bluuebunny/crossref_metadata_2025_split huggingface dataset:
TML‐6 is a novel anti‐aging and Aβ‐lowering drug candidate with potential for anti‐Aβ antibody drug combination therapy
Authors: Yu Hsu Chia‐ , Wang Hui‐Chen , Shie Feng‐Shiun , Hsueh Jung‐Tsung , Wu Chiu‐Chu , Hou Ting‐Yi , Lin Tzu‐Han , Su Ih‐Jen 
Published: December 2023

AbstractBackgroundThese suggest that TML‐6’s ability to enter the brain parenchyma and possibly interact with and reduce Aβ, while possessing anti‐aging and anti‐inflammatory properties contributes to its effects on alleviating AD‐like pathology and behavioral deficit in APP/PS1 mice. Importantly, TML‐6 is safe and has promising drug bioavailability and exposure in pre‐clinical development. Taken together, TML‐6 exhibits promising druggability and meets the current strategy to develop as a first‐in‐class oral therapeutic drug for AD.MethodTML‐6 was applied to investigate the binding with Aβ peptide (1‐40 or 1‐42), hERG, and safety panel screening assay in vitro. Further, the effects of TML‐6 treatment on reducing AD‐like pathology, TML‐6 concentration in plasma‐to‐brain ratio, and inflammaging biomarkers in APP/PS1 mice were evaluated. Lastly, pharmacokinetic and toxicology studies in rats and dogs were performed.ResultData from pre‐clinical development showed that TML‐6 bound Aβ1‐40 and Aβ1‐42 in vitro and improved behavioral deficits with reduced inflammaging in AD model mice (e.g., TNF‐α, IL‐1β, & IL‐6). The TML‐6 levels in the plasm and brain tended to dose‐dependently increase in AD mice, which inversely correlated with behavioral deficits and AD‐like pathologies. TML‐6 was well tolerated in toxicology in rats and dogs and had no off‐target safety pharmacology issue by hERG & safety panel screening. Most importantly, formulation optimization of TML‐6 exerted satisfactory drug bioavailability and exposure.ConclusionThese suggest that TML‐6’s ability to enter the brain parenchyma and possibly interact with and reduce Aβ, while possessing anti‐aging and anti‐inflammatory properties contributes to its effects on alleviating AD‐like pathology and behavioral deficit in APP/PS1 mice. Importantly, TML‐6 is safe and has promising drug bioavailability and exposure in pre‐clinical development. Taken together, TML‐6 exhibits promising druggability and meets the current strategy to develop as a first‐in‐class oral therapeutic drug for AD.
SNX19 in human autopsy brains and cerebral organoids
Authors: Ma Liang , Wang Jinghui , Chen Qiang , Estevez Vanesa , Sargurupremraj Muralidharan , Kleinman Joel , Weinberger Daniel , De Jager Philip L , Hsieh Jenny , Seshadri Sudha 
Published: December 2023

AbstractBackgroundThe gene encoding sorting nexin SNX19 is highly expressed in neurons. SNX19 modulates synaptic functions that have been implicated in Aβ formation and tau phosphorylation. In our recent postmortem brain transcriptomic study (n = 409), we found an association of SNX19 gene expression with increased schizophrenia risk. To date, this gene has not been studied in AD. In this project, we will define AD risk single nucleotide variants (SNVs) at this locus, linking the SNVs to SNX19 gene expression and DNA methylation sites in human postmortem brains. we will test the hypothesis that SNX19 induces neuronal dysfunction and Alzheimer’s disease (AD)‐related pathologies in hiPSCs derived cerebral organoids.MethodWe collected human postmortem bulk brain dorsolateral prefrontal cortex (DLPFC) RNA‐seq data from Religious Orders Study/Memory and Aging Project (ROSMAP N = 656). We obtained two human induced pluripotent stem cells (hiPSCs) from HipSci.ResultWe performed a multi‐trait analysis and identified single nucleotide variants (SNVs) in SNX19 that were associated with AD and DSST. To uncover the regulatory mechanism linked to the SNX19‐AD risk SNVs, we examined the possible association of these SNVs with SNX19 abundance. As expected, the SNVs are significantly associated with SNX19 gene expression in DLPFC from 656 aging brains generated by ROSMAP (p‐value < 1e‐20).Given the role of DNA methylation in influencing local gene expression and splicing in the human brain, we evaluated the association between SNV genotype and DNA methylation levels from 401 autopsy brains in our schizophrenia study. We identified cg14779329 as the top hit with schizophrenia functional SNV rs10791098. Interestingly, this CpG site was replicated to be associated with DSST‐risk SNVs in 692 ROSMAP brains.To determine whether SNX19 protein influences aspects of neurodegeneration, we have performed CRISPR gene editing in hiPSCs. We are generating cerebral organoids to assess the SNX19 impact on neuronal morphology, AD‐related pathologies and synaptic function.ConclusionOur study identified novel AD factors at SNX19 in human postmortem brains and will define its role in AD using human‐derived tissue cultures.
Influence of lung function on macro‐ and micro‐structural brain changes in mid‐ and late‐ life: a large population‐based cohort study in the UK Biobank
Authors: Wang Jiao , Dove Abigail , Yang Wenzhe , Bennett David A. A , Xu Weili 
Published: December 2023

AbstractBackgroundLung function has been associated with cognitive decline and dementia, but the extent to which lung function impacts brain structural changes remains unclear. We aimed to investigate the association of lung function with structural macro‐ and micro‐ brain changes across mid‐ and late‐ life in a large population‐based cohort study.MethodThe study included a total of 37,590 neurologic disorder‐free participants aged 40‐70 years from the UK Biobank, who underwent brain magnetic resonance imaging (MRI) scans 9 years after baseline. After 2.5 years, a subsample (n = 3,941) underwent a second MRI scan. Lung function was assessed using a composite score based on forced expiratory volume in 1 second, forced vital capacity, and peak expiratory flow, and divided into tertiles (i.e., low, moderate, and high). Regional brain volumes (including total brain, gray matter, white matter, hippocampus, and white matter hyperintensities) and diffusion markers (fractional anisotropy [FA] and mean diffusivity [MD]) were assessed. Data were analyzed using linear regression and mixed‐effects models.ResultAt baseline, lung function ranged from ‐3.43 to 22.91 among all participants. In multi‐adjusted linear regression, low lung function was dose‐dependently related to smaller brain volumes and lower white matter integrity. Compared to high lung function, low lung function was associated with smaller total brain (β [95% CI]: ‐0.083 [‐0.097, ‐0.070], gray matter ‐0.145 [‐0.161, ‐0.130], white matter ‐0.017 [‐0.031, ‐0.004], and hippocampal ‐0.102 [‐0.128, ‐0.075]) volume, as well as poor white matter health (FA ‐0.165 [‐0.195, ‐0.135] for lower, WMH 0.269 [0.242, 0.295] and MD 0.168 [0.140, 0.196] for higher). Over the 2.5 years follow‐up, low PF was associated with reduced white matter (‐0.021 [‐0.041, ‐0.002]) and hippocampal (‐0.078 [‐0.110, ‐0.046]) volume, reduced FA (‐0.063 [‐0.091, ‐0.035]), and increased WMH volume (0.065 [0.016, 0.114]) and MD (0.121 [0.089, 0.154]). After stratification by age, the associations remained significant among adults aged 40‐60 years and 60+ years.ConclusionLow lung function is associated with macro‐ and micro‐ structural brain changes involving both neurodegenerative and vascular pathologies. This association is significant in both mid‐ and late‐ life.
Determinants underlying COVID‐19 vaccination behaviour in people with young‐onset dementia and their carers in the United Kingdom: A mixed‐methods study
Authors: KAFADAR Aysegul Humeyra , Jones Katy A , Stephan Blossom CM , Dening Tom 
Published: December 2023

AbstractBackgroundVaccine hesitancy is a risk to global health and has become particularly salient considering the COVID‐19 pandemic. To date, no studies have investigated COVID‐19 vaccination behaviour in people with young‐onset dementia (YOD) and their carers. This study aimed to fill this gap.Method26 participants with YOD and 24 carers for a person with YOD (i.e., aged <65 years) from the UK were enrolled. Participants filled out a self‐administered online questionnaire including demographic data, history of COVID‐19, and adulthood vaccination. Following this, participants attended a one‐to‐one semi‐structured interview focused on their experiences and thoughts on COVID‐19 vaccines and the vaccination process.ResultThe mean age of participants with YOD was 42.2 (range 26‐60), 88.5% were male, and 96.2% self‐identified as Black. The mean age of carers was 31.7 (range 19‐54 years), 70.8% were male, and 79.2% self‐identified as Black. In total, more than 30 reasons for acceptance and hesitation were identified. Willing to protect themselves, loved ones, and the community were identified as important reason to accept the vaccination by both groups. Recommendations from family members or healthcare professionals and wanting to go back to normal life were two of the most commonly repeated acceptance reason for people with YOD. Meanwhile, two of the most frequently mentioned acceptance reasons in carer groups were believing vaccination is the right thing to do and knowing the severity of COVID‐19.Several causes of vaccine hesitancy were mentioned by both groups, including fear of vaccine side effects and hearing negative news about the vaccination. In addition, people with YOD, but not carers, also identified fear of needles and suspicion that vaccination would exacerbate dementia as important causes of vaccine hesitancy. Important difficulties experienced in the vaccination process included long queues for vaccination, remote vaccine centre locations, and needing to be accompanied to the hospital for each dose.ConclusionParticipants delayed or refused COVID‐19 vaccination largely due to resolvable reasons such as a lack of time, issues around queuing, inaccurate information about vaccines, or previous negative experiences. Future research should explore the factors of COVID‐19 vaccination behaviour in women and in other ethnic groups.
Towards inclusive trial design for vascular cognitive impairment in the diverse context of India
Authors: Alladi Survana 
Published: December 2023

AbstractBackgroundThe burden of vascular contribution to cognitive impairment and dementia is substantially higher in low and middle‐income countries like India compared to the high‐income countries (HIC). Nearly 40% of 5.3 million people with dementia are estimated to be due to vascular aetiology. This high burden of vascular cognitive impairment (VCI) is due to a greater prevalence of vascular risk factors such as diabetes, hypertension and stroke as well as low awareness and a wide treatment gap. Lack of validated diagnostic instruments in various regional languages and availability brain imaging pose challenges to diagnosis of VCI. These factors pose unique challenges to reducing the burden of VCI in India. Novel clinical trials are being implemented to risk of progression of VCI, but these efforts are mainly restricted to HIC. The limited availability of evidence for effective treatment and preventive strategies in the context of diverse countries like India are major impediments to effective public health interventions to reduce burden.MethodWe present results from a large cohort of 2000 individuals from multiple centres across the country including individuals at high risk of developing VCI, patients with vascular mild cognitive impairment and vascular dementia. Languages spoken by patients included Kannada, Telugu, Hindi, Malayalam, Urdu, Bengali and English among others. A were illiterate and around 60% were bilingual.ResultsHarmonised cognitive and functional measures adapted to multiple Indian languages and educational variability were used to detect VCI in the diverse population. MRI imaging to detect vascular imaging biomarkers was performed to detect infarcts, cortical atrophy, microbleeds and white matter lesions, for accurate identification of vascular damage and neurodegeneration. Collaborations between multiple centres in a systematic manner are ongoing. Novel public health initiatives with support of policy makers are also being implemented to improve brain health by increasing awareness and reducing risk of stroke and dementia in the community.ConclusionsThese large‐scale efforts towards developing clinical‐trial readiness of VCI cohorts in the community across India will be crucial to fill research evidence gaps and implement clinical trials in India in concurrence with ongoing global efforts.
Attenuating DNA hypermethylation enhances insulin signaling and reduces apoptosis in an in vitro model of DLB
Authors: Lin Chih‐Li , Tsou Sing‐Hua , Huang Chien‐Ning , Chang Ching‐Chi , Ho Ying‐Jui 
Published: December 2023

AbstractBackgroundDementia with Lewy bodies (DLB) is the second most prevalent degenerative dementia after Alzheimer’s disease (AD). The cause of DLB is known to be associated with abnormal protein aggregations called Lewy bodies within affected neurons. Studies have shown that Lewy bodies are mainly composed of α‐synuclein. Normal α‐synuclein is a water‐soluble monomer. However, when triggered by certain factors, the folding of the protein changes, causing it to aggregate and accumulate inside neurons. Previously, we have demonstrated that amyloid β (Aβ) can promote α‐synuclein aggregation and neurotoxicity, which provides a molecular mechanism that reasonably explained the pathogenesis of DLB. A major risk factor for DLB is known to be aging, but its role in disease progression, especially with regard to epigenetic regulation, is still unclear.MethodIn this study, we investigated whether DNA hypermethylation, a common phenomenon in cellular aging, might be a factor in the progression of DLB. Through the in vitro experimental mode of DLB, we analyzed the content of α‐synuclein aggregations, the difference in cell viability and the activity changes of methylation‐related pathways in mouse HT‐22 neuronal cells.ResultWe found that the DLB neuronal cells display a significant tendency to undergo DNA hypermethylation, which inhibits stemness and reduces the content of neurotrophic factors. This makes it more difficult for neuronal cells to survive under stress. In addition, DLB neuronal cells also showed significant insulin resistance, which interferes with autophagic clearance, upregulates the senescence‐related pathways, and exacerbates the aggregation and accumulation of α‐synuclein.ConclusionDLB cells significantly increase the hypermethylation and thus inhibit insulin signaling, making the affected cells more vulnerable to neurotoxicity. Accordingly, the administration of epigenetic regulators by targeting neuronal DNA hypermethylation may lead to develop novel therapeutic strategies against DLB.
Increasing Cognitive Evaluations in Primary Care: Implementing the GSA KAER Model at a Large Healthcare System
Authors: Gaster Barak 
Published: December 2023

AbstractThere is widespread recognition that patients with Alzheimer’s disease and related dementias (ADRD) receive better care if they receive an earlier diagnosis. In 2022, the Alzheimer’s Association published a survey of primary care providers (PCPs) indicating that a large majority agree that making an early diagnosis of ADRD is important. However, more than half of PCPs said that they lack the knowledge and confidence to assist in making such a diagnosis.Starting in 2021, the University of Washington launched the Cognition in Primary Care Program to meet that need. Developed with funding from the Centers for Disease Control and Prevention, as an adaptation of the Gerontological Society of America’s KAER Toolkit, the primary goals of the Cognition in Primary Care Program are to increase cognitive evaluations by PCPs and to increase the number of patients diagnosed with ADRD and mild cognitive impairment (MCI).Using practical training modules for PCPs with concise, evidence‐based checklists embedded in the electronic health record (EHR), the program has now been widely adopted by PCPs in a wide variety of clinics serving diverse populations of patients. Evaluations by PCPs describe the program as being of high quality and relevant to their practice. Results on the General Practitioners’ Attitude and Confidence Scale for Dementia (GPACS‐D) six months after the intervention show confidence in evaluating cognition. In addition, the number of MoCA tests uploaded to the EHR increased from 2.7 per month to 5.8 per month, and there was high utilization of the EHR checklist tools. Preliminary data also show that the number of visits in which PCPs have billed a diagnosis of MCI increased from 7.5 per month to 14.4 per month.The strengths of the Cognition in Primary Care Program include its emphasis on actions that PCPs can take to promote brain health and the implementation of innovative EHR tools which PCPs can use in their clinical practice. The Cognition in Primary Care Program is an effective model, shown to be acceptable to PCPs, easy to integrate into a large health system, and successful at increasing cognitive evaluations in the primary care setting.
Feasibility Testing of a Brief Memory Care Plan Tool
Authors: Gholizadeh Shadi , Harris Amy , Buell Kathryn M. , Popolizio Elizabeth M. , Muskat Jennifer Johnson , Smith Erica C. , Feldman Andrew J. , Citron Ken 
Published: December 2023

AbstractBackgroundAs interest shifts from a biomedical, task‐based approach to dementia care to a more person‐centered approach, understanding and adoption of behavioral, non‐pharmacological approaches to supporting people living with Alzheimer’s disease and other dementias (PwD) is increasing. Previous research has identified that the quality of the assessment and care plan is associated with the quality of care delivery and likelihood of a person‐centered approach. Home care agencies are an important but understudied source of nonmedical care for PwD. Having dementia‐specific tools to aid in the design and delivery of care can help support person‐centered care delivered by home care teams.MethodA brief web‐based memory care plan tool targeting care goals, care challenges, and techniques was piloted in two offices in the United States with a sample of people living with dementia (N = 34) receiving professional home care services. Nine individuals in care management‐type positions overseeing the nonmedical home care completed the memory care supplements for existing clients over two weeks. The care managers also completed a survey about their experience with the tool.ResultsThe tool was identified as acceptable and useful by the care managers. The three most common care goals identified were the following: providing cognitive engagement and stimulation, preventing challenging behavioral expressions, and reducing social isolation. The three most common challenges were the following: anosognosia, resistance to accepting care in the home or resistance toward the personal care approach, and communication challenges. An important functional aspect of the tool that was identified was the necessity of fillable free text options alongside structured responses to allow care managers to personalize goals, challenges, and techniques.ConclusionThese findings support the feasibility of a brief web‐based tool that can be completed in under 10 minutes developed to identify key care goals, challenges, and associated techniques for people living with dementia. Given the feasibility and acceptability of incorporating this tool into the broader home care assessment, a methodologically robust trial should be considered to further explore the effectiveness and value of the tool on outcomes relevant to the PwD and care partner.
Vascular dysfunction as a potential link between infection and Alzheimer’s disease
Authors: Li Pengfei , Wu Yan , Halushka Perry , Liu Meng , Fan Hongkuan 
Published: December 2023

AbstractBackgroundMicrobial infections are a risk factor for Alzheimer’s disease (AD). Herpesvirus and Gram‐negative bacteria have been detected in brain tissue samples of AD patients, indicating an infectious etiology of AD (Lotz et al., Front. Cell. Neurosci., 2021; 15:691136). Multiple mechanisms that contribute to brain injury after infections including disruption of the blood‐brain barrier (BBB), neuro‐inflammation, brain hypoperfusion, and accumulation of amyloid‐β (Aβ) in the brain are also observed in AD patients. However, the host and pathogen factors contributing to breakdown of the BBB and mechanisms leading to neuro‐invasion of pathogens in AD remain to be investigated.MethodThe cecal ligation and puncture (CLP) model, which is a murine polymicrobial infection model, and 5xFAD transgenic mice were used to evaluate vascular dysfunction in infection and AD. Brain pericyte markers, pericyte/endothelial cell (EC) coverage, vascular leakage, and Aβ accumulation were determined in infection and AD models. In addition, brain pericytes were isolated from infection and AD models, and pericyte Fli‐1 levels were determined by Western blot. The effects of Fli‐1 on Aβ‐induced pericyte loss were assessed.ResultWe demonstrated that pericyte markers CD13 and PDGFRβ and Pericyte/EC coverage were significantly decreased in brain tissue at 24 hours post CLP. Similarly, greater pericyte loss was also observed in 5xFAD mice compared to WT mice. Pericyte loss is associated with vascular leakage, as evidenced by IgG infiltration into the brain tissue 24 hours after CLP. Soluble Aβ 40 levels in the hippocampus were increased at 30 days after CLP. IgG infiltration into the brain tissue and increases of Aβ 40 levels were also observed in 5xFAD mice at 6 months of age. To elucidate the underlying mechanism of pericyte loss in infection and AD, brain pericytes were isolated from CLP mice and 5xFAD mice. Our data demonstrated that pericyte Fli‐1 levels were significantly increased in CLP mice and 5xFAD mice, and suppression of Fli‐1 decreased Aβ‐induced pericyte loss.ConclusionThese composite results indicate that Fli‐1 contributes to pericyte loss, vascular dysfunction, and Aβ deposition, and they suggest that upregulation of pericyte Fli‐1 may represent a potential link between infection and AD.