bluuebunny/crossref_metadata_2025_split huggingface dataset:
Polygenic risk scores predict cognitive impairment as measured by the Preclinical Alzheimer Cognitive Composite (PACC) score in the ADNI cohort
Authors: Pither Richard , Daunt Paula , Davidson Greg , Gibson Alex , Gao Qian , Oshota Olusegun 
Published: December 2021

AbstractBackgroundThe development of diagnostic tools to identify disease risk is critical to enable selection of suitable individuals for inclusion in clinical trials and cohort studies. The utility of Polygenic Risk Scores (PRS) is gaining increasing attention for generating an individual genetic risk profile and subsequent estimation of future disease risk in Alzheimer’s Disease. We have previously reported on the performance of our PRS to differentiate Alzheimer Disease cases from healthy controls in the ADNI cohort and also cognitive decline using ADAS‐Cog13 and CDR‐SB scales. In this work we have analysed whether the PRS is able to predict more subtle changes in cognition by using PACC scores of ADNI cohort participants. The aim being to demonstrate the utility of PRS approaches in longitudinal studies and future clinical practice.MethodThis study explored the performance of the Cytox genoSCORE™ PRS algorithm as measured using a receiver operating characteristic curve (ROC) curve to predict a PACC score of <‐1, as measured upon entry into the study. 724 subjects who entered the study as either cognitively normal, or with a diagnosis of mild cognitive impairment are included in the analysis based on availability of PACC scores and of genetic data in the ADNI database. Further analyses to predict longitudinal changes in PACC have also been performed.ResultIn a population of 724 individuals genoSCORE™ has an accuracy as measured by area under the curve (AUC) of 65.6% in predicting those individuals with cognitive impairment as measured by the PACC scale (threshold <‐1). A similar analysis performed using age as the predictor in the same group showed no discernible correlation with lower PACC scores.ConclusionIdentifying individuals of higher risk for cognitive decline due to Alzheimer’s Disease irrespective of their baseline cognitive performance will allow clinical trialists to enrich their studies with more appropriate patients. In addition, use of such risk evaluation techniques in clinical practice will enable clinicians to make more informed decisions on how to manage their patients. Cytox is able to provide a robust end‐to‐end process to provide this comprehensive genetic risk assessment.
Plasma Aβ 42:40 ratio tracks with changes in brain amyloid PET SUVr in the core and open label extension of the phase 2 proof of concept study ban2401‐g000‐201 following treatment with lecanemab in subjects with early Alzheimer’s disease
Authors: Swanson Chad J , Kanekiyo Michio , Kaplow June , Dhadda Shobha , Irizarry Michael C , Koyama Akihiko , Li David JianJun , Verbel David , Gordon Robert , Heanue‐Travers Helena , Hodgkinson Mark , Kramer Lynn D 
Published: December 2021

AbstractBackgroundLecanemab (BAN2401) is a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ species (oligomers, protofibrils) and insoluble fibrils. Lecanemab reduced the amyloid PET standard uptake value ratio (SUVr) and slowed clinical decline in an 18‐month Phase 2 proof of concept study in early Alzheimer’s disease (Alz Res Therapy 13; 2021). An Open label extension (OLE) with 10 mg/kg IV biweekly lecanemab dosing was implemented after analysis of the Core study, with an intervening gap period off‐treatment ranging from 9‐54 months (mean 24 months). The present study aimed to evaluate longitudinal plasma Aβ 42:40 ratio (C2N PrecivityAD assay) and the relationship to longitudinal amyloid PET in the Core study, gap period, and OLE.MethodThe amyloid PET sub‐study in the Core study assessed baseline, 12 months and 18 months SUVr with florbetapir, and participants in the OLE amyloid PET sub‐study were imaged at baseline, 3 or 6 months, and 12 months. Plasma samples were collected at the same timepoints and analyzed as described previously (West et al, Mol Neurodegen 2021). Mean changes from Core or OLE baseline and Pearson correlation coefficients were calculated at the group and individual levels for amyloid PET SUVr and plasma Aβ 42:40 ratio, accounting for repeated measures.ResultOLE subjects with plasma samples (N=121) were evaluated for this analysis. Lecanemab produced dose dependent reductions in PET SUVr, with corresponding increases in plasma Aβ 42:40 ratio in Core and OLE. In the OLE, reductions in PET SUVr were dependent on OLE baseline SUVr; PET reductions in the OLE were inversely correlated with increases in plasma Aβ 42:40 ratio. Changes in plasma Aβ 42:40 ratio were inversely correlated with changes in PET SUVr at the group and individual levels in the Core (group: r=‐0.939, p=0.0056; individual: r=‐0.49; p<0.0001) and OLE (group: r=‐0.907, p=0.0007; individual: r=‐0.31 p=0.0012) studies.ConclusionLecanemab dose‐dependent reduction in brain amyloid PET SUVr correlate with increases in plasma Aβ 42:40 ratio. These data align with the OLE clinical data and suggest that plasma Aβ 42:40 ratio has the potential to track the anti‐amyloid effects of lecanemab in AD patients.
Development and assessment of a brief screening tool for psychosis in dementia
Authors: Cummings Jeffrey L , Atri Alireza , Ismail Zahinoor , Dickerson Brad C , Ballard Clive , Grossberg George T , McEvoy Bradley , Foff Erin 
Published: December 2021

AbstractBackgroundHallucinations and delusions associated with dementia‐related psychosis (DRP) can occur in persons with dementia—however, quickly screening for these symptoms in busy clinical settings can be challenging. We developed the DRP3 Screen, a novel tool to screen for psychosis in clinical settings; performed an Alignment Exercise to determine association of the DRP3 Screen with established psychosis/DRP reference assessments; and retrospectively assessed the ability of the DRP3 Screen to detect patients with DRP enrolled in a clinical trial (HARMONY, NCT03325556).MethodsThe DRP3 Screen comprises 3 yes/no questions and was developed by Acadia Pharmaceuticals Inc. in collaboration with an international team of six subject matter experts (SMEs). Through facilitated discussions, the panel developed questions addressing key aspects of psychosis in dementia. SMEs independently rated level of alignment (Table) of the questions with current reference assessments (SAPS‐H+D, NPI‐Q, IPA Criteria) to determine if the symptoms itemized in those assessments would be captured by ≥1 DRP3 Screen question. Criteria for association with a reference assessment item was mean rating ≥2.0 for at least one DRP3 Screen question (95% CI, lower limit ≥1.3). Inter‐rater reliability of the Alignment Exercise for individual reference assessments was assessed using Fleiss’ kappa statistic. For retrospective application of the DRP3 Screen to HARMONY, patients were considered likely to have been identified by the DRP3 Screen if they were positive (score ≥2) on ≥1 SAPS‐H+D items that were positively associated with the DRP3 Screen.ResultsAll items across 3 reference assessments (except SAPS‐H+D D6, somatic delusions) were associated with the DRP3 Screen. Mean level of alignment segregated to none/some (0.3‐1.8) and most/all (2.3‐3.0) with significant inter‐rater agreement of the DRP3 Screen with the SAPS‐H+D, NPI‐Q and IPA Criteria, (kappa values: 0.37, 0.26, and 0.45, respectively; p<.0001). Retrospective application of the DRP3 Screen to HARMONY identified all trial enrollees.ConclusionsThe novel DRP3 Screen is a brief tool designed to assess the presence of hallucinations and delusions in persons with dementia. Potential for its clinical application has been established through association with current reference assessments, with significant agreement among raters; and through successful retrospective application to an existing trial population.
Data‐driven approach for early detection of pathological pathways in middle‐aged adults with family history of sporadic Alzheimer’s disease
Authors: Peña‐Gomez Cleofé , Akinci Muge , Sánchez‐Benavides Gonzalo , Shekari Mahnaz , Grau‐Rivera Oriol , Operto Grégory , Milà‐Alomà Marta , Sala‐Vila Aleix , Salvadó Gemma , Kollmorgen Gwendlyn , Suridjan Ivonne , Blennow Kaj , Zetterberg Henrik , Molinuevo Jose , Gispert Juan Domingo , Suarez‐Calvet Marc , Arenaza‐Urquijo Eider M 
Published: December 2021

AbstractBackgroundIn a sample of cognitively unimpaired (CU) middle‐aged adults with family history (FH) of sporadic Alzheimer’s disease (AD), we (i) classified participants based on similarity patterns of expression in cerebrospinal fluid (CSF) biomarkers of AD, axonal damage, synaptic dysfunction, neuroinflammation, and glial response, and (ii) characterized the participants expressing these patterns using neuroimaging, demographics, clinical, and FH variables.Method254 CU participants with FH of sporadic AD from the ALFA study (Table 1) underwent imaging, lumbar puncture, clinical, and neuropsychological evaluations. CSF‐biomarkers Ab42, Ab40, NfL, neurogranin, sTREM2, YKL40 and GFAP were measured by Roche NeuroToolKit immunoassays; p‐tau181 and p‐tau217 were measured with an in‐house Simoa‐based assay, p‐tau231 with an ADx ELISA, and SYT1 and SNAP25 using immunoprecipitation mass spectrometry. Participants were clustered using an agglomerative clustering algorithm according to their similarity of CSF‐biomarker expression–Subsequently, we performed statistical groups comparisons.ResultFour clusters were identified. Higher Aβ burden (lower Aβ42/40) was the hallmark of only 1 cluster (C1: “AD‐like”, mean centiloid [CL]: 15), while the other 3 clusters showed lower Aβ burden but higher expression of Glial (C2), Tau (C3, “SNAP‐like”), or synaptic (C4) markers (mean CL: ‐2.6, ‐4.5, ‐2.2, respectively) (Figure 1). The “AD like” cluster comprised the oldest participants with the lowest memory performances (C1<C2<C3<C4), the highest frequency of APOE‐ε4 carriers (C1>C3>C2>C4), participants with the closest age to the parental onset (C1>C2>C4>C3), and low gray matter in the hippocampus and AD‐sensitive regions (C1<C3<C4). The “Glial” cluster showed a higher proportion of hypertensive participants (C2>all) with preserved executive performances and hippocampus (C2>all). The “SNAP‐like” cluster, composed mainly by females (80%), showed the highest proportion of participants with both parents affected with AD and the lowest hippocampus volume (C3<all). The “Synaptic” cluster showed a greater proportion of males, with the best memory performance among the clusters.ConclusionIn CU middle‐aged adults, we identified differential expressions of CSF‐biomarkers conforming to Aβ‐dependent and independent biological pathways, some of which resemble previously described biomarker conditions such as SNAP. These distinct biomarker expressions were associated with specific imaging and clinical features. Longitudinal studies are warranted to investigate the clinical progression of participants showing these distinct biomarker profiles.
Wisconsin healthcare utilization cost among American Indians/Alaskan Natives with and without ADRD
Authors: Johnson Adrienne L , Norton Derek L , Mundt Marlon P , Seep Elaina , Wyman Mary F , James Taryn T , Zuelsdorff Megan , Lambrou Nickolas H , Umucu Emre , Gleason Carey E 
Published: December 2021

AbstractBackgroundThe annual cost of Alzheimer’s disease and related dementias (ADRD) in the US is $355 billion; that rate is expected to triple by 2050. Individuals ADRD accrue higher healthcare utilization costs than peers without ADRD, including those with comorbid conditions (e.g., cancer, coronary artery disease, diabetes). Although research examining prevalence of ADRD in American Indians/Alaskan Natives (AI/AN) is limited, recent data suggest the prevalence of ADRD in the AI/AN population is 49% higher than in the Non‐Hispanic White population. Only one study has evaluated the healthcare utilization of AI/ANs, which showed greater utilization rates among those with (versus without) ADRD diagnosis and a rapid increase in utilization following ADRD diagnosis. We have yet to comprehensively analyze the additive cost of ADRD within the US among AI/ANs.MethodPost‐paid electronic health record data from Wisconsin Department of Health Services were retrospectively analyzed to compare non‐Tribal and Indian Health Service utilization costs among Medicaid enrolled AI/ANs, ages 40 and older, based on the presence or absence of ADRD throughout data review (7/1/2015 through 7/1/2020). Three separate analyses were completed, separated by payer programs: fee‐for‐service, HMO, and long‐term care. In each analysis, controls (individuals without ADRD) were matched to cases (individuals with ADRD) using exact matching across the subclasses defined by crossings of age group, sex, diabetes status, and emphysema status (Tables 1‐3). Weighted Wilcoxon rank sum tests were then used to compare total payable costs per capita. Tests accounted for both the subclass sampling strata and weights produced through the matching process. Weighted Chi‐square tests of association were also employed to confirm balance was achieved across age groups, sex, diabetes status, and emphysema status in the matching process; no weighted imbalances occurred.ResultAmong all three programs, AI/ANs with dementia had significantly higher healthcare utilization costs than those without dementia, after matching for age, gender, diabetes and emphysema status.ConclusionAI/ANs with ADRD accrued at $25,000 more over 5 years, on average, compared to those without ADRD. The greatest cost disparity was in long‐term care waiver programs ($50,879). Cost‐effective interventions aimed at ADRD prevention and treatment among AI/ANs are greatly needed.
Brain target occupancy of LY3372689, an inhibitor of the O‐GlcNAcase (OGA) enzyme, following administration of single and multiple doses to healthy volunteers
Authors: Kielbasa William , Shcherbinin Sergey , Goldsmith Paul , Phipps Krista M , Biglan Kevin , Mancini Michele , Russell David , Constantinescu Cristian , Gunn Roger N , Nuthall Hugh Norman , Mergott Dustin J. , Lowe Stephen L , Collins Emily C 
Published: December 2021

AbstractBackgroundLY3372689, an O‐GlcNAcase (OGA) enzyme inhibitor, is being developed as a potential treatment of tauopathies, including Alzheimer’s disease. OGA inhibition is proposed to delay the progression of tau‐related diseases by slowing the accumulation of hyper‐phosphorylated, insoluble tau filaments. We report on single dose (SD) and multiple dose (MD) clinical studies testing the effect of LY3372689 on brain OGA enzyme occupancy (EO).MethodA positron emission tomography (PET) radioligand, 18F‐LY3316612, was used to assess brain OGA EO in healthy volunteers (HV). In the SD study [NCT03944031], 0.25, 1 and 5 mg LY3372689 were evaluated across 4 cohorts (N = 4 HV per cohort). Each HV had PET scans at baseline and two post‐dose intervals. Post‐dose scans occurred at 2 and 24 hours at 0.25, 1, and 5 mg, with additional scans for 1 mg at 30 and 54 hours. The MD study [NCT04392271] consisted of 1 cohort (N = 4 HV) given 1 mg LY3372689 once daily for 14 days. Each HV had a baseline PET scan, and PET scans at 24 hours post‐dose after the 1st and 14th administration of LY3372689. Plasma pharmacokinetics was assessed in these studies.ResultIn the SD study, the mean brain OGA EO at 5 mg was 98% at 2 hours and 93% at 24 hours. At 1 mg, the mean EO was 97% at 2 hours, 81% at 24 hours, 68% at 30 hours, and 30% at 54 hours. The EO at 0.25 mg was lower at 2 hours (26%) compared to 24 hours (46%). The Emax and EC50 values were estimated to be 97% and 0.1 ng/mL, respectively. In the MD study, the OGA EO at 24 hours after the 1st and 14th administration of 1 mg LY3372689 was 84%.ConclusionPET studies in healthy volunteers demonstrated that LY3372689 can achieve high brain target occupancy of the OGA enzyme. Brain OGA EO was maintained after multiple dosing, supporting the durability of target engagement for longer clinical trials. The human PET data will be used to support LY3372869 dose selection for efficacy trials in tauopathies.
Serious mini‐games for cognitive function assessment
Authors: L'Yvonnet Thibaud , De Maria Elisabetta , Robert Philippe , Rigault Jean‐Paul , Zeghari Radia , Manera Valeria , Moisan Sabine 
Published: December 2021

AbstractBackgroundThe presence of neurocognitive disorders (NCD) must be detected at an early stage of the disease progression and monitored by clinicians overtime, in order to provide early individualized interventions. Today, a reliable diagnosis requires a heavy set of neuropsychological tests, often coupled with biomarker evidence. There is growing interest in finding objective, fast to administer, and reliable behavioral markers that could complement classical clinical assessment and help detecting early changes in cognitive performance. Serious games have been proposed as promising tools to screen cognitive deficits in people with NCD [1]. In this study, we investigated the interest of employing a battery of mini‐games developed by CoBTeK lab to distinguish elderly patients with mild NCD from patients without cognitive decline.MethodsIn the context of an ongoing project, we recruited 20 subjects with mild NCD (14 females; age: M=75.5, SD=5.7; MMSE, M=26.1; SD=2.2) and 10 subjects with subjective cognitive decline ‐ SCD (9 females; age: M=71.0, SD=7.6; MMSE, M=29.2, SD=1.2) at the Nice Memory Center. Participants played four mini‐games on a tablet, each game assessing a different cognitive function: selective and sustained attention, episodic memory, inhibitory control, and sensitivity to reward. We collected different data including scores, responses, response times, and videos (focused on hand gestures).ResultsPreliminary data analysis focused on one mini‐game (assessing sensitivity to reward) suggests that participants with mild NCD had an almost significantly lower sensitivity to reward. Once the data analysis is complete for the 4 mini‐games, and the final sample size of 50 participants is reached (by the end of June 2021), we plan to integrate all the collected data into a predictive behavior model compliant with model checking techniques.ConclusionsConverging with previous findings, these very preliminary results suggest that mini‐games could be interesting to differentiate patients with mild NCD from subjects without cognitive impairment. Predictive behavior model based on mini‐games may in the next future help clinicians identify individuals that meet the profile of NCD. Reference: Robert P et al. (2014) Recommendations for the use of Serious Games in people with Alzheimer’s Disease, related disorders and frailty. Front Aging Neurosci. 6:54. doi:10.3389/fnagi.2014.00054
Communication difficulty and application of communication skills under the use of personal protective equipment
Authors: Kanamori Takuya , Uchiyama Masayo 
Published: December 2021

AbstractObjectiveThe study aims to investigate the difficulties in communicating and application of communication skills of nurses wearing Personal Protective Equipment (PPE) when interacting with persons with cognitive impairment.MethodA web‐based questionnaire survey was conducted among 500 registered nurses of the digital researching company in Japan in March 2021. Participants were asked to rate their difficulty in communicating with persons with cognitive impairment while under the use of PPE using a 4‐point Likert scale. Further, they answered the Communication Skill Index (CSI) to evaluate the application of communication skills when interacting with a person with cognitive impairment. The CSI consists of 23 items, each ranging from 1 to 4. A high CSI score suggests frequent application of communication skills. The relationship between these factors were analyzed statistically using the Student’s t‐test and Spearman’s correlation coefficient test.ResultsThe study participants’ mean age, proportion of women, and mean length of working experience were 40.0±9.9, 83.2%, and 14.8±9.7 respectively. All participants used facemasks, 31.2% of them used safety glasses, and 13.2% of them used medical gowns while caring for persons with cognitive impairment. The mean score of the communication difficulty was 2.6±0.8, and 55.6% of the participants found it difficult to communicate with persons with cognitive impairment while under the use of PPE. Further, participants using safety glasses and medical gowns had significantly higher communication difficulty than those who only wore facemask (p<0.05). The mean score of total CSI was 72.7±11.3, and the mean score of each item ranged from 2.6 to 3.6. “Use other words to reflect what the person with cognitive impairment has said” was the lowest, while “speak slowly” was the highest. A significant correlation was found between communication difficulty and total CSI score, and a score of 6 on CSI items, such as “use a gesture” and “ask only one question at once” (P<0.05).ConclusionMajority of the nurses wearing PPE find it difficult to communicate with persons with cognitive impairment. Thus, they must consciously apply their communication skills.
Association between magnetoencephalography resting‐state brain oscillatory activity in regions with early Alzheimer’s disease neuropathology and global cortical atrophy
Authors: Brinson Zabecca S. , Proskovec Amy L. , Yu Fang F. , Longoria Anthony , Rossetti Heidi , Kelley Brendan J. , Berry Jarett D. , Maldjian Joseph , Davenport Elizabeth M. 
Published: December 2021

AbstractBackgroundPrevious magnetoencephalography (MEG) studies have shown that individuals with mild cognitive impairment and Alzheimer’s disease (AD) demonstrate increases in δ and θ, decreases in α and β, and lower ratios of relative power between high and low frequency bands compared to controls. This analysis investigates the association between global cortical atrophy, a measure of neurodegeneration, and MEG resting‐state oscillations in cortical regions that show early AD neuropathology.MethodEighteen cognitively impaired adults (mean age: 65.2 years, 56% female) and 18 age‐and‐sex‐matched controls (mean age: 65.7 years, 44% female) were included in this analysis. All completed a 6‐minute resting‐state MEG scan and a T1w structural brain MRI scan. Processed MEG data was filtered into canonical frequency bands. Mean relative power (MRP) and α/δ, β/δ, α/θ, (α+β+γ)/(δ+θ) ratios were computed for 6 AAL atlas regions: angular gyrus, anterior cingulum, hippocampus, parahippocampal gyrus, posterior cingulum, and precuneus. Global cortical volumes (GCV) normalized by intracranial volumes were computed using FreeSurfer 6.0. Linear mixed effects modeling was performed for each region, with MRP or spectral ratio as the outcome and normalized GCV as the predictor. Age and sex were covariates and cognitive status was included as a random effect.ResultNormalized GCV was negatively associated with MRP‐θ in the precuneus (β=‐0.0085, p=0.034), posterior cingulum (β=‐0.0088, p=0.032), and angular gyrus (β=‐0.0077, p=0.043); positively associated with MRP‐α in the precuneus (β=0.0161, p=0.006), posterior cingulum (β=0.0140, p=0.007), and angular gyrus (β=0.0128, p=0.027); positively associated with the α/δ ratio in the precuneus (β=0.1468, p=0.006) and posterior cingulum (β=0.1068, p=0.012); and positively associated with the α/θ ratio in the precuneus (β=0.1398, p=0.044). Higher beta coefficients were found for the cognitively impaired vs. nonimpaired for the α/δ ratio in the precuneus (β=0.1532 vs. 0.1404) and posterior cingulum (β=0.1119 vs. 0.1017) and the α/θ ratio in the precuneus (β=0.1876 vs. 0.0920).ConclusionStronger spontaneous θ activity, weaker spontaneous α activity, and lower spectral ratios are associated with global cortical atrophy, a known pathological process in AD. The precuneus α/θ ratio may be able to distinguish cognitively impaired from nonimpaired subjects and help in determining those at risk for AD.