bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gender and sex bias in clinical trial recruitment in Alzheimer's disease: Findings from Fundació ACE
Authors: Abdelnour Carla , Valero Sergi , Rosende‐Roca Maitee , Lafuente Asuncion , Hernandez Isabel , Tartari Juan Pablo , Santuccione Antonella , Ferreti Maria Teresa , Maguire Peggy , Buendía Mar , Pancho Ana , Tarraga Lluis , Benaque Alba , Gurrutxaga Miren , Ruiz Agustín , Boada Mercè 
Published: December 2020

AbstractBackgroundFDA has made great efforts to promote inclusion of women in clinical trials. The aim is to protect specific biological gender and sex issues and encourage drug developers to consider specific clinical outcomes and drug‐safety profiles in terms of gender and sex. Alzheimer’s disease (AD) affects predominantly women, who double men in the number of patients diagnosed with dementia. Therefore, we explored gender and sex bias in the inclusion criteria for clinical trials in AD. Here our aim was to compare main inclusion criteria for clinical trials in MCI and dementia patients in terms of sex.MethodPatients evaluated at FACE from 1996 to 2019 with CDR 0,5 to 2 evaluated from 1996 to 2019 were analyzed. Then, we used the main inclusion criteria for AD clinical trials to compare the sample in terms of sex and syndromic diagnosis. The chosen variables were age, sex, education, comorbidities, treatment and MMSE score. Logistic regression analysis was used accounting for these variables.ResultFrom a total sample of 20,203 MCI and dementia patients, we selected potential candidates for clinical trials with complete information regarding age, years of education, MMSE, comorbidities and treatment. After adjusting for age, years of education, comorbidities and treatment, in the dementia sample only age and years of education showed statistically significant differences. Whereas in the MCI sample: age, years of education, treatment and comorbidities showed statistically significant differences (Table 1 and 2).ConclusionWomen with MCI and dementia are less likely to participate in a clinical trial due to older age and less years of education than men. Another factor that prevent women for participating in clinical trials is their comorbidities when compared to men, whereas men are excluded due to treatment criteria more often than women. These results show that there is a pre‐selection bias against women in AD clinical trials because of demographic characteristics. Therefore, participation of women in clinical trials does not reflect the prevalence of AD among women and is not representative of reality. Efforts should be made to provide equal opportunities to potential clinical trials candidates regardless of gender.
An ultrasensitive immunoassay for detection of p‐tau181 in blood
Authors: Chen Yao , Chang Lei , Blennow Kaj , Zetterberg Henrik , Ball Andrew J. 
Published: December 2020

AbstractBackgroundA high‐sensitivity blood‐based p‐tau181 assay could potentially provide a valuable tool for Alzheimer’s disease (AD) research and drug discovery. In this study we describe development of a high‐performance blood‐based p‐Tau181 assay using Simoa technology.MethodA fully automated bead‐based digital Simoa immunoassay was developed to detect p‐tau181 in serum, plasma and CSF. A monoclonal antibody targeting p‐tau181 was used as capture antibody and a biotinylated antibody against tau was used as detector. Antibody selection was based on specificity for target analyte and generation of quantifiable signal in human serum and plasma samples. Assay conditions were optimized for maximal sample detection and analytical performance. The assay was evaluated for sensitivity, parallelism, cross‐reactivity to total tau, spike recovery, and analyte detectability in normal human serum, plasma and CSF.ResultAnalytical performance was characterized for sensitivity (LLOD 1.0pg/mL), quantifiability (100% of samples above LLOQ for CSF and plasma, 87% for serum), cross reactivity (<5% cross reactivity to total tau), linearity of sample dilution (81%‐122% in plasma (n=11) and 78%‐152% in serum (n=6)) and recovery of sample spike (70%‐94% in plasma (n=10) and 68%‐126% in serum (n=5)). Disease differentiation was studied by measuring plasma p‐tau181 level in 20 age‐matched AD patients and 20 healthy control samples obtained from a commercial source. Mean p‐tau181 was significantly higher in the AD patients than in the healthy controls (78.61pg/ml in AD versus 42.18pg/ml in HC, p=0.01). Differentiation power of p‐tau181 in CSF was also evaluated in 11 healthy control and 13 age‐matched AD patients (samples from U. Gothenburg). Mean CSF p‐tau181 level was significantly higher in the AD patients than in the controls (8551pg/mL in AD; 973pg/ml in healthy controls, p<0.05). A strong correlation (R² = 0.9293) between 20 matched serum and plasma samples was also observed.ConclusionThis Simoa p‐tau181 assay enables measurement of this important analyte in blood and CSF samples. Efforts are underway to bring make this assay widely available as a new tool to facilitate research in AD and other neurodegenerative diseases. Ongoing studies using a larger cohort of clinical samples will determine the clinical utility of this assay.
Hourly, daily, weekly or monthly? Choosing the right data granularity for analysis of digital biomarker trajectories
Authors: Wakim Nicole I , Braun Thomas M , Kaye Jeffrey , Dodge Hiroko H 
Published: December 2020

AbstractBackgroundThe use of digital biomarker data provides the opportunity for frequent functional and cognitive assessments that were not previously available. Digital biomarker data are often collected in the form of time stamped data, which requires processing for interpretable applications in health care research. In general, time stamped data can be averaged, or condensed, into daily, weekly, or even monthly time intervals, which are referred to as time granularities. Data with fine time granularity can improve the fit of a model and increase signal strength, but it can also require more computational time and storage for analysis. There are no published guidelines explaining how to determine the best time granularity. We aim to provide a guideline to find a balance between computational efficiency and integrity of the data when analyzing longitudinal trajectories based on high frequency digital biomarker data in dementia research. We also provide a real‐world example to show how the guidelines can be applied.MethodsThere are four important factors of data that we need to investigate when determining appropriate granularity: (i) duration of follow‐up, (ii) variables of interest in analysis, (iii) pattern detection, and (iv) signal to noise ratio (SNR). Follow‐up time helps determine the highest reduction of time granularity that is feasible for the data. Variables of interest may only be available at certain time granularities. For pattern detection, clinical information about biological patterns will help determine time granularity. SNR uses variability in the data to determine how likely a signal will be detected during trajectory analysis.ResultThese factors are applied to an example involving walking speed derived from a longitudinal cohort study, the Intelligent Systems for Assessing Aging Change study (ISAAC). The data have been collected at the Oregon Center for Aging and Technology (ORCATECH) at the Oregon Health and Science University.ConclusionWe highlighted common challenges researchers face when analyzing digital biomarkers and how we can use the guideline in selecting an appropriate time granularity before conducting analyses. The guideline will help improve scientific rigor in digital biomarker analyses.
Alterations of cortical thickness and gray‐white matter contrast in Alzheimer’s disease and Lewy body‐related cognitive impairment
Authors: Jeon Seun , Kim Hosung , Ye Byoung Seok , Evans Alan C. 
Published: December 2020

AbstractBackgroundGray and white matter alteration has been known in patients with neurodegenerative diseases including Alzheimer’s disease‐ (ADCI) and Lewy body‐related cognitive impairment (LBCI). We examined a distinct pattern of cortical thickness (CTH) and gray‐white matter contrast (GWC) alterations in these degenerative neurological diseases. Since the T1‐weighted MRI signal is closely related to myelin content, the GWC may reflect disease‐related alterations of myeloarchitecture along the cortical surface.MethodsT1‐weighted MRIs were obtained from patients (demo‐matched, CDR‐SOB≤9) with ADCI (n=97), LBCI (n=93), and healthy controls (n=37). We measured CTH using the CIVET processing pipeline. GWC was calculated at each vertex as the difference between gray matter (sampled at 50% CTH) and white matter intensity (sampled at 1mm subcortical white matter), then this was normalized by their average. Group differences (controls vs. patients) and correlations (with neuropsychological scores) were examined using general linear models covarying for age, sex, education, intracranial volume, and several vascular risk factors. Results were corrected for multiple comparisons using random field theory p<0.05 (cluster‐forming threshold p=0.001).ResultsPatients with ADCI showed altered CTH in the brain regions typically affected in AD including the bilateral medial temporal, lateral temporo‐parietal, and posterior cingulate cortices. The pattern of GWC alteration was smaller and no change was shown in the lateral temporal lobe (Figure 1A). LBCI patients showed altered CTH in superior frontal, lateral temporal, basal frontal and occipital cortices. The GWC alteration pattern was shown in larger area, notably in the limbic and occipital cortices (Figure 1B). Memory function, in the AD‐spectrum, was more closely associated with CTH, while in the LB‐spectrum, it was more closely with GWC (Figure 2). Frontal/executive function has stronger association with CTH than with GWC in the AD‐spectrum, while the LB‐spectrum showed independent patterns of association in those measures (Figure 3). The visuospatial function was only associated with CTH in AD‐spectrum, and in LB‐spectrum, it was greater in CTH than in GWC (Figure 4).ConclusionsWe demonstrated distinct patterns of CTH and GWC alteration in ADCI and LBCI. Consideration of heterogeneous atrophy patterns may be important when planning prevention and treatment strategies, as they may have different responses to treatment in the disease progression.
Cerebrospinal fluid neuroinflammatory biomarkers along the Alzheimer disease continuum in Down syndrome
Authors: Carmona‐Iragui Maria , Iulita M. Florencia , Barroeta Isabel , Fernandez Susana , Altuna Miren , Videla Laura , Benejam Bessy , Valldeneu Sílvia , Muñoz Laia , Alcolea Daniel , Blesa Rafael , Lleó Alberto , Fortea Juan 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is the main medical problem and cause of death for adults with Down syndrome (DS). Glial activation is an early phenomenon central to AD pathophysiology; however, whether glial biomarker profiles in DS differ from sporadic AD remains unanswered. We compared cerebrospinal fluid (CSF) glial biomarkers along the AD continuum between DS individuals and sporadic AD cases and its relationship with CSF neurodegeneration biomarkers.MethodSingle‐center cross‐sectional study. We classified individuals with DS into three clinical subgroups: without cognitive impairment (aDS), prodromal AD (pDS) or with AD dementia (dDS). We determined CSF‐YKL40 and progranulin protein (PGRN) levels by ELISA (Quidel and Adipogen, respectively) and we compare them along the AD continuum in DS. For comparisons, we included subjects with sporadic prodromal AD (pAD) and AD dementia (ADd) and healthy controls. We studied correlations of YKL40 and PGRN with CSF‐total‐tau (Fujirebio‐Europe), phospho‐tau (Fujirebio‐Europe) and NfL (UmanDiagnostics) within participants with DS. We used Mann‐Whitney tests corrected for multiple comparisons and Spearman coefficients for correlations.ResultParticipants included were 56 aDS, 17 pDS, 27 dDS, 28 pAD, 55 ADd and 147 controls. YKL40 levels were lower in aDS compared to controls (p<0.0001) and along the AD continuum in DS compared to sporadic cases (pDS vs pAD, p= 0.0004 and dDS vs ADd, p=0.0002) (Figure 1a). Symptomatic AD was associated with an 88.8% increase in YKL40 levels in DS and with a 69.9% increase in sporadic AD. There were no differences in PGRN levels along the AD continuum in DS or between DS and sporadic AD; however, PGRN levels were lower in aDS than in HC (Figure 1b). Both YKL40 and PGRN levels positively correlated with total‐tau (r=0.3, p<0.001; r=0.4, p<0.001), phospho‐tau (r=0.87, p<0.001; r=0.41, p<0.001) and NfL, (r=0.82, p<0.001; r=0.43 p<0.001) levels in the group with DS.ConclusionCSF glial biomarkers in subjects with DS differ from that in healthy controls and sporadic AD. However, symptomatic AD is characterized by similar changes in astrocyte and microglial activation markers such as YKL‐40 and PGRN. Differences in the immune system and response to AD might have important therapeutic implications and deserve further research.
Novel ex vivo MRI atlas of the medial temporal lobe can be used to characterize structural changes due to Alzheimer’s disease pathology
Authors: Ravikumar Sadhana , Wisse Laura , Xie Long , Ittyerah Ranjit , Das Sandhitsu R. , Detre John A. , Grossman Murray , Lavery Madigan , Lim Sydney A. , Irwin David J. , Schuck Theresa , Trojanowski John Q. , Artacho‐Perula Emilio , Martin Maria Mercedes Iniguez de Onzono , Lee Eddie B. , Mizsei Gabor , Tisdall Dylan M. , del Mar Arroyo Jimenez Maria , Munoz Monica , Gonzalez Jose Carlos Delgado , Parada Marta Corcoles , de la Rosa Prieto Carlos , Sanchez Sandra Cebada , Prabhakaran Karthik , del Pilar Marcos Rabal Maria , Romero Francisco Javier Molina , Robinson John L. , Wolk David A. , Insausti Ricardo , Yushkevich Paul A. 
Published: December 2020

AbstractBackgroundFinding effective biomarkers that can support early‐stage clinical trials is a major challenge in Alzheimer’s Disease (AD). MRI measures of structural change in the medial temporal lobe (MTL) have proven to be sensitive to change in the early stages of AD. However, other frequently comorbid non‐AD factors (e.g. cerebrovascular disease, TDP‐43 pathology) also cause changes in the MTL. For MRI biomarkers to detect changes specifically linked to AD pathology, patterns of structural change must be linked to the underlying neuropathology. To provide this linkage, we use ex vivo imaging with pathologically derived ratings of AD and non‐AD pathology to study the localized effects of the disease on MTL structure. We hypothesize that such an analysis can be used to define MTL “hotspots” where in vivo measures will be more sensitive to disease progression in preclinical AD than current state of the art biomarkers.MethodEx vivo MTL specimens from 24 donors were scanned at 0.2x0.2x0.2mm3 on 9.4T MRI. The specimens contain varying degrees of pathology spanning the spectrum of AD and common co‐morbid non‐AD pathologies. For 21 specimens, a pathologist provided semi‐quantitative ratings of tau and TDP‐43 severity (Table 1). Extending on techniques developed in our prior work, a computational atlas of the MTL was built via groupwise registration of all specimens’ MRI scans (Adler et al, 2018; Ravikumar et al, 2020). The atlas was used to investigate the correlation between tau pathology and cortical thickness.ResultThe developed atlas achieves excellent groupwise alignment and captures anatomical variability in the MTL despite its complex geometry (Figure 1). Correlation analysis between tau pathology and atrophy (correcting for age and TDP‐43) reveals significant clusters near the transentorhinal region and subiculum (Figure 2).ConclusionThese correlation patterns are consistent with the early Braak stages and resemble results from a previous study which looked at the association between in vivo tau PET measures and atrophy (Das et al, 2019) (Figure 3). In future work, our novel ex vivo atlas will be leveraged to study variability in the distribution of tau pathology in 3D, by mapping quantitative serial pathology images into the atlas space (Figure 4).
Hypoconnectivity between locus coeruleus and medial temporal lobe during novelty predicts accelerated Aβ‐related cognitive decline
Authors: Engels Nina , Prokopiou Prokopis C. , Uquillas Federico d’Oleire , Scott Matthew R. , Schultz Aaron P. , Papp Kathryn V. , Farrell Michelle E. , Rentz Dorene M. , Sperling Reisa A. , Johnson Keith A. , Jacobs Heidi I.L. 
Published: December 2020

AbstractBackgroundTauopathy can be detected in the locus coeruleus (LC) decades before clinical symptoms or Aβ‐pathology. Following involvement of the LC, tau progresses to the medial temporal lobe (MTL), possibly via hyperactivity or connectivity. Given LC’s modulating role on brain function and its early involvement in proteinopathies that affect LC’s interaction with other brain regions, it is conceivable that individual variability in LC functional connectivity (FC) with the MTL will be related to Alzheimer’s disease (AD)‐related cognitive functioning. The LC plays an important role in novelty processing, learning and memory. Therefore, we aimed to examine whether LC‐MTL FC during novelty predicts Aβ‐related cognitive decline.MethodAll participants (N = 153; number of observations = 772; Figures 1,2) were clinically normal and part of the Harvard Aging Brain Study. Baseline PiB‐PET (cut‐off = 1.324 DVR), 3T‐fMRI data on a face‐name encoding task and longitudinal neuropsychological PACC5 data were obtained. The fMRI‐task instructed participants to remember face‐name pairs and stimuli consisted of novel and repeated faces. A dilated ex‐vivo validated LC‐template was registered to each individual using ANTs. SPM and ICA‐AROMA were used for motion and physiological artefact removal. An FDR‐corrected gPPI‐analysis (with age, sex, education covariates) established five regressors: novelty; repetition; LC BOLD‐activity; novelty x LC BOLD‐activity; repetition x LC BOLD‐activity. A linear contrast was created by subtracting the repetition interaction regressor from the novelty interaction regressor. LME models assessed whether the association between PACC5 and FC was dependent on PiB (linearly and quadratic), while correcting for age, sex, education and their interactions with time. Bonferroni correction was applied.ResultThe gPPI‐analysis demonstrated negative LC‐MTL FC during novelty versus repetition for every region of interest (p‐FDR<0.05; Figure 3), thereby indicating hypoconnectivity. The LME‐analysis revealed that hypoconnectivity of the LC‐Parahippocampal Gyrus predicted worse PACC5 performance, which accelerated at elevated PiB levels (p = 0.013; f = 0.11; Bonferroni‐adjusted; Figure 4). Similar results were apparent for LC‐hippocampus and LC‐amygdala FC.ConclusionThis study demonstrates that the LC is less functionally connected with the MTL during novelty, and that this hypoconnectivity predicts Aβ‐related cognitive decline. This suggests that LC‐MTL hypoconnectivity might act as a marker of AD‐related processes. Future work will assess the relationship between LC FC and tau pathology.
Gait impairments on single and dual tasks in cerebral amyloid angiopathy
Authors: Sharma Breni , Gee Myrlene , Zwiers Angela , Sekhon Ramnik , Charlton Anna , Ismail Zahinoor , Camicioli Richard , Smith Eric E. 
Published: December 2020

AbstractBackgroundCerebral Amyloid Angiopathy (CAA) is a small vessel disease wherein amyloid beta protein is deposited in the vessels of the cerebral cortex and leptomeninges. Little is known about CAA and gait impairment, even though gait is known to be affected by Alzheimer’s disease (AD). We hypothesized that gait would be impaired in CAA compared to normal controls (NC), and that more complex mental tasks would elicit further impairments in AD compared to CAA.MethodParticipants were NC (n=44), non‐demented CAA (n=31), and mild AD‐dementia (n=16). The ProtoKinetics Walkway was used to capture footfalls over a 6 m walk during a single task (walking only) and two dual tasks of differing complexity (counting backwards by ones [simple task] and naming animals [complex task]). For gait velocity, the dual task cost was calculated as the percent change during dual task compared to preferred pace walking. Analysis of covariance was used to test group differences, controlling for age, sex, and height.ResultCAA participants were older and more likely to be men (Table 1). Gait parameters during preferred pace walk, dual task with counting backwards, and dual task with animal naming are shown in Tables 2‐4. Across all three tasks, both CAA and AD performed poorer than NC on mean Stride Length, Stride Length variability, mean Stride Time, mean Velocity, and mean Cadence. However, mean Stride Width, and Stride Width variability did not differ. There were no differences between CAA and AD (Tables 2‐4). On measures of Velocity, the dual task cost for going from single task to counting backwards (simple dual task) was greater in AD than NC but not in CAA than NC (Table 5). The dual task cost for going from single task to naming animals (complex dual task) was greater in AD than CAA and NC.ConclusionGait is impaired in CAA to a similar extent as in AD, however dual task cost was higher for AD possibly because of greater cognitive impairment. Future research should investigate causes of gait impairments in CAA, including the effects of hemorrhagic and ischemic lesions such as white matter hyperintensities.
Stakeholders' perception of the adoption potential of TAP: Lessons from Chile
Authors: Moraga Carolina , Gajardo Jean 
Published: December 2020

AbstractBackgroundChile’s National Plan of Dementia has been implemented since 2017. This national strategy has the urgent need to develop or adopt non pharmacological interventions targeting people with dementia and caregivers. The Tailored Activity Program (TAP) is an evidenced‐based program that has been translated to different contexts, however, its outreach in Chile is still under development. This study describes how key stakeholders involved in the National Plan of Dementia in Chile perceive this intervention’s characteristics.MethodThis is a qualitative study addressing the perceptions of key policy makers involved in the National Plan of Dementia on the characteristics of the TAP. Interviews were recorded and transcribed, and content analysis was used to describe stakeholders’ perception. Written consent was completed by all participants. Ethical approval was obtained from the Scientific Ethics Committee of Adults, Metropolitan Health Service, Santiago, 2019.ResultSeven stakeholders were interviewed, all directly involved in the design, implementation, or evaluation of the actions part of the National Plan of Dementia in Chile. Six main categories describing stakeholders’ perception of TAP were produced: 1) Feelings towards TAP, 2) How they see TAP, 3) What to expect from TAP, 4) Institutional fit, 5) Profiles of providers, and 6) Suggestions for a pilot study.ConclusionStakeholders in Chile show a positive perception of the TAP, offering relevant information on the potential adoption of the TAP in a new context.