bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluating the sensitivity of Centiloid quantification to pipeline design and image resolution
Authors: Shekari Mahnaz , García David Vállez , Collij Lyduine E. , Heeman Fiona , Roé‐Vellvé Núria , Bullich Santiago , Buckley Christopher , Barkhof Frederik , Farrar Gill , Pemberton Hugh , Gispert Juan Domingo ,   AMYPAD consortium
Published: December 2022

AbstractBackgroundWider use of amyloid PET in clinical routine requires validated and standardized quantification methods. Therefore, the impact of pipeline design and post‐processing smoothing on Centiloid(CL) quantification was evaluated.MethodsThis study has been performed using 725 amyloid PET scans from the two AMYPAD trials(PNHS and DPMS) that were acquired with either [18F]flutemetamol or [18F]florbetaben(Table1). Using SPM12, 32 pipelines were created and calibrated to render CL with combinations of:• 4 reference regions (Whole Cerebellum, Cerebellar Gray, Whole Cerebellums+Brainstem, Pons)• target VOI (standard GAAIN vs subject‐based)• reference region type (standard GAAIN vs subject‐based)• analysis spaces (native vs MNI)The impact of the pipeline design factors on CL values assessed using Generalized Estimating Equation(GEE) analyses. Individual morphometric variables including total intracranial volume(TIV), and grey/white matter volumes in the reference and target regions implemented in the model. To mimic differences in image resolution, PET scans were smoothed by 3mm and 6mm Gaussian filters. CL was calculated for original and corresponding smoothed PET scans. The agreement between CL values with/without smoothing evaluated using the intra‐class correlation coefficient(ICC). Bland‐Altman plots were used to demonstrate mean absolute differences between CL values after smoothing. Differences above 5CL were considered relevant.ResultsThere was no statistically significant relationship for CL as a function of tracer, analysis space or target region, while RR selection and its definition did have a significant impact on CL values(Table2). More specifically, the pons provided the lowest mean CL(25.06±4.51) compared to the whole‐cerebellum(35.04±4.25) and the cerebellum grey‐matter(36.99±4.16)(Table3). Using GAAIN RR provided slightly higher mean CL values (ΔCL:4.15±1.04) compared to a subject‐based method (Table4). ICC between CL values of non‐smoothed vs smoothed PET images was 0.99 for both post‐smoothing filters(p<0.001). Differences in image resolution had minimal effect on CL values for individuals with low to moderate levels of amyloid while the effect became higher for individuals with the higher amyloid burden(Figure1)
ConclusionCL quantification is robust against differences in individual morphometric measures, analysis space, image resolution, tracer and target VOI. However, reference region choice can significantly influence CL values, with the pons showing the highest discrepancies relative to other reference regions.
Racial and Ethnic Disparities in Measures of Consumer Assessment of Healthcare Providers and Systems among ADRD Patients
Authors: Chen Jie , Albaroudi Asmaa 
Published: December 2022

AbstractBackgroundThis study examines the consumer reported health care quality and racial and ethnic disparities among ADRD patients.MethodThe main datasets included 2017 Medicare inpatient claims data, Medicare Beneficiary Summary File, and the Medicare Shared Savings Program ACO data. Consumer Assessment of Healthcare Providers and Systems (CAHPS) scores were used to measure the quality of physician‐patient relationship among ADRD patients enrolled in ACOs.ResultWhites reported higher CAHPS total score compared to Black, Hispanic, and Asian ADRD patients, and social determinants of health explained 11% ‐13% of disparities between White vs. Black and White vs. Hispanic. Compared to Whites, Black, Hispanic, and Asian ADRD patients reported significantly lower CAHPS measures on access, communication, and rating, Hispanics reported higher scores on the measure of health promotion, and Hispanics and Asians reported higher scores on shared decision making.ConclusionOur results demonstrated significant variations of CAHPS score by race and ethnicity among ADRD patients who were enrolled in ACOs.
Monitoring abnormal nocturnal behaviour in the homes of patients living with dementia
Authors: Soreq Eyal , Kolanko Magdalena A , Monica Ciro della , Ravindran Kiran K.G. , Revell Victoria Louise , de Villèle Paul , Barnaghi Payam , Dijk Derk‐Jan , Sharp David J ,   CRT group
Published: December 2022

AbstractBackgroundPeople living with dementia (PLWD) often exhibit marked sleep disturbances. These cause substantial care challenges and may be causally related to dementia progression. Collecting ecologically valid data on sleep disturbance in naturalistic settings has been difficult. As a result, sleep assessments in PLWD are generally limited to short studies in sleep laboratories or data collection from wearables, where compliance is problematic. Here, we demonstrate how passive internet of things (IoT) sensors can be used to monitor the effects of dementia on nocturnal behaviour and physiology.MethodUsing the Withings under‐mattress pressure sensor, we validated bed occupancy and physiological measures in 35 older adults tested both at home and in the laboratory. We then examined data collected between 2019 and 2021 from the general population (N=13,663) and from a cohort of PLWD taking part in the UK DRI study of home monitoring for PLWD (N=46). More than 4 million unique bed mat observations were analysed.ResultArise time across all subjects was negatively correlated with time to bed (Fig.1a, r(13,617)=‐0.5, p<.0001). Bed occupancy increased with age, but PLWD spent more time in bed than age‐matched controls (Fig.1b) and had more nocturnal awakenings (Fig.1c). Explainable gradient boosting machine learning was successfully used to classify data from individual nights (PLWD vs. general population). PLWD probability was related to specific changes, such as increased awakenings, high or low time spent in bed, high heart rate and low breathing rate (Fig.2). We also explored variations in night‐time behaviour and physiology over time for individual PLWD (Fig.3a). High within‐subject variability was present, which related to disease progression, intercurrent illness and changes in medication. Data from each night was transformed into a risk score for each metric (Fig.3b) and a compound risk score. These quantify the risk of abnormal night‐time behaviour and physiology produced by dementia (Fig.3c) and reflect clinically relevant changes in PLWD.ConclusionTaken together our work demonstrates how digital biomarkers collected passively using under mattress technology can be used to automatically monitor the nocturnal effects of dementia across large populations. The approach is also potentially applicable for preclinical screening and the evaluation of treatments effects.
Overestimation of performance after a memory task in cognitively unimpaired individuals is related to lower cortical thickness in Alzheimer’s disease vulnerable regions and to executive decline, particularly in men.
Authors: Sánchez‐Benavides Gonzalo , Arenaza‐Urquijo Eider M , Brugulat‐Serrat Anna , Operto Grégory , Garcia Marina , Shekari Mahnaz , Gispert Juan Domingo , Suárez‐Calvet Marc , Milà‐Alomà Marta , Minguillón Carolina , Fauria Karine , Molinuevo Jose Luis , Grau‐Rivera Oriol ,   ALFA study
Published: December 2022

AbstractBackgroundLow awareness of cognitive decline is a common feature in Alzheimer’s disease (AD) dementia, and it relates to higher risk of progression in individuals with Mild Cognitive Impairment. Previous research suggests that, in cognitively unimpaired individuals, it has prognostic value and is related to AD biomarkers. We aimed at exploring the associations between the ability to judge performance after a memory task and demographic, clinical (cognitive complaints), structural neuroimaging, cognitive and amyloid status variables in cognitively unimpaired individuals.MethodsWe analyzed data from 225 ALFA+ study participants (mean[SD] age = 68.9[4.9], 63.6% female). We defined a discrepancy score between objective and subjective memory measures by subtracting the self‐ratings of performance in the delayed recall of the Memory Binding Test (range 0–100) from the percentage of words actually recalled. Structural MRI (AD signature cortical thickness), amyloid (PET visual read), and Subjective Cognitive Decline (SCD) status measures were available. We classified individuals as decliners vs non decliners (change >‐0.5 z‐score after 3 years) using executive and memory composites. Linear models with the discrepancy score as dependent variable and age, sex, education, AD signature, amyloid and SCD status as predictors, and with decline/non decline in executive and memory composites as predictors, were constructed.ResultsMales overestimate their memory performance more than females (p = 0.003, Figure 1). Lower cortical thickness in the AD signature was also related to overestimation (p = 0.035, Table 1). Age, education, amyloid and SCD were not significant predictors and did not interact with sex or AD signature. Decline in the executive composite was related to overestimation of performance (p = 0.048), being this association driven by men (men p = 0.032, women p = 0.403, Figure 2). We did not find associations with decline in memory performance.ConclusionsOur results suggest that, in cognitively unimpaired individuals, the overestimation of objective memory performance relates to lower cortical thickness in AD vulnerable regions and to a subtle decline in executive abilities. Men seem to overestimate their ability more than women, particularly those that have decline in executive scores. Future research to define the value of altered self‐judgment of cognitive ability in presymptomatic stages of AD and its relationship with SCD is granted.
Progression of white matter signal abnormalities in predementia frontotemporal dementia mutation carriers
Authors: Lee Hyunwoo , Chatterjee Atri , Gibson Erin , Beg Mirza Faisal , Popuri Karteek , Mackenzie Ian R , Rosen Howard J. , Kantarci Kejal , Boeve Bradley F. , Boxer Adam L , Tartaglia Carmela , Hsiung Ging‐Yuek Robin ,   ALLFTD Consortium
Published: December 2022

AbstractBackgroundWhite matter signal abnormalities (WMSA) are frequently observed on magnetic resonance imaging (MRI) scans of people with frontotemporal dementia (FTD). We hypothesized that carriers of mutations in progranulin (GRN+), chromosome 9 open reading frame 72 (C9orf72+) and microtubule associated protein tau (MAPT+) have increased rates of progression of WMSA compared to non‐carrier individuals prior to onset of dementia, and that different mutations may have different rates of WMSA accumulation.MethodParticipants were recruited through the ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Study. We selected participants with Clinical Dementia Rating scale (CDR) scores of 0 and 0.5. If a participant developed FTD during the follow‐up, we only analyzed observations collected before the conversion. WMSA were defined as hyperintensities on FLAIR MRI. Total WMSA volumes were normalized to the respective intracranial volumes. We used a linear mixed effects model, with random intercepts and slopes, to compare the baseline burden and the longitudinal progression of total WMSA volumes between mutation carriers and controls. The model was adjusted for baseline age, sex, education, baseline Montreal Cognitive Assessment (MoCA) scores, and MRI acquisition sites.ResultWe analyzed MRI data from 199 participants who had at least two MRI visits (46 C9orf72+, 17 GRN+, 35 MAPT+, 101 non‐carrier controls; up to five years of follow‐up). We did not find significant group differences in baseline demographic features, except that MAPT+ was younger than non‐carrier controls (average age: C9orf72+=47, GRN+=56, MAPT+=40, controls=47). Baseline WMSA volumes were not significantly different between mutation carriers and controls. Longitudinally, the rates of WMSA volume increase in C9orf72+ and MAPT+ were comparable to controls; whereas, GRN+ had higher rates of WMSA volume increases compared to controls (p=0.01).ConclusionWMSA may accumulate at higher rates in GRN+ prior to the onset of FTD, which is consistent with the frequent presence of white matter diseases observed in symptomatic FTD patients with GRN mutations. Future work is warranted to investigate the association between white matter structural changes and cognitive/psychiatric changes in FTD mutation carriers.
Disparities in Recruitment and Screen Failure by Race and Ethnicity in the Harvard Aging Brain Study (HABS)
Authors: Levin Raina , Vila‐Castelar Clara , Samaroo Aubryn H , Muniz Martha C. , Martinez Jairo E. , Gonzalez Christopher , Garza‐Naveda Ana Paola , Quiroz Yakeel T. , Rentz Dorene M. , Johnson Keith A. , Sperling Reisa A. 
Published: December 2022

AbstractBackgroundDespite progress, disparities in Alzheimer’s Disease (AD) research participation continue to be a problem. Underrepresentation of certain racial and ethnic groups can result from several factors, including narrow recruitment strategies and strict exclusion criteria, and hinders our understanding of AD. We examined racial/ethnic differences in recruitment and screen failure in the Harvard Aging Brain Study (HABS), a longitudinal observational study, to elucidate these discrepancies.MethodWe analyzed HABS screening data from September 2010 to December 2021. Eligible participants were 50‐90 years old, cognitively intact (based on CDR, Logical Memory, and MMSE scores), in stable physical health, and had a study partner who could answer questions about their daily functioning. Participants were categorized into four mutually exclusive racial/ethnic groups based on self‐report data: Hispanic/Latino, White, Black, and other (Asian, American Indian/Alaskan Native, >1 Race, or did not disclose). Screen fail reasons were divided into clinical/cognitive, MRI/PET contraindications, medical and psychiatric history, and other. Statistical analyses included chi‐square, odds ratio, and t‐tests.ResultThe racial/ethnic breakdown of the 514 screened participants was 72.0% White, 14.0% Black, 10.9% Hispanic/Latino, and 3.1% other. Black participants had lower mean years of education than White participants (p < .05; Black, Mean [SD] = 14.28 [2.76]; White, 16.00 [2.96]). A total of 18.7% of participants screen failed with 17.8% of White, 19.4% of Black, and 28.6% of Hispanic/Latino participants (p > .05). Clinical/cognitive test scores were the most common reason for screen failure across all participants (41.7%), followed by medical history (26.0%). There were differences across racial/ethnic groups; compared with White participants, Black (odds ratio (OR), 2.6, 95% CI, 1.1‐5.6; p < .05) and Hispanic/Latino (OR, 2.7; 95% CI, 1.0‐6.1; p < .05) were more likely to meet exclusion criteria for cognition.ConclusionWhile efforts have been made to broaden recruitment strategies, create a Spanish‐language cohort, and revise exclusion criteria, racial/ethnic differences in recruitment and screen failure of HABS participants persist. This reflects a continued need to identify more culturally appropriate cognitive tests, norms, and cutoffs. Discovering and analyzing disparities by race/ethnicity will inform future efforts to create inclusive cohorts, leading to more representative AD research.
The CDR‐SB and other clinical trial mistakes made due to regulatory momentum
Authors: Dickson Samuel P. , Hogan Nathaniel J. , Nicodemus‐Johnson Jessie , Knowlton Newman , Hennessey Sean , Hendrix Suzanne B. 
Published: December 2022

AbstractBackgroundIn 2013 the FDA released a draft guidance for developing drugs for the treatment of early stage Alzheimer’s disease (AD) with the CDR‐SB suggested as a suitable scale for a primary outcome. Since that time, this suggestion has been treated as a regulatory requirement, but a single endpoint is preferable to the co‐primary endpoints necessary in mild‐to‐moderate populations or when using an outcome besides the CDR‐SB. Although it is true that AD progression is mostly represented by a single dimension, the FDA incorrectly claimed that CDR‐SB represents this dimension, when this would be true only for an empirically‐derived composite outcome, like ADCOMS. Years of damaging regulatory momentum surrounding clinical trial outcomes has resulted in equivocal results in nearly all development programs. The only major approval in almost two decades (aducanumab) was granted without definitive success in the primary outcome (CDR‐SB) partially because of this.MethodPublic FDA statements and documents were analyzed. Historical data from ADCS, ADNI, and publicly‐available clinical trial results were used to provide performance metrics for outcomes including CDR‐SB, ADAS‐Cog, ADCS‐ADL, ADCS‐CGIC, ADCOMS, and iADRS.ResultDespite regulatory pressure to use CDR‐SB in early AD and co‐primary endpoints in mild‐to‐moderate populations, these endpoints are suboptimal methods for assessing the efficacy of treatments in slowing disease progression. CDR‐SB represents a 23 degree departure from the axis of disease progression. While being a composite of cognitive and functional domains itself, other proposed composite outcomes are required to demonstrate independent effects on cognition and function, despite a greater than 70% correlation between the cognitive and functional domains of CDR‐SB. The alternative of using co‐primary endpoints for a disease‐modifying treatment may require as much as a tenfold increase in sample size compared to a composite endpoint.ConclusionThe use of CDR‐SB as the primary outcome already cost Biogen (aducanumab) credibility, will likely cost Eisai (Ban2401) around 500 patients, and will continue to cost the AD community effective treatments for years to come. Those suffering from AD are failing to benefit from treatment advances because regulatory momentum surrounding clinical trial outcomes has made it nearly impossible for clinical trials of otherwise effective treatments to succeed.
Inflammatory biomarkers are associated with changes in cerebral large artery thickness and lumen diameter in older adults
Authors: Cambronero Francis E. , Liu Dandan , Bown Corey W. , Kresge Hailey A. , Moore Elizabeth E. , Pechman Kimberly R. , Khan Omair A. , Davis L. Taylor , Gifford Katherine A. , Hohman Timothy J. , Blennow Kaj , Zetterberg Henrik , Jefferson Angela L. 
Published: December 2022

AbstractBackgroundAge‐associated remodeling of cerebral large arteries contributes to worse systemic and brain health in older adults. Vessel wall imaging (VWI) is a neuroimaging technique that offers the critical ability to quantify thickness and lumen diameter across arterial segments of the circle of Willis (CoW). Inflammation, a well‐known feature of aging, cerebrovascular disease, and Alzheimer’s disease, may be a central driver of age‐related changes in CoW morphology. We investigate if fluid biomarkers of inflammation predict key features of intracranial arterial aging, including CoW thickening and dilatation over time.MethodsVanderbilt Memory and Aging Project participants were studied (n=96, 73±7 years, 80% male, mean follow‐up=3.0 years). Baseline systemic inflammatory biomarkers (TNF‐α, IL‐6) were quantified from blood plasma samples. Baseline neuroinflammatory biomarkers (sTREM2, YKL‐40, MMP‐2, MMP‐3, MMP‐9) were quantified from cerebrospinal fluid samples. Intracranial artery lumen diameter and thickness were manually measured across the basilar artery (BA) and bilateral segments of the internal carotid artery (ICA), anterior cerebral artery (ACA), and middle cerebral artery (MCA) using serial VWI MRI. Linear mixed effects regressions related time x inflammatory biomarker (one predictor per model) to longitudinal VWI lumen diameter and thickness outcomes, adjusting for baseline age, sex, race/ethnicity, education, Framingham Stroke Risk Profile, cognitive status, apolipoprotein ε4 status, T1‐weighted intracranial volume, and time.ResultsHigher CSF sTREM2 levels related to faster luminal narrowing (right ACA, p‐value=0.001). Higher CSF YKL‐40 levels related to faster luminal narrowing (right ACA, p‐value=0.07). Lower CSF MMP‐2 levels related to faster wall thickening (left MCA, p‐value<0.05). Lower CSF MMP‐3 levels related to luminal narrowing, while higher CSF MMP‐3 levels related to luminal widening (left ICA, p‐value=0.05). TNF‐α, IL‐6, and MMP‐9 were unrelated to any VWI changes (p‐values>0.14).ConclusionResults suggest neuroinflammatory biomarkers are largely related to longitudinal intracranial artery narrowing and thickening. However, additional associations between MMPs and luminal widening may reflect the mixed nature of MMP activity on cerebrovascular remodeling. Immune responses mediated by astroglial and microglial activity as well as MMPs may be key pathophysiological mechanisms underlying age‐related cerebral arterial remodeling.
Developing a new clinical interview to assess awareness in dementia.
Authors: Alexander Catherine Maria , Martyr Anthony , Clare Linda ,   in collaboration with the IDEAL programme research team
Published: December 2022

AbstractBackgroundPeople with dementia differ in degree of awareness of difficulties. Awareness can influence well‐being, communication and relationships, and impact on personal safety and decision‐making in everyday and clinical situations. Evaluating awareness could facilitate person‐centered care. A scoping review identified the lack of a brief, multidimensional clinical tool. We aimed to develop and test a new awareness interview for clinical use.MethodMeasure development was informed by scoping review findings, available evidence about awareness phenomena in dementia, and considerations of suitability for remote as well as in‐person administration. Some items were drawn from existing validated measures, covering awareness of functional ability, memory, and socio‐emotional functioning, and new items were developed to assess awareness of medication management and mobility, providing a profile of awareness across these domains. Scoring was based on calculation of discrepancies between self‐rating and either informant ratings or objective memory task performance, as well as self‐reported acknowledgement of specific symptoms. The interview was tested for feasibility and acceptability in a remotely‐administered pilot study. The interview was administered to 31 community‐dwelling people with mild‐to‐moderate dementia recruited in England in 2020‐2021, via telephone or Zoom video‐call. A caregiver, acting as an informant, completed a corresponding questionnaire in advance. Cognitive ability of the participant with dementia was assessed with the Montreal Cognitive Assessment‐5 minute protocol (MoCA‐5 min). Structured and open‐ended feedback was obtained from participants and caregiversResultThe interview was completed by 29 participants with MoCA‐5 min scores ranging from 9.5 to 29.Two participants with lower MoCA‐5 min scores were unable to complete the interview. Remote administration was straightforward with few challenges, taking on average under 11 minutes. Awareness profiles showed a spectrum of awareness across domains. Feedback indicated that interview questions were acceptable and understandable, but certain aspects, such as the memory task, could be somewhat upsetting as they highlighted current difficulties.ConclusionThe new Healthcare Awareness Profile Interview (HAPI) shows potential as an evidence‐based brief clinical tool for assessing awareness in people with mild‐to‐moderate dementia. Following discussions with clinical advisory and patient and public involvement groups, a final version will be prepared for a larger validation study.