bluuebunny/crossref_metadata_2025_split huggingface dataset:
Developing an oligogenic risk score for Alzheimer’s disease (adORS)
Authors: Lee Garam , Suh Erica H , Jung Sang‐Hyuk , Wen Zixuan , Shen Li , Kim Dokyoon , Initiative Disease Neuroimaging 
Published: December 2022

AbstractBackgroundPolygenic risk score (PRS) has become a popular approach for estimating an individual’s genetic risk for disease, recently including Alzheimer’s disease. However, its limitations reveal the need to improve genetic modeling of the disease, i.e. pinpointing relevant genetic drivers for score calculation and improving interpretability and clinical utility. We propose a novel genetic risk score for Alzheimer’s disease (adORS), which—compared to PRS—combines a smaller set of more informative risk variants using known biomarkers to better predict those with high or low risk of disease, as well as mild cognitive impairment (MCI) conversion to AD.MethodGenetic variants of 1,704 patients (364 controls, 550 AD cases, 273 MCI converters [MCIc], and 517 MCI non‐converters [MCInc]) were collected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Participants were classified based on diagnosis at their last visit. Variants were transformed into a gene‐based burden to amplify the variance held by each variable, enabling smooth model estimation and gene‐level interpretation. The risk score was estimated based on genes exhibiting high correlations with well‐known biomarkers, FDG and AV45. PRS were generated with clumping and thresholding using the PLINK data analysis toolset. We compared the performances between adORS and PRS on two tasks: controls vs AD classification and MCI conversion prediction.ResultTop 20 highly correlated genes including known AD‐relevant genes such as TOMM40 and APOC1 were used to calculate the AD risk score. Overall, adORS demonstrated better prediction performance than PRS (Table 1). adORS also showed better distinguishability between cases and controls and predicted lower risk scores in controls and MCInc patients versus higher risk scores in AD cases and MCIc. Additionally, adORS is well‐calibrated compared to PRS (Figure 1). The number of AD and MICc patients increases smoothly as the risk score increases.ConclusionWe proposed a new method to calculate an AD‐specific genetic risk score. The main advantage of adORS is to use only significant AD‐relevant genes for calculation, yielding a score that is a better predictor of AD status and progression. Experiments demonstrated that adORS has enhanced performance of prediction accuracy, calibration, and interpretability over PRS.
Adult learning enrichment for people living with dementia and their caregivers: Early observations of introducing andragogic principles in adapting an existing museum‐based program.
Authors: Hoffmann Edye 
Published: December 2022

AbstractFace‐to‐face community engagement for individuals living with dementia and their caregivers was drastically reduced by the pandemic. In response to these restrictions, the Portals to the World program (based in Cambridge, England) was adapted from museum‐based to a virtual setting.This environmental change reduced the existing anchors of museum access, art enrichment, and one‐to‐one engagement with staff and volunteers. Our adaptations to this new environment stressed a more andragogic (adult learning) model of enrichment that built on our existing program. We moved away from art‐making and in‐person gallery engagement with subject specialists but kept our multi‐week course design.We prioritized purposeful learning, ownership, layers of experience, and immediate value (usually with emerging research topics or contemporary exhibitions). These added layers of learning replaced the environmental anchors we had used in the past. We also addressed challenges linked to the virtual environment and other impairments present for the participants, such as vision and hearing. Throughout, we aimed to continue the sense of non‐traditional respite, improving the connection between care partners, peer‐to‐peer engagement, as well as access to high‐value museum objects and learning from subject specialists.Our early observations and continued developments reveal advantages and disadvantages in delivery and expectations. These observations highlight contradictions in caregiver expectations between their understanding of dementia and learning. There were also challenges in where value should be placed: social capital, identity capital or economic capital, all while holding high value in access to the program and the course itself.
ULTRASENSITIVE NEUROFILAMENT LIGHT CHAIN (NfL) IMMUNOASSAY FOR THE SMCxPRO™ ASSAY PLATFORM
Authors: Wiese Rick , Ko Alex , Sweetwater Rose , Fiske Jared 
Published: December 2022

AbstractBackgroundThe recent advent of ultrasensitive assay technologies has enabled the measurement of low‐abundance blood‐based biomarkers of neurodegenerative conditions, thereby addressing the need for invasive nature of cerebrospinal fluid (CSF) collection, allowing for large scale sample acquisition and screening in research, and empowering studies into the transition between health and disease. Utilizing the SMCxPRO™ ultrasensitive immunoassay platform, we have developed an assay for the detection of neurofilament light chain (NfL) in human serum, plasma and CSF samples across healthy and diseased states. NfL is a valuable neurodegenerative biomarker for accessing progression and treatment of Alzheimer’s Disease (AD), Multiple Sclerosis (MS) and Huntington’s Disease, and is under investigation as a potential biomarker for several other neurological disorders.MethodRigorous assay development procedures were undertaken in an effort to produce an NfL immunoassay capable of accurately and reproducibly detecting NfL in human serum, plasma, and CSF samples.ResultA robust kit for consistent and reliable NfL measurement at sub‐pg/mL concentrations has been developed and characterized using Single Molecule Counting (SMC™) ultrasensitive immunoassay technology. The developed assay demonstrates excellent performance characteristics for spike/recovery values and dilutional linearity (90‐110% for all three matrices). NfL was detected in all sample types tested. Increased NfL sample levels in AD and MS samples as compared to normal serum, plasma and CSF samples was also observed.ConclusionOur SMC™ NfL immunoassay kit provides a valuable tool for research in the areas of neurodegenerative disease and neurological injury.
Whole Blood Expression of the Vascular Endothelial Growth Factor Family Relates to Cognitive Performance
Authors: Libby Julia B. , Seto Mabel , Khan Omair A. , Liu Dandan , Petyuk Vladislav A , Gifford Katherine A. , Dumitrescu Logan , Jefferson Angela L. , Hohman Timothy J. 
Published: December 2022

AbstractBackgroundThe vascular endothelial growth factor (VEGF) family is involved in angiogenic signaling and has been implicated in Alzheimer’s Disease (AD). Previous work from our team has found that higher transcript levels of VEGFB, PGF, FLT1, and FLT4 in the brain relate to worse cognitive performance and higher levels of AD neuropathology. This study explored whether comparable associations are observed when measuring mRNA in whole blood.MethodTranscriptomic, cognitive, and biomarker data were acquired from the Vanderbilt Memory & Aging Project. Participants (n=335) included older adults (age=72+/‐7.32) with normal cognition (n=203) or mild cognitive impairment (n=132). Expression of the ten genes in the VEGF family were quantified using RNA sequencing of blood. Outcomes included a composite measure of memory and cerebrospinal fluid (CSF) levels of β‐amyloid, total tau, and phosphorylated tau (ptau181). Linear regression models related VEGF family member expression to baseline cognitive performance and AD biomarkers. Linear mixed effects regression models assessed longitudinal change in cognition. All models covaried for age at baseline and sex. To aid in interpretation, Pearson correlations between blood and brain expression were calculated leveraging data from 137 participants from the Genotype Tissue Expression Project (GTexportal.org).ResultAt baseline, higher levels of VEGFB mRNA were associated with better memory performance (Figure 1, β=0.47, p=0.008). In longitudinal analyses, higher baseline expression of PGF was associated with more rapid decline in memory (β= 0.02, p=0.04). No other significant associations were observed (p‐values>0.09). Among GTEx participants, higher expression of VEGFB in blood was correlated with lower expression in the brain (Figure 2, r=‐0.19, p=0.02). PGF correlations did not reach statistical significance (r=0.09, p=0.27).ConclusionHigher PGF expression in blood relates to worse cognitive outcomes, consistent with previous findings in the brain. In contrast, higher levels of VEGFB in blood relates to better performance, opposite of the previously observed association in the brain. Notably, in GTEx we observed opposing correlations between blood levels of VEGFB and brain levels of VEGFB, suggesting that higher levels of VEGFB in the blood may indeed reflect lower levels in the brain. Our results highlight the potential of VEGFB and PGF as blood biomarkers in aging and AD.
An Old Pathway Learns Two New Tricks: Role of Complement in Postoperative Cognitive Dysfunction, and in Synaptic Damage in APOE4 carriers
Authors: Berger Miles ,   MADCO‐PC and INTUIT Study Groups
Published: December 2022

AbstractBackgroundGenetic studies in both mice and humans suggest a role for complement in Alzheimer's disease, but exactly how complement contributes to preclinical AD progression is unclear. It is also unclear to what extent complement may play a role in AD risk within APOE4 carriers, or in the pathophysiology of perioperative neurocognitive disorders in older adults.MethodWe developed a hybrid proteomics platform, which uses both LC‐MS/MS for unbiased discovery across the entire human proteome, as well as stable isotope labelled (SIL) peptides for complement proteins to precisely quantify complement protein‐derived peptides (as would normally be possible only in a targeted proteomics assay). This platform was then used to study proteins and pathways altered in the CSF of APOE4 carriers vs non‐carriers, in which the vast majority of both groups were amyloid negative. We also used this platform to study pre‐operative samples from patients who did and those who did not develop postoperative delirium. Generally Applicable Gene Set Enrichment (GAGE) analysis was used to study alterations within specific protein pathways in both APOE4 carriers, and in patients with postoperative cognitive dysfunction.ResultIn our unbiased data, we detected >9,000 different peptides from 884 different proteins in over 100 CSF samples from older adults with normal cognition, including over 200 different complement protein‐derived peptides. In the complement proteins for which we had SIL peptides, we found an average reduction of ∼8.4% ± 0.5% in the levels of more than 50 peptides from each protein in the classical, alternative and mannose binding lectin complement cascades in APOE4 homozygotes versus APOE4 non‐carriers; the odds of this happening by chance would be 1 out of 2 x10^15. We also found reductions in complement proteins (and a significant change in the complement pathway as a whole) at multiple time points before and after surgery in patients who developed postoperative cognitive dysfunction.ConclusionThese results suggest that CNS complement pathway activation may play a role in both postoperative cognitive dysfunction, and in APOE4‐induced brain damage even in the absence of amyloid pathology.
Structural Modularity is a Feature of C9orf72 Intrinsic Network Degeneration
Authors: Sihag Saurabh , Massimo Lauren , Burke Sarah E , Phillips Jeffrey S , Cook Philip , Duda Jeffrey T , Gee James C. , Satterthwaite Theodore , Grossman Murray , Benatar Michael , McMillan Corey T 
Published: December 2022

AbstractBackgroundGenetic forms of frontotemporal degeneration (FTD) and amyotrophic lateral sclerosis (ALS) provide an important target for early therapeutic interventions. However, pre‐symptomatic biomarkers to monitor disease progression are lacking. Prior neuroimaging studies suggest disruption of functional and structural networks are an early feature of neurodegenerative disease. Network modularity quantifies the degree of segregation between sub‐networks. We hypothesize that structural network modularity is a marker of neurodegeneration in C9orf72 carriers.MethodWe evaluated diffusion magnetic resonance imaging (dMRI) in two independent cohorts of C9orf72 carriers and controls: University of Pennsylvania Prodromal Study (Penn‐C9) including symptomatic C9orf72 carriers (SC9; N=27; FTD=20; ALS=7), asymptomatic C9orf72 carriers (AC9; N=24), and healthy controls (HC; N=29); and Human Connectome Project‐FTD (HCP‐FTD) also including SC9 (N=12), AC9 (N=12), and HC (N=20) individuals. We quantified modularity in 7 intrinsic networks of 400 nodes from the Schaefer Atlas using participation coefficient (PC), where lower PC corresponds to higher modularity, and also investigated its constituent measures: within‐network connectivity for each network and pairwise between‐network connectivity. Modularity metrics were residualized in the Penn‐C9 dataset using linear regression to adjust for age. Statistical analyses on residualized scores were first performed in Penn‐C9 and cross‐validated in the HCP‐FTD dataset.ResultANCOVAs on residualized scores in Penn‐C9 revealed group differences in PC for limbic network with SC9 lower than HC (partial‐η2=0.12, p=0.011). We also observed group differences in within‐module connectivity for limbic (partial‐η2=0.16, p=0.0016) and dorsal‐attention (partial‐η2=0.1, p=0.019) networks with SC9 lower than HC. Cross‐validation in HCP‐FTD revealed group differences in modularity metrics for limbic network (PC: partial‐η2=0.29, p=0.0012 and within module connectivity:partial‐η2=0.28, p=0.0016) with both metrics lower in SC9 relative to HC. The group differences were significant between AC9 and HC in Penn‐C9 and the means of aforementioned metrics for AC9 were between HC and SC9 in both datasets, suggesting an intermediate state towards modularity.ConclusionWe observed cross‐validated evidence of greater network modularity, in limbic network, for SC9 relative to HC and intermediate evidence of modularity in AC9. Limbic network is plausible as earliest loci of TDP‐43 pathology in FTD. We suggest that structural network modularity may be an early feature of C9orf72 disease progression.
Hippocampal metabolism in preclinical Alzheimer’s disease
Authors: Rahmani Maryam , McAvoy Mark , Chang Ryan , Raichle Marcus E. , Benzinger Tammie L.S. , Morris John C. , Vlassenko Andrei G. , Goyal Manu S. 
Published: December 2022

AbstractBackgroundHippocampal metabolism has been variably reported to be decreased in Alzheimer’s disease (AD), and is less well studied during preclinical stages of AD. Since AD is associated with significant hippocampal atrophy, careful segmentation and partial volume correction methods are necessary. Here we performed manual segmentation of the hippocampus coupled with regional partial volume correction to estimate hippocampal glucose (rCMRGlc) and oxygen (rCMRO2) metabolism from positron emission tomography (PET) studies in cognitively normal adults with and without brain amyloid deposition.MethodMulti‐tracer PET including [18F]fluoro‐deoxyglucose (FDG), 15O‐O2, 15O‐CO, and 15O‐H2O was performed in cognitively normal older adults with high brain amyloid‐β burden (n=17) and age and sex‐matched individuals with no brain amyloid burden (n=14). Hippocampi were manually segmented, including careful exclusion of intruding and surrounding CSF‐filled spaces. Partial volume correction was performed using the symmetric geometric transfer matrix approach. Mean standardized uptake value ratio (SUVR) for rCMRGlc and rCMRO2 were calculated, normalized to the whole brain and pons for confirmation.ResultsWe found no significant decrease in hippocampal rCMRGlc in amyloid positive adults, despite their lower hippocampal volume compared to amyloid negative adults. We also saw no significant decrease in hippocampal rCMRO2 in the amyloid positive adults. These results were unaffected by choice of whole brain or pons as the reference region.ConclusionHippocampal metabolism appears to be relatively preserved in cognitively normal amyloid positive adults. Reported alterations in hippocampal metabolism might therefore be more closely linked to the onset and progression of cognitive impairment.
Regional tau PET patterns predict prospective domain‐specific cognitive decline in Alzheimer’s Disease
Authors: Malpetti Maura , Iaccarino Leonardo , Tanner Jeremy A , Mundada Nidhi S. , Cobigo Yann , Arora Anupa , Pontecorvo Michael J. , La Joie Renaud , Rabinovici Gil D. 
Published: December 2022

AbstractBackgroundTau‐PET binding patterns are heterogenous, with regional binding showing strong cross‐sectional correlations with domain‐specific cognitive performance and longitudinal correlations with prospective neurodegeneration. The goal of this study was to evaluate whether regional patterns of baseline tau‐PET predict prospective longitudinal decline in specific cognitive domains in early symptomatic AD.MethodsSeventy‐nine amyloid‐positive participants with a clinical diagnosis of mild cognitive impairment (MCI, n=47) or AD dementia (n=32) underwent a 18Flortaucipir PET (80‐100 minutes after injection), structural MRI, and neuropsychological testing as part of the AVID A05 study (Table 1). Cognitive assessment was repeated after 9 and 18 months. Single‐test annualized w‐scores (age‐corrected z‐scores) at each time point were calculated against 52 controls (age=67.5±10.3) and combined in composite scores for episodic memory, semantic memory, executive function, language, and visuospatial domains. Latent growth curve models were applied to longitudinal composite scores to estimate the rate of annual decline (slope) in each participant. Standardized uptake value ratio (SUVR) images were created using inferior cerebellar gray matter as the reference region. Voxelwise regression analyses were used to identify patterns of baseline tau‐PET associated with longitudinal changes in each cognitive domain. Regression analyses were repeated using cortical regional baseline SUVR values, extracted using FreeSurfer, as predictors of subsequent cognitive decline.ResultsPatients significantly declined in all domains (Figure 1). Differential FTP‐PET patterns showed significant negative associations with domain‐specific annual rates of decline (r≤‐0.3, p<0.001; r≤‐0.5, pFWE<0.05 at voxel level, Figure 2). Specifically, higher tau‐PET SUVR in temporo‐parietal regions was predictive of faster decline in episodic memory, tracer retention in the left anterior temporal lobe related to worse semantic memory, while a more extensive and asymmetric tau‐PET pattern in (L>R) fronto‐temporal regions and (R>L) fronto‐parietal regions related to a faster decline in language and visuospatial domains, respectively. Executive decline showed small inter‐individual variability. Region‐based analyses highlighted similar tau‐PET patterns as predictive of domain‐specific decline (pFDR<0.05, Figure 3).ConclusionAt a group level, differential regional patterns of tau are associated with domain‐specific cognitive decline in MCI and early AD dementia. Tau PET may be a useful precision medicine tool for predicting patient‐specific trajectories in early symptomatic AD.
Impact of meningeal and age‐related off‐target binding on longitudinal [18F]MK6240 quantification
Authors: Tissot Cécile , Lussier Firoza Z , Ferrari‐Souza João Pedro , Servaes Stijn , Bezgin Gleb , Ferreira Pamela C.L. , Bellaver Bruna , Leffa Douglas Teixeira , Therriault Joseph , Vermeiren Marie , Kunach Peter , Stevenson Jenna , Rahmouni Nesrine , Chamoun Mira , Benedet Andréa Lessa , Wang Yi‐Ting , Arias Jaime Fernandez , Kang Min Su , Villemagne Victor L , Tudorascu Dana L , Cohen Ann D , Klunk William E , Baker Suzanne L. , Gauthier Serge , Rosa‐Neto Pedro , Pascoal Tharick A 
Published: December 2022

AbstractBackground[18F]MK6240 tau‐PET can detect changes in the early and late stages of tau tangles accumulation. However, off‐target binding, often observed in the meninges and neuromelanin‐containing cells, can interfere with longitudinal tracer quantification. Here, we investigated the association of longitudinal changes in off‐target and target signals using [18F]MK6240.MethodWe assessed individuals from the TRIAD cohort with [18F]MK6240 tau‐PET and clinical evaluation. Longitudinal analyses included 83 cognitively unimpaired (CU) and 37 cognitively impaired (CI) individuals. Age‐related off‐target binding was estimated comparing 36 CU young individuals (<25 y.o) and 28 CU elderly amyloid/tau negative (40‐65 y.o). A t‐test was used to compare both groups. The ratio between baseline and follow‐up SUVR measured changes in off‐target and target regions. Pearson correlations tested the associations between regions, and Bonferroni analysis corrected for multiple comparisons.ResultAlthough averaged images did not present a striking visual difference in [18F]MK6240 uptake between CU young and elderlies, t‐test revealed significant differences between groups in the cerebellar white matter and subcortical regions (Figure 1). Table 1 depicts the percentage of area of selected regions overlapping with the age‐related off‐target binding. Notably, we did not observe a significant association between longitudinal changes in age‐related or meningeal off‐target binding with longitudinal change in target regions (Braak‐II, BraakIII‐IV, BraakV‐VI), whereas changes in target regions were highly correlated (Figure 2).ConclusionDespite not being visually perceptible, [18F]MK6240 presents age‐related off‐target binding in subcortical regions, similar to regions reported using [18F]Flortaupicir. The overlap between age‐related off‐target and Braak IV region (∼3%) may lead to the confounding results in quantifying this region. The lack of correlation between off‐target and target [18F]MK6240 changes suggests little influence of the off‐target binding on longitudinal tracer quantification. Our results suggest that although off‐target uptake appears to have a modest influence on longitudinal quantification, it is necessary to consider both age‐related and meningeal off‐target signals for an accurate tracer assessment.