bluuebunny/crossref_metadata_2025_split huggingface dataset:
Introducing rrAD420, an anatomical template and multi‐modal atlas for older adults
Authors: Scheel Norman , Keller Jeffrey N. , Binder Ellen F. , Vidoni Eric D , Burns Jeffrey M. , Stowe Ann M , Kerwin Diana R. , Vongpatanasin Wanpen , Cullum Munro , Zhang Rong , Zhu David C 
Published: December 2022

AbstractBackgroundRisk Reduction for Alzheimer’s Disease (rrAD) is a recently completed randomized controlled trial assessing the effects of aerobic exercise training and pharmacological cardio‐vascular interventions on neurocognitive function in hypertensive older adults with a family history of dementia or subjective cognitive decline. The comprehensive neuroimaging protocol included anatomical, functional, and physiological MRI scans, obtained at baseline and after two years of intervention. 420 older subjects (68.8±5.9 years) were scanned on five different 3T MRI scanners (two Siemens, two GE, and one Philips). Brain atrophy and ventricular enlargement are common in this elderly study population, leading to substantial deviations from the standard MNI152 template (25.02±4.9 years). Severe artifacts might occur when transforming non‐normative brains into MNI standard space. Using the high‐quality baseline data of this study, we aim to integrate images from multiple modalities to create a reference that is better suited to investigate older populations.MethodsFor each subject, we acquired T1 MPRAGE, T2 FLAIR, ASL, DTI, and resting‐state fMRI. Each scan underwent rigorous manual quality control and linear sequence‐specific high precision alignment to the T1 image. All T1 images then underwent non‐linear DARTEL registration into a common space to create cohort‐specific transformations. We then transformed all images into the new common space, namely
rrAD420
(Figure 1). Averages across subjects make up cohort‐ and modality‐specific templates (Figure 2). Seed‐based and data‐driven decompositions of resting‐state fMRI and DTI data created functional and structural connectivity atlases (Figure 3). Anatomical dual regression transforms common brain atlases from MNI into rrAD420 space, facilitating cross‐referencing.ResultsThe rrAD420 templates and atlases integrate multimodal neuroimaging data of older populations into a common space, accounting for cohort‐specific distinctions, such as cortical atrophy and enlarged ventricles. It provides references to commonly used brain parcellations which are integrated with functional and structural atlases created from the rrAD cohort. Thus, rrAD420 provides a reference framework for comprehensive multimodal MRI analyses of elderly cohorts.ConclusionsThrough rrAD420, longitudinal multi‐modal image analyses can now be carried out using templates unique to this population. Furthermore, rrAD420 should also apply to older populations in general, facilitating data integration, and biomarker detection.
Development of fully automated plasma immunoassay using by HISCLTM series for classification of neurological disorders
Authors: Ishiki Kengo , Watanabe Shunsuke , Yamashita Kazuto , Miura Masahiro , Iwanaga Shigeki , Sato Toshiyuki 
Published: December 2022

AbstractBackgroundATN classification system (A: β‐amyloid (Aβ) deposition, T: pathogenic tau accumulation, N: neurodegeneration) has been widely accepted as a research framework for not only characterization of Alzheimer's disease (AD), but also for discrimination of AD from other neurological disorders (OND) such as Parkinson disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Currently, the different pathological processes are represented by the biomarker normality/abnormality which is diagnosed by neuroimaging and/or measuring the biomarker levels in cerebrospinal fluid. A simple diagnostic method needs to be established to evaluate pathological processes in routine clinical practice. Blood‐based biomarkers would be appropriate for clinical applications because of their simplicity and accessibility. We have developed plasma Aβ1‐40, Aβ1‐42, threonine‐181 phosphorylated tau (p‐tau181), and tau immunoassays and reported that the plasma biomarker levels were significantly different between AD, mild cognitive impairment (MCI), and cognitively normal (CN) groups, suggesting the possibility of characterizing AD. Here, we present the results of the ATN biomarker profile of OND samples using our fully automated assay.MethodWe measured Aβ1‐40, Aβ1‐42, p‐tau181, and tau using commercially available plasma samples on a fully automated immunoassay platform, HISCLTM series. The platform can achieve high degrees of sensitivity and requires only 30 µl of sample and 17 minutes to complete the measurement per assay. The plasma ATN biomarker profiles were evaluated in AD, MCI, CN, and OND groups.ResultAll plasma biomarker levels were significantly different between the AD and CN groups. Plasma p‐tau181 showed the most significant difference between the AD group and OND group. The median plasma p‐tau181 concentration in AD groups was more than twice higher compared to OND groups.ConclusionOur results indicated the possibility of discriminating AD from OND by plasma p‐tau181 and tau levels. Our fully automated plasma assay system may have a potential to be a simple diagnostic method to evaluate the pathological process in routine clinical practice for discriminating AD from OND based on ATN classification system.
Subjective reports of problems remembering names reflect performance on neuropsychological tests for recalling proper names.
Authors: Van Hulle Carol A. , Basche Kristin E , Hale Madeline R , Koscik Rebecca Langhough , Sanson‐Miles Leah , Johnson Sterling C. , Hermann Bruce P , Mueller Kimberly D 
Published: December 2022

AbstractBackgroundSubjective memory complaints (SMC) are common in middle‐aged adults. Associations between SMC and cognitive ability have been inconsistent perhaps because SMC measures rarely specifically match measured cognitive domains. We examined the relationship between objective and subjective evaluations of participants’ ability to recall proper names.Method
N = 1254 participants enrolled in the Wisconsin Registry for Alzheimer’s Prevention (WRAP), who were cognitively unimpaired at baseline and had paired SMC and proper noun recall for 1–7 visits were included in these analyses (median visits = 4. A proper name (PN) delayed recall score (0‐9) was created from item‐level data from the Wechsler Memory Scale‐Revised Logical Memory II subtest. Participants also completed the Memory Functioning Questionnaire (MFQ), a 17 item self‐appraisal (1‐ major problems to 7‐ no problems) of frequency of forgetting. We examined the association between the MFQ item “frequency of forgetting names” (FFN, M = 4.0 [1.3]) with PN score (M = 4.3 [2.2]) at most recent visit using OLS linear regression. Age, sex, years of education, APOE risk score, and number of visits (i.e practice effects) were included as covariates. We also examined a baseline FFN*age at visit interaction to characterize changes in PN score over time (linear mixed effects models; random intercepts).ResultSample characteristics are shown in Table 1. For participants with multiple visits, PN score was fairly stable between baseline and most recent visit (r = 0.54), as was FFN (r = 0.61). FFN was significantly associated with concurrent PN score (b = 0.14 [beta = 0.09], p = <.001, see Table 2, Figure 1). Excluding 82 participants who converted to cognitively impaired at their last visit did not change these results (beta = 0.10, p <.001). In longitudinal analyses, the baseline FFN*age interaction was not significant (estimate = .01, p = .26), although PN score declined slightly with age (estimate = ‐0.07, p <.001).ConclusionMeasures of SMC tend to focus on broad ratings (e.g., how would you rate your memory), and often do not correlate with objective measures among unimpaired people. These results demonstrate a significant association between subjective appraisal of and objective performance on name recall.
Investigating a new neocortical mask for Centiloid quantification
Authors: Bourgeat Pierrick , Dore Vincent , Benzinger Tammie L.S. , Tosun Duygu , Li Shenpeng , Goyal Manu S. , LaMontagne Pamela , Jin Liang , Rowe Christopher , Weiner Michael W. , Morris John C. , Masters Colin L , Fripp Jurgen , Villemagne Victor L 
Published: December 2022

AbstractBackgroundThe Centiloid (CL) project was developed to harmonise the quantification of Amyloid PET scans to a unified scale. The neocortical mask used for quantification was obtained using a private dataset of 19 mild AD patient and 25 older controls imaged using 11C‐PiB. The mean difference SUVR images were smoothed, subtracted and thresholded at 1.05 SUVR. While this threshold was chosen to maximise areas of specific Amyloid binding while avoiding areas of non‐specific binding, it was not evaluated in terms of agreement between different tracers or group separation. In this study, we created a new mask using an independent dataset of 11C‐PiB images, and investigated its impact on inter‐tracer agreement, tracer variability and group separation.MethodUsing the AIBL and OASIS databases, 63 mild AD (MMSE=20‐24;CL>20) and 63 Healthy controls (MMSE>=28;CDR=0;CL<20) matched based on age and gender, were selected. Their 11C‐PiB images were spatially normalised using the SPM CL pipeline and transformed into SUVR using the whole cerebellum. A mean AD‐HC difference image was computed and thresholds of [0.6‐1.2] SUVR were explored. The resulting masks were evaluated in the 5 Amyloid tracers using the GAAIN head‐to‐head calibration datasets in terms of inter‐tracer agreement, variance in the young controls (YC) and YC‐AD effect‐size (ES). The recalibrated CL were evaluated on the AIBL dataset with the ES on the HC‐AD and HC‐MCI using baseline and rate of change (CL/yr).ResultUsing a higher threshold resulted in a smaller neocortical mask, better targeting regions of high Amyloid update. In the GAAIN dataset, the smaller masks led to higher R2 for each 11C‐PiB/18F‐Tracer pairs and higher YC‐AD ES. They also led to a lower variance in the YC for all tracers except for Flutemetamol. In AIBL, while it increased the ES at baseline, it decreased in the HC‐MCI when using CL/yr.ConclusionWhile using a smaller neocortical mask improved inter‐tracer agreement and reduced variance in YC, the results in AIBL indicate that it might not be as sensitive to detect early changes as highlighted with poorer HC‐MCI ES.
The effect of genetic background and immunophenotype on microglial response to AD pathology
Authors: Cornelissen Tom 
Published: December 2022

AbstractBackgroundA major hurdle in developing effective treatments for Alzheimer’s Disease (AD) is the fact that pathological hallmarks, such as amyloid beta (Aβ) plaques, develop decades before the first clinical symptoms emerge. Moreover, the risk of developing AD is strongly influenced by genetic background. In addition, the role of microglia in the disease pathway is undeniable, albeit dual and complex. We therefore aim to determine the influence of patient genetic background and immunophenotype on the microglial response to AD pathology.MethodSubject material was sequenced and underwent deep immunophenotyping. Based on their scores patient iPSCs were divided in a high risk and low risk group of developing AD. This microglial response is determined by (i) their phagocytic capacity and (ii) their (change in) morphology. iPSC cells were differentiated into microglia (Mancuso et al., 2019), followed by RT‐qPCR to verify their identity. When microglia are incubated with pHrodo beads, these are phagocytosed and transported to the acidic lysosome, yielding a pH dependent increase in fluorescence, measured with an Operetta confocal microscope. Microglial morphology was recorded in an Incucyte and tracked and scored (e.g. amoeboid, rod‐like, size, motility …) automatically by AI based software. The change in morphology was assessed after addition of stressors such as LPS or Aβ1‐42.ResultPhagocytotic capacity of a reference microglia strain, measured by pHrodo intensity, reached a maximum level approximately 2 hours after addition of the pHrodo beads. When cytochalasin D, an Actin polymerization inhibitor, was added to the medium, the phagocytosis process is inhibited and baseline pHrodo intensity levels are observed. In addition, the addition of LPS seemed to change the morphology of microglia to a more elongated rod‐like shape with less motility.ConclusionThe phagocytic capacity of microglia could be dependent on the genetic background and immunophenotype of the iPSC strain. Similarly, the effect on morphology (e.g. more rod‐like shape) as an answer to stressors (e.g. LPS) could be dependent on the microglia strain. The differential microglial response based on genetic background and immunophenotype might yield insight into the further segmentation of different types of Alzheimer’s Disease and personalized therapeutic approaches.
Clinical performance and robustness of blood‐based biomarkers for early detection of amyloid pathology associated with Alzheimer’s disease
Authors: Blennow Kaj , Kurka Hedwig , Suridjan Ivonne , Jethwa Alexander , Hastreiter Maximilian , Carboni Margherita , Kollmorgen Gwendlyn , Rabe Christina , Bittner Tobias , Fowler Christopher , Masters Colin L. , Zetterberg Henrik , Hansson Oskar 
Published: December 2022

AbstractBackgroundAccurate and robust blood‐based biomarkers (BBBMs) of Alzheimer’s disease (AD) are required for identification of symptomatic patients with low likelihood of amyloid pathology before confirmatory diagnostic evaluation. Further evidence on the clinical performance and robustness of BBBMs is required to identify patients for clinical trials and in routine clinical practice. We evaluated the clinical performance and robustness of amyloid‐β 1–42 (Aβ42), amyloid‐β 1–40 (Aβ40), apolipoprotein E4 (ApoE4), phosphorylated‐tau 181 (pTau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NFL) as BBBMs of AD.MethodAnalyses were performed retrospectively using plasma samples from AIBL, BioFINDER, and CREAD cohorts, comprising cognitively normal individuals and patients with subjective/objective cognitive impairment, mild AD, or amyloid screen failure. BBBMs were measured at two laboratories using automated Elecsys® prototype immunoassays (cobas e 601 and e 411 analyzers; all Roche Diagnostics International Ltd). Clinical performance of single BBBMs and combinations of BBBMs (using logistic regression) was assessed using area under the receiver operating characteristic curve (AUC‐ROC) analysis. Negative percent agreement (NPA), prevalence‐adjusted negative and positive predictive values (NPV and PPV), and screen‐out rate were compared at 85% positive percent agreement (PPA). Robustness, defined as the change in clinical performance when adding ±10% bias and random variability, was calculated at 85% PPA.ResultAcross cohorts, the best performing single BBBM was pTau181 (AUC: 81.6–89.3). The best performing combined BBBM models across cohorts were pTau181+Aβ42 (AUC: 85.6–93.4), pTau181+ApoE4 (AUC: 83.7–91.8), and pTau181+Aβ40 (AUC: 84.8–90.2); clinical performance for these combined BBBM models in terms of NPV and PPV was comparable, providing high NPVs (>90%) and screen‐out rates (>50%). For combined BBBM models including Aβ42 or Aβ40, robustness at 85% PPA was lower compared with models not including Aβ42 or Aβ40 across cohorts. Considering both clinical performance and robustness, pTau181 and pTau181+ApoE4 were the best performing single and combined BBBM models, respectively, across cohorts.ConclusionAcross cohorts, pTau181+ApoE4 was the best performing BBBM model for detecting patients with low likelihood of amyloid pathology. These findings support the suitability of these BBBMs to inform diagnostic assessments for patients with low likelihood of AD.
The Utility of Blood Based Biomarkers in Detecting Neurological Complications of COVID‐19 in Critically Ill Patients
Authors: Cooper Jennifer G , Stukas Sophie K , Grey Rebecca , Ghodsi Mohammad , Ahmed Nyra , Hoiland Ryan , Thiara Sonny , Foster Denise , Harper Megan , Panenka William J , Silverberg Noah Noah , Stoessl Jon A. , Sossi Vesna , Sekhon Mypinder S , Wellington Cheryl L 
Published: December 2022

AbstractBackgroundNeurological and neuropsychiatric complications have been documented in patients with COVID‐19. This study aims to investigate the utility of two neurological blood‐based biomarkers to predict neurological complications and mortality due to COVID‐19 in the intensive care unit (ICU). Neurofilament light (NF‐L) is a marker of axonal damage and glial fibrillary acidic protein (GFAP) is a marker of astrocytic activation.MethodsPatients with respiratory failure were prospectively enrolled from the ICU at Vancouver General Hospital. COVID‐19 patients were excluded if the diagnosis was an incidental secondary finding upon ICU admission or if their enrollment was >10 days after ICU admission. Control patients were excluded if their enrollment was >4 days after ICU admission or if their primary diagnosis was non‐respiratory. Plasma samples were collected upon admission study enrollment, with additional samples collected on day 7 and day 14 from COVID‐19 patients. Plasma NF‐L and GFAP were quantified using the Quanterix Simoa HD‐X analyzer. Group comparisons were performed using a Mann‐Whitney test. Trajectory analysis was performed using a Wilcoxon test or Friedman one‐way ANOVA. Area under receiver operating curve (AUROC) analysis was calculated to predict neurological complications and mortality during ICU stay.ResultsOf the 242 patients enrolled, 209 were confirmed positive for SARS‐CoV‐2 while 33 served as ICU controls. Median age was 61 years for the COVID‐19 group, 64 years for controls. Upon ICU admission, NF‐L was 32% lower and GFAP was 24% lower in those with COVID‐19 compared to controls after correcting for age. NF‐L concentrations increase by doubling each week of ICU stay, while GFAP remained stable. Over the course of their ICU stay, 16% COVID‐19 patients were diagnosed with a neurological complication and 17% died. Plasma NF‐L and GFAP demonstrated a moderate to strong ability to predict neurological complications (AUROC: NF‐L=0.702; GFAP=0.722) and mortality (AUROC: NF‐L=0.815; GFAP=0.809) during ICU stay.ConclusionsUpon ICU admission, NF‐L and GFAP were lower in patients with COVID‐19 compared to controls. NF‐L, but not GFAP, increased over the course of ICU stay in patients with COVID‐19. Both markers were able to predict neurological complication or ICU mortality with moderate to strong accuracy.
Pharmacologic Stabilization of Retromer Rescues Endosomal Pathology Induced by Defects in the Alzheimer’s gene SORL1
Authors: Knupp Allison , Mishra Swati , Young Jessica E. 
Published: December 2022

AbstractBackgroundDefects in the Sortilin‐related receptor 1 gene, SORL1, are highly pathogenic Alzheimer’s disease (AD), on par with other causal AD genes. SORL1 is a key regulator of endosomal trafficking in neurons, and loss of SORL1 function disrupts trafficking pathways that are vital for neuronal health. SORL1 has been found to interact with retromer, a trafficking complex that is a ‘master conductor’ of endosomal outflow. Here we rely on retromer pharmacological chaperones that stabilize retromer in vitro, and thus enhance retromer function in cells to test the hypothesis that they will correct AD‐associated neuronal pathologies.MethodWe used an isogenic series of human induced pluripotent cell lines either deficient in SORL1 expression (SORL1 KO or SORL1+/−) or harboring a one copy of a missense variant linked to increased risk for AD (SORL1Var). We treated neurons derived from these hiPSCs with the established retromer chaperone, TPT‐260, and tested whether they corrected indicators of AD’s defining endosomal, amyloid, and tau pathologies.ResultWe observed that TPT‐260 treatment was able to correct all of these pathological indicators, however the degree of rescue of some of the phenotypes was dependent one whether the neurons harbor at least one functional copy of SORL1 or whether they are fully deficient.ConclusionMore than just validating that SORL1‐retromer acts a trafficking functional unit in neurons, our work sheds new light on how SORL1‐retromer is linked to AD’s cardinal pathologies and illuminates how this pathway can be therapeutically harnessed.
In vivo imaging of the mouse cholinergic projection system using [18F]FEOBV
Authors: Onuska Kate M. , Shanks Hayley R. C. , Qi Qi , Prado Vania , Thiessen Jonathan , Hicks Justin , Fox Matthew , Prado Marco , Schmitz Taylor W. 
Published: December 2022

AbstractBackgroundPositron emission tomography (PET) with the [18F]‐Fluoroethoxybenzovesamicol ([18F]FEOBV) radiotracer is a promising tool for in vivo imaging of VAChT – a protein found specifically in the cholinergic system. However, the sensitivity and specificity of [18F]FEOBV uptake to known changes in VAChT protein levels remains untested. The aim of this study is therefore to use [18F]FEOBV in mouse lines where VAChT protein expression is held under precise genetic control to determine whether [18F]FEOBV brain uptake reflects the endogenous levels of VAChT present in different genetic mouse models.Method6‐month‐old VAChT conditional forebrain knock‐out mice (VAChTNkx2.1‐Cre‐flox/flox, n = 6), VAChT hyper expressing mice (VAChTChAT‐ChR2‐eYFP, n = 6), and littermate controls (VAChT flox/flox , n = 6; C57BL/6J, n = 6), received an intravenous injection of [18F]FEOBV and were imaged dynamically on a microPET scanner for 2 and a half hours.ResultWhen compared to controls, VAChT conditional forebrain knock‐out mice demonstrated decreased [18F]FEOBV uptake in striatal regions of the mouse brain (Figure 1, left panel). In contrast, VAChT hyper expressing mice displayed widespread increases in brain [18F]FEOBV uptake when compared to controls (Figure 1, right panel).ConclusionTogether, these findings suggest that [18F]FEOBV brain uptake is a sensitive and specific measure of known changes in VAChT protein expression.