bluuebunny/crossref_metadata_2025_split huggingface dataset:
Measuring attitudes, motivations and barriers to presymptomatic dementia testing
Authors: Makri Marina , Gkioka Mara , Moraitou Despoina 
Published: June 2023

AbstractBackgroundThe increasing biomarkers testing and new methods of presymptomatic screening for dementia have risen questions like: Should people get tested? Would they want to know whether they will get this fatal, untreatable disease? This has picked the demand for a well‐structured counseling program for dementia screening. In this direction, it is important to meet the needs of the target group; however, not much is known about people with a family history of dementia attitudes about testing, the motivations and barriers, and the expectations relevant to future counseling programs about testing for dementiaMethodThis study was comprised of a validation study of a new psychometric tool and a cross‐sectional survey to assess the attitudes, buries and motivations to dementia testing. The content of the questionnaire was based on (1) a literature review, (2) the Perceptions Regarding Investigational Screening for Memory in Primary Care (PRISM‐PC) Questionnaire (M. Boustani et al., 2008), (3) a board of Clinical expert opinions. Two hundred eight (208) people enrolled in this cross sectional study. Participants came from Greece, ages ranged from 18‐70 (M = 35.5, SD = 5.7). and the majority of the sample was female (93.3%). Psychometric properties were assessed through construct validity (principal component analysis) and internal consistency (Cronbach’s alpha).ResultExploratory factor analyses revealed the presence of four factors. The first factor labelled as “Perceived harms of testing”, the second “Acceptance of testing”, the third “Perceived benefits of testing”) and the fourth factor “Need of knowledge”. The reliability of each factor separately was satisfactory to very satisfactory (.70‐.87). Cronbach’s alpha coefficient for all the final 25 items of the initial questionnaire was good (Cronbach’s α = 0.82), suggesting very satisfactory internal consistency.ConclusionThis is the first study that created a questionnaire for measuring the attitudes of Greek people towards dementia and genetic screening. Capturing data via this questionnaire might help clinicians, policymakers, and health services researchers in dementia understand better peoples’ perspectives related to the pros and cons of dementia screening and develop effective counseling programs and prevention strategies.
First‐in‐Human (FIH), Single‐ and Multiple‐Ascending‐Dose (SAD/MAD) studies in healthy subjects of E2511, a novel tropomyosin receptor kinase a (TrkA) positive allosteric modulator (PAM)
Authors: Aceves Pau , Hall Nancy , Dayal Satish , Yagi Takuya , Chang Julia , Mikamoto Masaki , Ringheim Garth E , Takesuya Tomioka , Hiramatsu Naoki , Gordon Robert , Giorgi Luigi 
Published: June 2023

AbstractBackgroundCholinergic innervation is affected in multiple neurodegenerative diseases associated with cognitive dysfunction. Loss of cholinergic neurons in Alzheimer’s disease (AD) is correlated with cognitive impairment. Nerve growth factor (NGF) plays a major role in the maintenance and function of cholinergic neurons. The activation of NGF‐induced trophic signaling via TrkA could be a promising therapy for neurodegenerative diseases including AD. E2511 is a novel small molecule TrkA biased PAM that has shown reinnervative effects on cholinergic neurons in nonclinical studies (without NGF‐associated hyperalgesia). The main objectives of the E2511 FIH Phase 1 studies (SAD [completed] and MAD [ongoing]) are to evaluate the safety, tolerability and pharmacokinetics in healthy subjects.Methods: Both SAD and MAD are randomized, double‐blind and placebo‐controlled studies. The SAD evaluated 5 cohorts (n = 8/cohort) in adults and 1 cohort in elderly subjects (n = 5). Food effect was evaluated in one SAD cohort. Safety was evaluated through the review of adverse events, physical examinations, clinical laboratory tests, vital signs, electrocardiogram and electroencephalograms. Blood samples were collected for determination of plasma E2511 concentrations. Repeat dosing with E2511 (once daily for 14 days) is under evaluation in the MAD study.Results: Single doses of E2511 were safe and well‐tolerated across the investigated doses in adult and elderly subjects. There were no dose‐dependent nor severe treatment‐emergent adverse events (TEAEs). There were no clinically significant changes in the evaluated safety parameters on E2511 compared to placebo. Pharmacokinetic results show that E2511 was rapidly absorbed (tmax: 1 hour). Plasma half‐life was 3.2 hours. Plasma exposures (Cmax and AUC) increased dose proportionally over the investigated dose range. Food led to a decrease of 19% in Cmax and 15% in AUC compared to fasted conditions. Plasma exposures in elderly and younger adult subjects were comparable. Evaluation of E2511 safety, tolerability and PK/PD following multiple doses is ongoing.ConclusionE2511 presented an adequate safety and PK profile in healthy adults and elderly subjects. These results support further development of E2511 as a disease‐modifying therapy for neurodegenerative diseases.
Effects of acquisition protocol on advanced diffusion MRI measures
Authors: Mishra Virendra R , Sreenivasan Karthik , Cordes Dietmar , Ritter Aaron 
Published: June 2023

AbstractBackgroundSeveral studies have suggested that advanced diffusion MRI (dMRI) measures derived through the analytic techniques of diffusion kurtosis imaging (DKI) and neurite orientation density and dispersion imaging (NODDI) might provide better sensitivity to predict the progression of Alzheimer’s disease (AD) when compared to conventional single tensor diffusion tensor imaging. Two popular simultaneous multislice (SMS) sequences, namely Alzheimer’s Disease Neuroimaging Initiative (ADNI)‐3 and Human Connectome Protocol (HCP) are currently widely used in the acquisition of such advanced dMRI data. Since HCP sequences require a custom connectome scanner, several variants of HCP protocol compatible with clinical MRI are in wide use. Before such techniques are used widely across the globe to understand AD, it is imperative to understand whether the absolute WM measures derived through such advanced dMRI measures are reproducible and whether harmonization of dMRI across sites employing different acquisition protocols is applicable. In this study, we hypothesize that higher spatial and angular resolution dMRI data will result in higher quantification of DKI and NODDI metrics, as compared with comparatively lower spatial resolution advanced ADNI‐3 sequences.MethodA 32‐year‐old healthy male participant was scanned over five weeks, both with Advanced ADNI‐3 protocol (114 directions, 2mm3 isotropic, b‐values = 500s/mm2, 1000s/mm2, and 2000s/mm2) and 2 variants of the HCP sequence (1.5mm3 and 2mm3) both with 3 b‐values (500s/mm2, 1000s/mm2, and 2500s/mm2) and 213 directions on a 3T Skyra scanner. Total scan time for the ADNI‐3 sequence was 11:37 minutes, 2mm3 CCF sequence was 18:41 minutes, and 1.5mm3 CCF sequence was 23:13 minutes. Various DKI and NODDI measures were computed on all repetitions in‐house. JHU atlas of WM tracts was used as a mask to extract values along each tract at each run separately.ResultAs shown in Figs 1‐4, dMRI‐derived measures were underestimated for most of the WM tracts for the ADNI‐3 sequence, although they had less variance across different runs. Second, NODDI measures were more reproducible across most WM tracts when compared to DKI measures across protocols.ConclusionAcquisition parameters affect the absolute quantification of advanced dMRI measures. Our data suggest that the pooling of dMRI data across various protocols should be performed with caution
Fukushimura Brain Bank ‐Nursing home based brainbank project in Japan‐
Authors: Kaneda Daita , Ogawa Norihiro , Kanesaka Takeshi , Hishida Chie , Sakurai Keita , Akatsu Hiroyasu , Yamamoto Sakon , Yamamoto Takayuki , Yoshio Hashizume 
Published: June 2023

AbstractBackgroundThe Fukushimura (welfare village), located in Toyohashi city, Japan, is a unique complex of various nursing home facilities including dementia homes, Day‐care houses, homes for disabled and mentally retarded, and the Fukushimura Hospital. This village is totally managed by private sector, the Sawarabi Medical Cooperative. About 800 elderly people reside in this area. The hospital plays a pivotal role within the village and acts as the central facility for each nursing homes.Fukushimura BrainBank (FBB) was established in 1990. The neuropathological investigation of FBB was initially conducted by Kenji Kosaka, who initially reported cortical Lewy bodies. Our research institute was approved in 2004 by the Ministry of Education, Culture, Sports, Science and Technology, as one of the non‐governmental institutes which is permitted to apply for governmental grants.MethodClinical information and neuroimaging analyses has been described in daily practice. For banking CNS specimens, the brains are separated into two hemispheres, one for neuropathological analyses with using several antibodies for beta‐amyloid, phosphorylated tau, alpha‐synuclein, and TDP‐43. Modified gallyas‐silver staining is applied for evaluating argyrophilic grain disease. The other hemispheres are stored for frozen sections. All the medical records and radiological images from the nursing home to hospital are stored in the research institute, which make it possible for the researchers to access the psychological symptoms observed by carers in the long duration of the disease.ResultThe number of autopsy became over 35 cases per year. Most of the patients had dementia or chronic devastating cerebrovascular diseases. Of note, geriatric residents with mentally retardation or cerebral palsy from childhood were included. At the end of 2021, more than 800 of frozen brains with detailed medical record are stored in FBB and readily available for research. The neuropathology database share the same coding system for Japanese Brain Bank Network for Neuroscience Research (JBBNNR). We already have over 20 collaborators and supply our samples for more than 30 research institutes in Japan.ConclusionThe challenge of FBB will play a unique and important role to clarify cliniconeuropathological correlation of the nursing home residential with various geriatric conditions with 3D(Disability, Dementia, and Developmental disorders).
Transcriptome profiling in AD cases to identify distinct associations with AD‐related neuropathology and protein levels in the brain
Authors: Allen Mariet , Quicksall Zachary , Wang Xue , Reddy Joseph S. , Bergman Jeremiah , Oatman Stephanie R , Nguyen Thuy , Malphrus Kimberly G. , Lincoln Sarah J. , Yamazaki Yu , Martens Yuka A , Zhao Na , DeTure Michael , Murray Melissa E. , Liu Chia‐Chen , Kanekiyo Takahisa , Dickson Dennis W. , Bu Guojun , Ertekin‐Taner Nilufer 
Published: June 2023

AbstractBackgroundGene expression changes have been identified in post‐mortem brain tissue of AD cases when compared with controls, implicating various genes and pathways. Such findings provide important insights into molecular dysregulation associated with this disease and nominate therapeutic targets. Here we investigate brain gene and co‐expression network changes in a cohort of AD cases to identify associations with degree of AD neuropathology including Braak stage (Tau), Thal phase (Amyloid beta) and brain tissue levels of five AD‐related proteins (apoE, Aβ40, Aβ42, tau, and p‐tau).MethodGene expression measures were collected from temporal cortex (TCX) tissue of 477 AD cases, available through the Mayo Clinic Brain Bank, using RNA sequencing (Illumina TruSeq mRNA) performed on the HiSeq4000. Following quality control 456 cases remained for analysis. Braak and Thal were provided by an experienced neuropathologist and TCX levels of five AD‐related proteins from three fractions (buffer‐soluble, detergent‐soluble, and insoluble) were measured by ELISA (Liu et al. 2020). Weighted gene coexpression network analysis (WGCNA) R package was used to build co‐expression networks. Genes and networks were tested for association with neuropathology and AD‐related protein levels, adjusting for relevant covariates.ResultA total of 57,353 genes were profiled, of which 19,044 were reliably expressed above background levels and formed 20 co‐expression modules. 36 genes were associated with Braak stage, 10 with Thal phase and up to 9,000 with the AD‐related protein fractions. Brain levels of pTau had the greatest number of associations, with an overrepresentation of genes involved in synaptic signalling and immune response gene ontology biological processes. 16 of the coexpression modules associated with at least one trait after Bonferroni correction for number of tests.ConclusionWe have identified a number of genes and networks associated with different aspects of AD neuropathology and associated proteins, further lending support to the involvement of synaptic and immune biology in AD. However it is not clear whether observed changes cause disease or are a consequence of the neurodegenerative process. Comparison of these findings across different proteins and fractions is expected to reveal common and distinct vulnerabilities associated with amyloid and tau, and different stages of protein aggregation.
Changes in urinary odd‐chain and even‐chain saturated fatty acids in Alzheimer’s Disease
Authors: Fonteh Alfred N. , Castor Katherine , Buennagel David P , Arakaki Xianghong 
Published: June 2023

AbstractBackgroundThe health benefits of odd‐chain saturated fatty acids (ocSAFA) have recently been recognized. We previously showed decreased unesterified ocSAFA in cerebrospinal fluid (CSF) of AD compared to MCI and cognitively healthy (CH). However, changes in ocSAFA relative to even‐chain saturated fatty acids (ecSAFA) have not been determined in other biofluids. Therefore, we aim to determine if levels of ocSAFA and ecSAFA may reveal AD pathology in urine.MethodsWe used neuropsychology and CSF measures of Ab42 and T‐tau to classify groups of elderly subjects as cognitively healthy (CH) with negative Ab42 (CH‐Ab‐), cognitively healthy with positive Ab42 (CH‐Ab+), MCI, and AD. We collected urine after an overnight fast and quantified unesterified fatty acids (UFA) and esterified fatty acids (EFA) using gas chromatography coupled with negative‐ion chemical ionization mass spectrometry. For data normalization, we measured ocSAFA species (C15:0, C17:0, C19:0) and ecSAFA species (14:0, C16:0, C18:0, C20:0, C22:0, C24:0) as a proportion of the sum of all UFA or EFA > C14:0 in urine. We calculated group differences using ordinary ANOVA with Tukey’s multiple comparison tests.ResultsUrine unesterified C15:0 levels were significantly higher in AD than in MCI and CT (p = 0.0016). Similarly, esterified levels of ocSAFA were higher in AD than in MCI and CT (p<0.0001). Although Aβ42 levels in CH‐Aβ+ and AD are not significantly different, unesterified C15:0, esterified C17:0, C19:0, and total esterified ocSAFA were significantly higher in AD urine than in CH‐Aβ+. Urinary unesterified ecSAFA levels did not change in AD compared with CH and MCI. In contrast, esterified ecSAFA decreased in AD compared to CH. While esterified C16:0 decreased, esterified C18:0 increased in AD urine compared to CH and MCI. These changes result in a significant decrease in the C18:0/C16:0 ratio in AD (Fig. 1). The ratio of esterified ocSAFA to ocSAFA was higher in AD than CH and MCI (p<0.0001) (Fig. 2).ConclusionsThese studies suggest that urine saturated fatty acids can reveal AD‐associated pathology. Therefore, measurement of urine fatty acids can be used to monitor AD‐linked biochemical pathways or to monitor therapies targeting saturated fatty acid metabolism in AD.
Single particle mass photometry provides size distributions of tau oligomers in CSF samples revealing strong differences between samples from Alzheimer’s patients and healthy controls
Authors: Awasthi Saurabh , Mayer Michael 
Published: June 2023

AbstractBackgroundTau oligomers are considered toxic species in neurodegenerative disorders and their abundance correlate well with the disease onset and pathology. Assays used for detection of these toxic tau oligomer species fail to detect their low levels and to differentiate between various oligomers. This limitation reduces the potential for early diagnosis and for possible intervention. A label‐free approach that can detect these biomarkers at low concentrations while also revealing their size distribution will be ideal.MethodHere, we use a combination of tau oligomer‐specific immunoprecipitation from human CSF samples and single‐molecule mass analysis based on so‐called mass photometry to determine the size of thousands of individual oligomeric species in solution in a label‐free manner.ResultSingle‐oligomer mass analysis makes it possible to determine the number of tau monomers in thousands of individual oligomer particles in CSF samples from human patients and control subjects. The method reveals a dramatic difference in the size distribution of tau oligomer species from Alzheimer’s patients compared to control subjects. In particular, samples from AD patients contain a significant fraction of trimeric tau oligomers, which are completely absent in the control samples.ConclusionSingle‐particle mass analysis of tau protein oligomers enables discrimination of samples from patients with AD from those of age‐matched control subjects. Furthermore, single‐particle based analysis of the size distribution of oligomeric species will help to shed light on the toxicity of various oligomers species.
Impact of study partner type on primary endpoint volatility in a phase 3 registration trial of mild‐to‐moderate Alzheimer’s disease
Authors: Ryan Mary M , Gillen Daniel L , Grill Joshua D. 
Published: June 2023

AbstractBackgroundIn Alzheimer’s disease (AD) clinical trials, participants are required to enroll with a study partner (SP) who ensures compliance and completes outcomes assessing participant cognitive and functional ability. The SP role is commonly filled by spouses and other family members. Spouse and non‐spouse SPs differ in numerous ways, including average time in contact with the participant. These differences may impact volatility of SP‐reported assessments, which may in turn impact trial integrity. We quantified the impact of SP type on the variance of SP‐reported Disability Assessment for Dementia (DAD) scores.MethodWe analyzed data from the Bapineuzumab 301 (ApoE e4 non‐carriers) and 302 (ApoE e4 carriers) phase 3 trials in mild‐to‐moderate AD, provided by the trial sponsor, Janssen Research & Development, LLC for use in these analyses. We compared the sample variances of end‐of‐study DAD scores for spousal and non‐spousal SPs in each trial. 95% confidence intervals (CIs) for the corresponding parameters were computed via bootstrapping. We used similar methods to compare the variances in the difference between baseline and end‐of‐study DAD scores for SP types.ResultAmong the 1,232 and 1,121 participants analyzed from trials 301 and 302, 818 (66.4%) and 837 (74.7%) had spousal SPs at baseline, respectively (Table 1). On the other hand, 665 (665/973 = 68.3%) and 697 (697/924 = 75.4%) spousal SPs in each trial completed the end‐of‐study visit, respectively. In trial 301, the variance of end‐of‐study DAD scores for spousal SPs were observed to be 14% lower compared to non‐spousal SPs (spousal/non‐spousal = 630.41/746.55 = 0.84, 95% CI = [0.71, 1.03]). In trial 302 this relative decrease was observed to be 9%, though with less precision (spousal /non‐spousal = 610.85/673.86 = 0.91, 95%CI = [0.77, 1.12]). Neither trial had significant differences in spousal vs non‐spousal variances of the change‐from‐baseline DAD scores (Trial 301: spousal/non‐spousal = 378.10/425.17 = 0.91, 95%CI = [0.66, 1.22]; Trial 302: spousal/non‐spousal = 354.38/352.22 = 1.01, 95%CI = [0.77, 1.35]). DAD variance over time is depicted in Figure 1. Differences in the linear trend of DAD variance did not significantly differ between SP types in either trial (Trial 301 Est.: ‐1.74, 95%CI: [‐3.58, 0.23]; Trial 302 Est.: 0.94, 95%CI: [‐5.83, 4.31]).ConclusionSP type was not associated with variation in SP‐reported study endpoints in this study.
Place of death among racial minority older adults with Alzheimer’s disease and related dementias
Authors: Rahemi Zahra , Malatyali Ayse , Cidav Tom , Montaner Olga F Jarrín , Dye Cheryl 
Published: June 2023

AbstractBackgroundAlzheimer’s and Related Dementias (ADRD) affects close to half of older adults before death. The age‐adjusted rate of ADRD is disproportionately higher in racial/ethnic minority populations. There are also disparities in end‐of‐life care for racial minority older adults with ADRD, including the type of care, place of care, and place of death. Place of death is associated with the quality, type, and cost of care that patients may receive. Place of death is increasingly being recognized as an indicator of end‐of‐life care quality. In surveys of the U.S. population, older adults, including racial minority older adults, increasingly state a preference for death at home compared to a hospital or nursing home setting. In this study, we investigated factors associated with place of death among older adults with ADRD.MethodWe conducted a secondary analysis of a national dataset, the Health and Retirement Study (HRS), using HRS Exit interviews related to deceased participants’ data from 2002‐2019.ResultOf the 7,214 decedents, 13% had a diagnosis of ADRD, 30% had cognitive impairment suggesting undiagnosed ADRD, and 57% were cognitively intact. Among the 3,102 participants with ADRD, Black participants were 80% more likely to die in the hospital and 46% less likely to die in a nursing home compared to white participants. We did not observe any significant effect of race on hospice use. Additionally, married participants were 89% more likely to die at home compared to unmarried participants. For every 1‐year age increase, participants were 1.6% less likely to die in the hospital, 3.8% less likely to die at home, and 6% more likely to die in nursing homes.ConclusionOur findings indicate that race, marital status, and age are significant predictors of place of death among older adults living with ADRD. Black participants with ADRD were less likely to die at home compared to their white counterparts. There are considerable racial differences in which patients with ADRD die at home or in institutions. There is a need for further research to understand the reasons for these variations in the efficiency and type of end‐of‐life care delivered to racial minorities.