bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Digital Maze Test (dMaze) Reveals Subtle Decision‐Making Difficulties in MCI: Hurrying to Keep Up?
Authors: Penney Dana L , Davis Randall 
Published: December 2022

AbstractBackgroundTraditional Maze tests are time‐consuming and insensitive to early AD cognitive changes. We combine behavior capture using a digitizing pen with novel test design to produce person‐centric/relative metrics that disembed cognitive from motor speeds. This enables comparison of complex decision‐making behavior across difficulty levels within a single test. We compare traditional measures with our person‐centric/relative measures.MethodParticipants were healthy (HC = 22), Mild Cognitive Impairment (MCI = 37), Alzheimer’s (AD = 39), and Parkinson’s (PD = 43) volunteers (N = 141). Diagnosis was determined by consensus using standard of care data (neuropsychological/neurological evaluations, MRI and DAT scans). Participant groups differed in age: HC (52.27) younger than PD (64.07), MCI (75.05) and AD (75.38) oldest. Groups differed in the expected direction for DCTclock and MoCA scores.The dMaze test contains a path‐following condition without choice points, followed by a choice (CH) condition with identical solution paths/motor demands. CH contains simple and complex choices. Relative measures use the participant’s overall speed to normalize within‐test speed deviations. We examined: Total Time (TTime) to completion, Max motor speed (MaxSpd) and Median speed (MedSpd), Choice point Average Speed (AveSpd) and Relative Average Speed (rAveSpd).ResultTTime in seconds differentiated (p = .001) AD (141.24) from HC (52.98) and PD (77.35), not MCI (103.16). MaxSpd was slowest (p = .004) for HC (59.82mm/sec) compared to all clinical groups (MCI = 76.71mm/sec, PD = 77.11, AD = 85.52). Groups did not differ for MedSpd or choice point AveSpd. Simple choice point rAveSpd differentiated only AD (p = .001) from HC, PD & MCI. Complex choice point rAveSpd differentiated HC from MCI (p = .05) and AD (p = .001). HC and PD did not differ, suggesting simple motor speed did not account for ink speed differences.ConclusionFast completion time despite slow maximum speed and relative average speed across choice points suggests HC use a modulated approach balancing speed and task difficulty. MCI faster relative maximum speed (hurrying) with completion time similar to HC, suggests a less well‐modulated approach. Relative speed differences for more complex choices may be sensitive to preclinical cognitive change even when total completion time is not. The ability to precisely measure and parse person‐centric motor and cognitive test behaviors provides opportunity to improve preclinical detection, disease monitoring and treatment efficacy.
Projection in Proxy Assessments of Everyday Preferences for Persons with Cognitive Impairment
Authors: Wilkins James M. , Locascio Joseph J , Gomez‐Isla Teresa , Hyman Bradley T. , Blacker Deborah , Forester Brent P. , Okereke Olivia I 
Published: December 2022

AbstractBackgroundA source of bias in surrogate decision‐making has been articulated alternatively as the false consensus effect, assumed similarity, and attributive/social projection by which proxies overestimate the degree that their values and preferences are shared by others, resulting in a projection of their own beliefs onto others in the process of surrogate decision‐making. The aims of this study are to assess for projection of proxies’ preferences onto surrogate assessments of everyday preferences for persons with cognitive impairment (CI) and to address cognitive and neuropsychiatric symptom burden as predictors of projection.MethodThe sample included 116 dyads of persons with CI (Clinical Dementia Rating Scale score ≥ 0.5) and their care partners. The Preferences for Everyday Living Inventory (PELI) was used to assess importance of preferences among persons with CI. Care partners completed two separate PELI assessments: one from the perspective of the persons with CI (i.e., acting as a surrogate decision‐maker) and one from their own perspective. To assess for projection of care partners’ preferences onto surrogate assessments of preferences for persons with CI, two‐step regression with multivariable‐adjusted general linear models was used.ResultSignificant projection effects were noted within the PELI domains of autonomous choice, personal growth, and keeping a routine (p < 0.0005). More significant cognitive impairment was associated with increased projection effects within the PELI domains of autonomous choice and personal growth (p < 0.01)ConclusionThe results of this study suggest that projection effects of care partners own preferences may be a significant source of bias in everyday proxy decision‐making for persons with CI, particularly for those with more significant CI.
Concordance of CSF biomarkers with amyloid PET at baseline in EMERGE/ENGAGE, phase 3 studies of aducanumab in patients with early Alzheimer’s disease
Authors: Rubel Carrie E. , Nisenbaum Laura , Chen Tianle , Dent Gersham , Fraser Kyle , Graham Danielle , Harrison Katie , He Ping , Racine Annie M , Rajagovindan Raj , Beaver John , Haeberlein Samantha Budd 
Published: December 2022

AbstractBackgroundRecent technical performance improvements with the introduction of fully automated platforms have made cerebrospinal fluid (CSF) biomarkers attractive alternatives to positron emission tomography (PET) for brain amyloid pathology confirmation in the diagnosis of Alzheimer’s disease. Growing the body of evidence demonstrating high agreement between CSF biomarkers and amyloid PET across multiple automated platforms is critical to ensuring widespread access to and adoption of CSF biomarkers. Adding to previous data generated with Lumipulse® CSF immunoassays, this study assessed CSF biomarkers on the Elecsys® platform as valid alternatives to PET for amyloid confirmation by conducting a concordance analysis using data from EMERGE and ENGAGE, including performance evaluation of the Elecsys® Gen2 recommended cutoff.MethodsEMERGE and ENGAGE were randomized, double‐blind, placebo‐controlled, global Phase 3 studies of aducanumab. Participants were 50‐85 years old and met clinical criteria for mild cognitive impairment due to AD or mild AD dementia. All enrolled participants had amyloid pathology detected by amyloid PET (visual read) during screening. Positive percent agreement (sensitivity), negative percent agreement (specificity), and overall percent agreement (OPA) were determined (with amyloid PET visual read as reference standard) for the following CSF biomarkers (and applicable ratios) using the Elecsys® immunoassay: using an internal cutoff value maximizing the Youden J index for Abeta40, Abeta42, phosphorylated tau (ptau181), tau; Abeta40/Abeta42, ptau181/Abeta42, tau/Abeta42; and for the ptau181/Abeta42 ratio using the Elecsys® Gen2 cutoff.ResultsN=349 participants (n=309 PET positive; n=40 PET negative) provided CSF at screening and were included in the analysis. Using internal cutoff values, tau, ptau181 and Abeta42 demonstrated OPA of 69%, 83% and 89% respectively, and CSF biomarker ratios showed increased diagnostic accuracy (OPA ≥95% for all ratios assessed). The Elecsys® Gen2 cutoff demonstrated excellent sensitivity(93%), specificity(82%), and OPA(92%).ConclusionsThese analyses demonstrate robust concordance between CSF biomarkers and amyloid PET visual read in EMERGE/ENGAGE and align with results generated previously. This supports the interchangeability of these biomarker methods for determination of amyloid positivity and applicability of the Elecsys® recommended cutoff in similar patient populations, with significant potential to improve accessibility of this critical biomarker for AD diagnosis in clinical trials and clinical practice.
Plasma Aβ42/40 and PET amyloid associations among late‐middle‐aged African Americans: Preliminary results from the AA‐FAIM study
Authors: Koscik Rebecca Langhough , Betthauser Tobey J , Van Hulle Carol A. , Zuelsdorff Megan , Salazar Hector , Carter Fabu P , Norris Nia , Green‐Harris Gina , Fischer Barbara L. , Chin Nathaniel A. , Gooding Diane C. , Cody Karly Alex , Meyer Matthew R. , Holubasch Mary S. , Kirmess Kristopher M. , Verghese Philip B. , West Tim , Venkatesh Venky , Yarasheski Kevin E. , Christian Bradley T , Johnson Sterling C. , Gleason Carey E. 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) models of disease progression have been built largely on non‐Hispanic White samples. Availability of AD blood‐based biomarkers may improve screening for AD risk and facilitate greater diversity in research studies; little is known about these biomarkers within African Americans (AA). Here, we characterized associations between plasma Ab42/40 and Positron Emission Tomography (PET) amyloid measures in an AA sample.MethodParticipants in the African Americans Fighting Alzheimer’s in Mid‐Life (AA‐FAIM) with >=1 PET scan and plasma Ab42/40 assay were included (n=34 participants; n=117 EDTA plasma samples). The ratio Ab42/40 was calculated from plasma Ab40 and Ab42 quantified by C2N Diagnostics (PrecivityAD™). PET 11C‐Pittsburgh compound B (PIB)‐derived amyloid measures included a mean cortical DVR (global PiB DVR), PET_A+ (DVR>1.19) and estimated PET_A+ duration at each plasma sample. In separate models where “time” was age or PET_A+ duration at each plasma sample (outcome=plasma Ab42/40), we used mixed effects models to estimate simple slopes from time*PET_A+ status interactions. Sensitivity, specificity and related statistics were calculated for two plasma_A+ cutoffs (0.0975, West et al., 2021; 0.089, Hu et al., 2022).ResultBaseline plasma sample and baseline PET scan average(sd) ages were 61(8.6) and 65(9), respectively. Closest plasma Ab42/40 explained 47% of variability in last global PiB DVR (mean(sd)=‐0.85(0.91) years plasma‐to‐PET). Seven(20.6%) participants were PET_A+. In longitudinal analyses, simple age‐slopes for plasma Ab42/40 change were ‐0.00061(0.00024) for PET_A+ and ‐0.00057(0.00018) for PET_A‐ (age*PET_A status interaction NS; model AICc=‐792.6). In a parallel mixed effect model, simple slopes were ‐0.00093(0.00026) for PET_A+ change/year and ‐0.00039(0.00012) for PET_A‐ change/year (interaction p∼0.06; AICc=‐800.6). Figures 1 and 2 depict relationships among plasma and PET amyloid measures. Positive and negative predictive values were 50.0% and 95.5% (0.0975 cut‐off) and 68% and 83% (0.089 cut‐off; see Figure 1 for additional statistics).ConclusionPreliminary results from this small African American sample provide encouraging data regarding plasma Ab42/40’s potential to screen for PET A+ in AAs. PET A+ duration explained more variability than age in plasma Ab42/40 trajectories. The on‐going AA‐FAIM study continues the critical effort to increase representation of AA in AD research, ensuring findings are broadly applicable.
Lipophilic Statins in Subjects with early Mild Cognitive Impairment and Low Serum Cholesterol: Association with Long‐Term Cerebral Metabolic and Cognitive Decline in a Prospective Longitudinal Multi‐Center Study
Authors: Padmanabham Prasanna S , Liu Stephen , Silverman Daniel H 
Published: December 2022

AbstractBackgroundWe recently reported that lipophilic statins, known to penetrate the blood‐brain barrier, were associated with accelerated decline in regional cerebral metabolism in subjects with early Mild Cognitive Impairment (eMCI) who had relatively low serum cholesterol levels (J Nucl Med. 2021;62:Suppl 1). In this study, we expand upon our past results by studying the relationship between metabolic decline in lipophilic statin users and their decline in neuropsychological test scores.MethodsSubjects with eMCI were drawn from a consecutive series enrolled in the Alzheimer's Disease Neuroimaging Initiative, identifying 70 having serum cholesterol levels below the 206 mg/dl median of non‐statin users and with clear histories of time‐frames of prescriptions and types of statins used – 41 taking lipophilic statins throughout the 2‐year follow‐up period (LS), and 29 demographically similar non‐statin users (nonS). FDG‐PET scans acquired at baseline and 2 years later were compared for each group, and standardized Volume of Interest (sVOI) methods were used to calculate rates of regional metabolic decline. Correlations between changes in regional metabolism and changes in neuropsychological test scores were assessed by linear regression.ResultsThe strongest association occurred between declining metabolism in the left parietotemporal cortex (PTC) and declining function, as indexed by the Functional Activities Questionnaire (FAQ), which was highly significant among LS users (p=0.0004), but not among nonS subjects (p=0.56). Decline of left PTC was also a significant correlate of decline in LS memory performance (p= 0.001), but not nonS (p = 0.11). Both the left posterior cingulate and right PTC declines correlated with LS MMSE decline (p = 0.01 for both), while that metabolic decline was again uncorrelated for nonS subjects.ConclusionSubjects with eMCI with low serum cholesterol levels , who nevertheless were persistently prescribed lipophilic statins over two years, underwent accelerated metabolic decline in the brain regions most significantly hypometabolic in patients with Alzheimer's disease that was in turn significantly correlated with decline in key measures of both function and cognition, in a manner specific to statin use.
Associations between gut microbial families and brain myelin in a human cohort
Authors: Yang Kao Lee , Heston Margo B. , Kohli Akshay , Kecskemeti Steven R , González Antonio , Knight Rob , Kaddurah‐Daouk Rima , Rey Federico E. , Bendlin Barbara B. 
Published: December 2022

AbstractBackgroundWe previously reported brain myelin (Dean et al, 2017) and gut microbial composition alterations (Vogt et al, 2017) in Alzheimer’s disease (AD). Prior animal studies suggest that myelin is impacted by experimentally altered gut microbiota (Keogh et al, 2021), suggesting that gut microbiota may be linked to brain myelination. However, little is yet known about the human gut microbiome and myelin alterations in the context of AD. Here, we examined the gut‐brain association in humans using biomarker and neuroimaging data.MethodAmyloid positive (n=27) and negative (n=91) participants from the Wisconsin Alzheimer’s Disease Research Center and the Wisconsin Registry for Alzheimer’s Prevention were included based on completion of one MPnRAGE (Kecskemeti et al., 2018) scan and donation of one stool sample. Myelin was assessed using MPnRAGE‐derived quantitative R1 and myelin content in 9 white matter tracts were examined as primary outcomes (Table). Intestinal microbiota composition was characterized using 16S rRNA sequencing of fecal samples. QIIME2 was used to denoise and classify features. Phyloseq was used to filter rare taxa, compute relative abundances, and agglomerate at the family taxonomic rank, resulting in 35 microbial families used as primary predictors. Multiple regression was used to test associations between each microbial family and regional myelin content. Benjamini‐Hochberg false discovery rate (FDR) adjustment was applied post‐regression; results were considered significant at q<.05.ResultMicrobial family Turicibacteraceae was positively associated with myelin indexed by R1 (Figure) in the forceps minor (b=.014, q=.037) and uncinate fasciculus (b=.011, q=.028). Across all white matter tracts, higher age was associated with lower R1. Interestingly, there was a significant Paraprevotellaceae‐by‐amyloid effect in the superior longitudinal fasciculus (b= ‐.017, p =.031) and Clostridiaceae‐by‐amyloid effect in the forceps major (b=.002, p=.037) though neither interaction survived FDR correction.ConclusionIn both the uncinate fasciculus and forceps minor, higher levels of Turicibacteraceae were associated with greater myelin content. Turicibacteraceae were previously identified as less abundant among individuals with AD; the current study’s microbial associations with large white matter tracts that are altered in AD warrants further study. Future studies will test additional metrics of AD pathology to clarify gut microbe and brain relationships.
Plasma NfL associated neurodegeneration in adults with Down syndrome
Authors: Padilla Concepcion , Bejanin Alexandre , Montal Victor , Pegueroles Jordi , Carmona‐Iragui Maria , Aranha Mateus Rozalem , Vera Elena , Zua Ania , Videla Laura , Altuna Miren , Benejam Bessy , Ribas Laia , Arranz Javier , Fernandez Susana , Iulita Maria Florencia , Barroeta Isabel , Blesa Rafael , Alcolea Daniel , Lleó Alberto , Fortea Juan 
Published: December 2022

AbstractBackgroundDown’s syndrome (DS) is a genetic form of Alzheimer´s disease (AD). Plasma NfL is a neurodegeneration biomarker which has shown excellent diagnostic and prognostic performances. However, its association with brain atrophy has not been established.MethodsSingle‐centre cross‐sectional study in adults with DS. Participants had blood drawn and underwent an MRI and were classified into asymptomatic and symptomatic AD patients after a structured neurological and neuropsychological evaluation blind to the biomarker data. Plasma Neurofilament light (NfL) levels were determined with SIMOA and cortical thickness (CTh) with Freesurfer. We assessed the correlation of plasma NfL levels with CTh across the cortical mantel and with the Dickerson´s CTh signature.ResultsWe recruited 169 adults with DS (74 females, mean age 42.85 [18.23 – 61.79] years old), of which 114 were asymptomatic (46 females, mean age 38.44 [18.23 – 57.17] years old) and 55 symptomatic (mean age 51.99 [39.40 – 61.79] years old). Plasma NfL levels were associated with cortical atrophy only in the symptomatic AD group in widespread medial and lateral posterior cortical regions (Figure 1). Plasma NfL showed a moderate negative correlation (r= ‐0.54; p<0.01) with Dickerson´s cortical signature (Figure 2).ConclusionsPlasma NfL levels are a good biomarker to track neurodegeneration in DS associated AD.
Disrupted RNA‐networks in Alzheimer’s disease
Authors: Uneri Ayse , Niere Farr , Deng Zhiyong , McArdle Colin J , Raab‐Graham Kimberly F 
Published: December 2022

AbstractBackgroundSynapse loss is well‐documented and underlies cognitive decline in Alzheimer’s disease (AD) and other comorbid neuropsychiatric disorders such as depression. To date, few molecular targets and mechanisms are identified to restore/maintain healthy synapses in AD. AD and depression both have disrupted mechanistic/mammalian target of rapamycin complex 1 (mTORC1) activity. Since mTORC1 is involved in protein synthesis, disruptions in mTORC1 activity creates an imbalance between mRNA translation and repression at synapses. We have demonstrated that mTORC1 signaling is overactive in the prefrontal cortex (PFC) of AD patients and animal models. RNA binding proteins (RBP) are significant regulators of mRNA translation. A single RBP can bind to multiple mRNAs to either enhance or repress their translation. Dysregulated expression of RBPs can thus lead to imbalanced mRNA translation and protein synthesis.MethodComputational methods, combined with the literature, have identified putative DJ‐1 mRNA binding proteins. DJ‐1 RNA‐immunoprecipitation were used to verify FMR1 mRNA as a target. A new protein synthesis assay was used to test if DJ‐1 expression affects FMRP expression. Network analyses was performed to identify new targets shared and unique to these two RNA binding proteins.ResultWe recently identified the mTORC1 regulated RBP, DJ‐1 (Park7) as a translational regulator whose expression can impact the expression and/or function of multiple proteins. We have found that Fmr1 mRNA, which is translated to the RBP, fragile X messenger ribonucleoprotein 1 (FMRP), is a target of DJ‐1. We have shown that FMRP functions to suppress the translation of various synaptic mRNAs to maintain proper transsynaptic signaling which is essential in the formation, stability, and remodeling of synapses. Notably, depression is often comorbid with AD. Furthermore, we have demonstrated that FMRP is required for antidepressant efficacy. Herein, we provide data that supports disrupted DJ‐1/FMRP expression at the synapse in preclinical models of AD. Network analysis of how these two RNA binding proteins interact will be discussed and their impact on synapse stability and behaviors in AD.ConclusionDJ‐1 and FMRP RNA networks are disrupted in Alzheimer’s disease. Network analyses linking these two proteins may reveal novel targets involved in synapse stability and comorbid neuropsychiatric disorders.
APOE and CLU cooperatively promote amyloid formation
Authors: Ding Zonghui , Haug Katelin , Fryer John D. 
Published: December 2022

AbstractBackgroundApolipoprotein E (APOE) and clusterin (CLU) are critical in the pathogenesis of Alzheimer’s disease (AD). Common coding variants in APOE (e.g. APOE4) impart at least 3‐fold higher risk of developing AD, while common noncoding variants in CLU impart smaller but still highly significant risk for AD. Using genetically engineered mouse models lacking either APOE or CLU, previous studies from our lab and others have shown that both are critical in the formation of amyloid. However, only a single published study has examined the combined effects of APOE and CLU in a mouse model of amyloidosis.MethodsWe generated mice that lacked both murine APOE and CLU (double knockout mice) on the APP/PS1 background of AD amyloidosis. We assessed these mice using histological analysis as well as single‐cell RNAseq profiling from brain tissue.ResultsCompared to APP/PS1 controls, we found that double knockout mice for both APOE and CLU had a striking reduction in the amount of amyloid plaques in the cortex. Moreover, we found that these double‐knockout mice were completely void of amyloid plaques in the hippocampus. Single‐cell RNAseq experiments revealed a strong reduction in the amount of activated microglia in these double knockout mice.ConclusionsContrary to a previous study that reported increased amyloid load in APOE‐/‐;CLU‐/‐ double knockout mice, we found a dramatic reduction in amyloid plaques and a concomitant loss of activated microglia when using genetically inbred (C57BL/6J) mouse lines. Further studies are needed to determine whether these effects are cell‐type specific (e.g. astrocyte‐derived APOE and CLU conditional knockouts) or whether these lipoproteins have synergistic roles in tau pathology.