectives of older adults and general practitioners on ageing and cognitive decline in primary care within the context of a decentralised antihypertensive dementia prevention trial
Authors: Hurden Alexandra , Anderson Craig S. , Cotter Isabella , Naismith Sharon L , Mowszowski Loren , Peters Ruth 
Published: December 2023

AbstractBackgroundBlood pressure (BP) lowering is the most promising strategy for dementia risk reduction.1 However, few clinical trials have been designed to evaluate the impact of BP lowering on dementia as a primary endpoint, and concerns persist over harms associated with this treatment, particularly in older, frailer people.2 Community engagement will guide the design and conduct of such a trial. To gain a better understanding of concerns and potential barriers in this topic, we undertook focus group discussions with memory‐clinic patients without dementia and interviews with general practitioners to gain insights on the topics of cognitive decline, antihypertensive medications, and motivation to participate in a dementia prevention trial.MethodTwo focus groups (N = 7) with memory‐clinic participants (patients [age ≥60yr] with a history of mild cognitive and/or memory complaints without dementia and family carers of a patient with dementia) and 5 individual interviews with practitioners (metropolitan Sydney) were conducted in July 2022. Thematic analysis was used to identify recurring themes .ResultThe most common themes identified by patients included: valuing clear and timely communication from practitioners; valuing accessible options and considerations for computer‐based testing and treatment; and having fears and experience of dismissal from practitioners and peers about their ageing and declining health. Practitioners identified similar priorities of: clear and timely communication and accessibility in the context of a clinical trial; and insights into how cognitive decline is noticed and how individuals are supported, across different community contexts (i.e., social groups with higher levels of social connection and neighbourly bonds corresponded with lower perceived impact of cognitive decline). Importantly, although practitioners expressed concern for their patients, they reported that time restrictions limited the comprehensiveness of their ability to provide diagnostics and care.ConclusionAlthough limited by sample size, this study identified large issues for the conduct of clinical trials and in community dementia care. These concerns need due consideration for future trial designs and primary healthcare guidelines in the areas of dementia prevention, diagnoses, and care.
References
1.	Peters et al., 2022 https://doi.org/10.1093/eurheartj/ehac584
2.	Veenhuizen et al., 2021 https://doi.org/10.1093/ageing/afaa198
A Europe‐wide randomised controlled trial of hearing and vision rehabilitation in dementia: Additional findings from the SENSE‐Cog trial
Authors: Leroi Iracema , Camacho Elizabeth , Chaghil‐Boissier Nathalie , Charalambous Anna Pavlina , Connelly JP , Constantinidou Fofi , David Renaud , Elliott Rachel , Frison Eric , Hann Mark , Holden Alison , Kennelly Sean P , Lawlor Brian , Longobardi Julie , Politis Antonios , Kontogianni Evangelia , Rao Vinay Sudhindra , Reeves David , Termote Monique , Thodi Chryssoula , Worthington Mark , Yeung Wai ,   SENSE‐Cog RCT Study Group
Published: December 2023

AbstractBackgroundHearing and vision impairments are highly prevalent in people with dementia (PwD) and may have a negative impact on quality of life and other dementia‐related outcomes. Intervening to optimise sensory impairment and support sensory function may be a means of improving dementia‐related outcomes. The SENSE‐cog Trial evaluated whether a home‐based multi‐part ‘sensory support’ intervention (SSI) is effective in improving quality of life and other key outcomes in PwD (including hearing and/or vision problems), and their partners.MethodThis was a pan‐European, multi‐centre, observer blind, randomised controlled trial (RCT), of PwD with hearing and/or vision impairment and their partners. We evaluated a multi‐part complex intervention of hearing and vision rehabilitation tailored to each participant dyad, compared to care as usual (CAU). The intervention included at a minimum: assessment and correction of hearing and/or vision impairments; home‐based, therapist‐delivered sensory support (i.e., adherence with devices; improving the sensory environment (i.e., lighting), communication training, and signposting to other support agencies.ResultAcross 7 centres in the UK, Ireland, Greece, France and Cyprus, 291 participants with dementia were randomised from May 2018 to May 2021 to receive either ‘care as usual’, or a multi‐component sensory intervention (10 visits over 18 weeks). Mitigating strategies to adapt study procedure to the COVID‐19 pandemic were implemented. Significant difference in Quality of Life at 36 weeks was not seen; however, significant differences at 18 weeks were seen, with average DEMQoL scores being lower (poorer QoL) in the CAU group by between 2.6 and 2.7 units/ points at this time point, adjusted for covariates. The focus of this presentation will be on secondary outcomes including activities of daily living and functional ability (dementia‐ or sensory‐related) across the two groups. No serious adverse effects were related to the intervention; low grade adverse effects related to the intervention were reported by five participants only.ConclusionHearing and vision support and rehabilitation in PwD living at home is a potentially important means of improving the lived experience of dementia and may represent a critical step in the diagnostic and post‐diagnostic care pathway. However, effects may not be sustained over the longer term.
Multi‐Omics Insights Into The Heterogeneity Of Depression In Alzheimer’s Disease
Authors: Chiba‐Falek Ornit , Upadhya Suraj , Lutz Michael W 
Published: December 2023

AbstractBackgroundDepression is a common, though heterogenous, comorbidity in late‐onset Alzheimer’s Disease (LOAD) patients. Moreover, individuals with depression are at greater risk to develop LOAD. In prior work, we performed pleiotropy analysis and found shared genetic etiology between LOAD and Major Depressive Disorder (MDD), suggesting inter‐relationship between LOAD and depression symptoms. However, the underpinning genetic, epigenetic, and transcriptomic etiologies predisposing the comorbidity of depression in LOAD, are largely unknown.MethodThis work applied various bioinformatics methods including analyses of polygenic risk scores (PRS), differential gene expression and DNA‐methylation. The discovery analyses were performed using ROSMAP datasets including, genotypes, transcriptomic, DNA‐methylomic and depression diagnosis. When available the NACC dataset was used for validation. In addition, MDD‐GWAS summary statistics from the Psychiatric Genomics Consortium were used to create the PRS.ResultWe constructed PRS based on MDD‐GWAS data and assessed its performance in predicting depression onset in LOAD patients. The PRS showed marginal results in standalone models for predicting depression onset in both ROSMAP (AUC = 0.540) and NACC (AUC = 0.527). Full models, with baseline age, sex, education, and APOEε4 allele count, showed improved prediction of depression onset (ROSMAP AUC: 0.606, NACC AUC: 0.581). In time‐to‐event analysis, standalone PRS models showed significant effects in ROSMAP (P = 0.0051), but not in NACC cohort. Full models showed significant performance in predicting depression in LOAD for both datasets (P<0.001). Next, we investigated differential gene expression in LOAD patients with and without comorbid depression and didn’t reveal significant association between differences in gene expression and the risk of depression in LOAD. Upon sex‐stratification, we identified 25 differential expressed genes (DEGs) in males, of which CHI3L2 showed the strongest upregulation, and only 3 DEGs in females. Finally, we tested differences in DNA‐methylation and found significant hypomethylation with only one CpG probe.ConclusionOur study is the first multi‐omics genome‐wide exploration of the genomic landscapes underlying the heterogeneity of depression in LOAD. Our developed PRS accurately predicted LOAD patients with depressive symptoms. Furthermore, we discovered sex‐dependent differences in gene expression associated with the risk of depression symptoms in LOAD. Collectively, our results have clinical implications for the diagnosis and treatment of depression in LOAD patients.
Ameliorative potential of thymoquinone in four vessel occlusion induced vascular dementia in rats
Authors: Rishitha Narahari , Muthuraman Arunachalam 
Published: December 2023

AbstractBackgroundVascular dementia (VaD) is a common type of dementia caused by reduction of blood flow to the brain via deprivation of brain cellular oxygen and nutrients supply. At present VaD is the second most occurring type of dementia in older adults and stoke patients. Around 55 million people have dementia globally. As per WHO survey is expected to rise to 78 million in 2030 and triple by 2050. Generally Hypo perfusion and thromboembolic events reduces the cerebral blood flow to the brain which leads to oxidative stress, hypoxia and inflammation further it causes mitochondrial dysfunction results in VaD. The current treatment for VaD relieves various unwanted side effects. However, the specific medicines with more potent and high efficacy are not explored yet. Neuro‐inflammation and oxidative stress has been widely correlated to be involved in the pathogenesis of VaD. Therefore, finding new therapeutic targets or drugs for VaD treatment is vital. Some of the herbal moieties and synthetic derivatives are reported to prevent cognitive disorders via amelioration of neurovascular disorders.MethodMale Wistar Albino Rats (weight, 150 to 180 g), Cerebral hypo perfusion (CPH) was done in rats to create hypoxia in order to induce VaD, after the CPH all animals were treated with Thymoquinone (TQ (5 and 10mg/kg)). Invitro study of mast cell degranulation, Behavioral assessments; Biochemical markers and Histopathological evaluation.Result4VO cause the potential neurovascular damage leads to significant changes in learning and memory functions along with the alteration of psychosocial and neuromotor functions. Besides, Four vessel occlusion (4VO) induces the bio‐molecular changes in hippocampus. Treatment of TQ shown significant (p < 0.05) ameliorative effect against 4VO induced cerebrovascular injury, cognitive impairments, neuroinflammation in rats. It is also comparable with the reference compound donepezil treatment. In the present study, it also showed the cognitive dysfunction with alteration of learning and memory functions. And, it also psychosocial behavior.ConclusionOur findings suggested that TQ may be use as a future medicine for metabolic and neurotoxic associated neurovascular disorders due to its potential anti‐oxidative, anti‐lipid peroxidative, anti‐inflammatory, and acetylcholinesterase inhibitory actions.