bluuebunny/crossref_metadata_2025_split huggingface dataset:
Principal component analysis of auditory ERPs discriminates mild cognitive impairment and Alzheimer’s disease from normal aging
Authors: Liljander Sara K. , Nieminen Jaakko O. , Keski‐Säntti Petra , Mutanen Tuomas P. , Lehtovirta Maarit , Ilmoniemi Risto J. , Partanen Juhani V. 
Published: December 2022

AbstractBackgroundSensory gating refers to an inhibitory mechanism of the brain that protects higher cortical centers from being flooded with repetitive, redundant sensory inputs. Sensory gating is modulated by cholinergic transmission, the deterioration of which is a prominent neurochemical feature of Alzheimer’s disease (AD), the most common form of dementia in the elderly. The study investigated whether alterations in inhibitory gating, assessed by event‐related potentials (ERPs) in response to repeated auditory stimuli, can discriminate AD and mild cognitive impairment (MCI) from normal aging.MethodEvent‐related electroencephalogram was recorded from 38 AD patients, 37 MCI patients, and 38 elderly cognitively normal control (NC) participants in a conditioning–testing paradigm. ERP waveforms, stimulus‐locked changes in power, and inter‐trial phase clustering (ITPC) were extracted and submitted to a covariance‐based principal component analysis (PCA) to yield data‐driven component measures.ResultNon‐parametric cluster‐based permutation tests revealed statistically significant differences for ERP waveforms in separating AD, for power in separating AD and MCI, and for ITPC in separating AD, MCI, and NC from the other two groups pooled together.ConclusionThe study confirms that alterations in auditory sensory gating can discriminate between AD, MCI, and normal aging. Auditory ERPs might serve as an objective, non‐invasive, and cost‐effective method for evaluating cognitive decline suggestive of AD and to monitor disease progression, therapeutic efficacy, or effects of novel drug candidates in clinical trials.
Uncovering single‐nucleus RNA velocity variations in neuropathologic Alzheimer’s disease
Authors: Adewale Quadri , Khan Ahmed F , Bennett David A , Medina Yasser Iturria 
Published: December 2022

AbstractBackgroundDifferential single‐nucleus (snRNA‐seq) gene expression analyses in Alzheimer’s disease (AD) provide fixed snapshots of cellular alterations, failing to detect the temporal dynamics of genes at individual cells. To overcome this limitation, here we analyze single‐nucleus RNA velocities (RNA‐vel) from the prefrontal cortex to characterize dynamic genetic and cellular differences in neuropathological AD progression. RNA‐vel is the rate of change of gene expression obtained by comparing intronic and exonic sequence counts. Comparison of AD pathology associated gene expression with parallel RNA‐vel differences reveals sets of genes and molecular pathways that underlie the static and putative dynamic regimes of cell type‐specific dysregulations underlying the disease.MethodWe used snRNA‐seq data from the prefrontal cortex of 48 subjects1 with varied levels of AD pathology from ROSMAP2. We then calculated both the expression and RNA‐vel differences between low AD‐pathology and mild‐to‐severe AD‐pathology. These differences were cell‐specific across six major cell types: excitatory neurons, inhibitory neurons, astrocytes, microglia, oligodendrocytes, and oligodendrocyte progenitor cells.1.	We characterized RNA‐vel differences associated with four AD neuropathology traits: neuritic plaque, neuronal neurofibrillary tangle, overall β‐amyloid load, and PHF tau tangle density.2.	We demonstrated the reproducibility of the RNA‐vel differences in two independent datasets: dorsolateral prefrontal cortex (N = 24) from ROSMAP3 and superior frontal gyrus (N = 6) from GEO4.ResultOnly 10 of 843 (1.2%) genes overlap between the differential RNA expression and velocity analyses, suggesting substantial AD‐pathology related differences between these two RNA descriptors. The genes with only velocity differences relate to cell developmental and synaptic processes. Conversely, the genes with only differential expression are majorly associated with mitochondrial activity and ribosomal processes. Many genes were reproduced in the independent datasets; these overlapping genes are again associated with neural development and synaptic activities across many cell types, as well as vascular‐ and immune‐related processes in astrocytes and microglia, respectivelyConclusionWe use RNA velocity to characterize, for the first time to our knowledge, the dynamical multicellular processes underlying neuropathological AD progression. The results support the validity of the novel RNA‐vel concept for achieving a complementary molecular characterization of AD, which may be obscured by typical analysis of RNA abundance alone.
The Panama Aging Research Initiative: Dementia‐related biomarker research in a low‐resourced setting
Authors: Britton Gabrielle B , Villarreal Alcibiades E , Oviedo Diana C , O'Bryant Sid E. , Edwards Melissa , Carreira Maria B , Rangel Giselle 
Published: December 2022

AbstractBackgroundThe Panama Aging Research Initiative (PARI) is a two‐cohort study of more than 800 adults aged 60 years and older. PARI has provided the first reports of modifiable and non‐modifiable risk factors of cognitive impairment and dementia, as well as various health conditions common among older adults in Panama, including chronic illnesses, polypharmacy and frailty. Our general objective consists of identifying biomarkers of memory impairment for improving early diagnosis of dementia, and specifically, Alzheimer’s disease (AD). Panama follows the global trend of smartphone use and rapid access to information. Therefore, the implementation of digital phenotyping as clinical tool could be a promising strategy to developing culturally appropriate cost‐ and time‐efficient protocols for early detection of cognitive impairment.MethodsOur ongoing community‐based cohort has undergone clinical interviews, neuropsychological testing, and assessments of frailty at two time points (14‐29 months apart). Fasting blood draws were obtained for measurements of genetic and blood‐based biological markers. Ongoing studies are evaluating genetic variation both in disease genes and in regulatory factors that modulate onset and progression of AD and other neurodegenerative diseases. In collaboration and with the support of the Davos Alzheimer’s Collaborative (DAC) Global Cohort Development program, we are also introducing the collection of longitudinal AD‐related digital phenotypes.ResultsBlood‐based biomarkers have been shown to be highly accurate in detecting AD and MCI, with promising results for early diagnosis of AD‐related cognitive impairment. We will discuss results of studies examining the combination of blood‐based biomarkers with standard neuropsychological tests to generate molecular profiles that could lead to early and timely MCI and AD diagnosis. We will further present how digital phenotyping will open up new opportunities that will help overcome challenges that arise when trying to apply conventional approaches in low‐resourced settings.ConclusionsBlood‐based and digital biomarkers could be used as a first screening tool, followed by additional diagnostic testing for those at risk for cognitive impairment. The DAC initiative to leverage existing infrastructures across cohort studies around the world is of particular relevance to refining our assessment processes and dementia risk profiling, and ultimately, developing novel interventions in low‐resource settings.
Mass spectrometry synuclein detection in human plasma
Authors: Lehallier Benoit , Vialaret Jérôme , Pons Marie‐Laure , Mondesert Etienne , Castelnovo Giovanni , Moreau Stéphane , Hirtz Christophe 
Published: December 2022

AbstractBackgroundSynucleins (alpha, beta, and gamma) are potential biomarkers for Parkinson’s disease dementia (PDD), Dementia of Lewy body (DLB) and the Multi system atrophy (MSA). Their quantification with Mass spectrometry (MS) represents an interesting approach as it can precisely quantify synuclein proteoforms including mutations, alternative splicing, phosphorylation and other post‐translational modifications.MethodsWe developed an antibody free method starting with 95 µl of plasma. Patient cohort of 155 samples was analyzed with 57% PD, 22% LBD, 6% MSA, and 15% of control (CTRL) patient samples. Briefly, plasma proteins were differentially precipitated, clean‐up on AssayMap BRAVO (Agilent Technologies) and digest with trypsin/lys C. Liquid Chromatography‐Multiple Reaction Monitoring (LC‐MRM, Nexera Mikros – 8060, Shimadzu) method was developed to monitor 14 peptides originated from the alpha, beta and gamma synuclein sequence and one hemoglobin peptide. Method was validated following the EMA guidelines and compare to alpha synuclein immunodetection with Meso Scale Discovery platform (U‐plex human alpha synuclein kit).ResultsQuantitative assay based on LC‐MRM was validated on total alpha (140aa), beta (134aa) and gamma (127aa) synuclein peptides, and 4 alpha synuclein proteoforms (126, 112, 98 and 41) using 3 proteotypic peptides (one for 126/98, one for 112/98 and one for 41). After cohort quantification, alpha and beta synucleins were quantified in plasma with good performances and are able to statistically discriminate CTRL vs PD; CTRL vs LBD; CTRL vs MSA, and MSA vs PD. A slight correlation was found between the quantities obtain between MSD and MS assays.ConclusionMS based assay was successfully developed and validated to plasma synuclein proteoforms. Analysis of patient cohort indicate the ability of this assay to discriminate PD, DLB and MSA with a specificity of 81% and a sensitivity of 87%.
Three year longitudinal changes of subcortical volumes in SuperAgers
Authors: Kim Geon Ha , Kim Bori R. , Jeong Jee Hyang 
Published: December 2022

AbstractBackground“SuperAgers” refer to older adults whose cognitive abilities were comparable to those in middle age or to those of young adults. Given that the volumes of the subcortical structures are the main structures of the frontal‐subcortical circuits that are associated with frontal function, investigating the changes of subcortical volumes in Superagers could help understand the underpinning neural characteristics in SuperAgers. Therefore, the purpose of this study to examine the longitudinal changes of subcortical structures in Superagers compared to typical agers.MethodsWe enrolled a total of 100 elderly (60 years old or older) with normal cognitive functions. The normal cognitive function was defined when participants scored above ‐ 1.SD of population norm on the tests of memory and scored above ‐ 1.5 SD on the tests of language, attention, visuospatial and executive functions. We defined the superagers based on their performance compared to middle‐aged adults (45 year old) on the delayed recall scores in both the Seoul Verbal Learning Test and the Rey Rey‐Osterrieth Complex Figure Test. We followed up cognitive function and brain MRI every year for three years. The T1 images of each subject were processed to obtain the anatomical parcellations of subcortical structures by the FreeSurfer software. Mixed effect model was used to analyze the longitudinal changes of subcortical volumes with age, sex and education years as covariates.ResultA total of 46 participants were classified as the superagers. At the baseline, SuperAgers demonstrated greater volumes not only in the hippocampus but also in the putamen, thalamus and pallidum. During the three year follow‐up, superagers continued to show greater volumes in the hippocampus, putamen, thalamus and pallidum.ConclusionThese results indicate that Superagers might be resilient to age‐related structural volume change not only in the hippocampus but also in other subcortical volumes such as putamen, thalamus and pallidum.
Thimet Oligopeptidase is a potential CSF biomarker for Alzheimer’s Disease
Authors: Hok‐A‐Hin Yanaika S. , Bolsewig Katharina , Ruiters Daimy N. , Lleó Alberto , Alcolea Daniel , Lemstra Afina W. , van der Flier Wiesje M. , del Campo Marta , Teunissen Charlotte E. 
Published: December 2022

AbstractBackgroundUsing antibody‐based Olink proteomics, we recently established that Thimet Oligopeptidase (THOP1) is a potential cerebrospinal fluid (CSF) biomarker for Alzheimer’s Disease (AD). THOP1 is a neuropeptidase able to degradate Aβ peptides. Here, we aimed to develop specific THOP1 immunoassays for further clinical validation and to enable future implementation of this biomarker.MethodWe developed and compared novel immunoassays for CSF THOP1 analysis on automated Ella™ and Simoa™ platforms. After analytical validation, THOP1 levels were measured in a selection of CSF samples from the original discovery study (24 cognitively unimpaired controls, 24 AD and 24 dementia with Lewy bodies (DLB) patients) on both platforms. Passing bablok‐regression analysis showed that platforms were comparable and thus we selected the Ella platform for further validation in two independent cohorts (Amsterdam Dementia cohort (ADC) including 56 controls, 45 mild cognitive impairment with amyloid pathology (MCI‐Aβ+), 55 AD and 55 DLB patients; Sant Pau Initiative on Neurodegeneration (SPIN) cohort including 53 controls, 50 MCI‐Aβ+, 47 AD and 50 DLB patients). Differences in THOP1 levels between diagnostic groups and correlations to the AD CSF biomarkers were tested by ANCOVA (corrected for sex) and Spearman correlation analyses.ResultTHOP1 levels moderately correlated between proteomics analysis and the novel assays (Olink‐Ella: rho=0.720; Olink‐Simoa: rho=0.584; Ella‐Simoa rho=0.713; figure 1). Consistent with results obtained on the Olink proteomics platform, THOP1 levels were significantly increased in AD compared to DLB patients (Ella: 1.6‐fold; Simoa: 1.7‐fold) and controls (Ella: 1.8‐fold; Simoa: p>0.05). We next showed increased THOP1 levels in both MCI‐Aβ+ (ADC: 1.2‐fold, p<0.05; SPIN: 1.4‐fold, p<0.001) and AD patients (ADC: 1.03‐fold, p>0.05; SPIN: 1.4‐fold, p<0.001) compared to controls (Figure 2). THOP1 levels correlated moderately with levels of t‐Tau (ADC: rho=0.644; SPIN: rho=0.721), p‐Tau (ADC: rho=0.480; SPIN: rho=0.712) and Aβ40 (ADC: not available; SPIN: rho=0.625) but not with Aβ42 (ADC: rho=0.110; SPIN: rho=‐0.09).ConclusionWe show increased CSF THOP1 levels in amyloid positive AD and MCI patients and correlation with CSF Aβ40, which together with literature showing colocalization of THOP1 with Aβ plaques suggests a relationship with Aβ‐production. The association of THOP1 to tau pathologies highlights the potential of this protein as a disease monitoring biomarker.
Plasma biomarkers of brain amyloid‐β and tau pathologies in Down syndrome
Authors: Janelidze Shorena , Christian Bradley T , O'Bryant Sid E. , Price Julie C , Laymon Charles M , Schupf Nicole , Klunk William E , Lott Ira T , Silverman Wayne , Rosas H. Diana , Zaman Shahid , Mapstone Mark , Lai Florence , Ances Beau M , Handen Benjamin L , Hansson Oskar ,   the Alzheimer’s Biomarker Consortium Down Syndrome (ABC‐DS)
Published: December 2022

AbstractBackgroundPlasma tau phosphorylated at threonine 217 (P‐tau217) and glial fibrillary acidic protein (GFAP) are promising diagnostic and prognostic biomarkers of Alzheimer’s disease (AD). We aimed to determine the usefulness of plasma P‐tau217 and GFAP to detect AD‐related pathology in individuals with Down syndrome (DS).MethodThis cross‐sectional study included adults with DS (N=300) and non‐DS sibling controls (N=37) with baseline blood samples enrolled in the Alzheimer’s Biomarker Consortium‐Down Syndrome study. Participants with DS all underwent plasma P‐tau217 and GFAP assessments as well as tau‐PET, β‐amyloid (Aβ)‐PET and cognitive testing. We examined association of plasma P‐tau217 and GFAP with tau‐PET, Aβ‐PET and cognitive measures using regression models and ROC curve analysis and investigated if combining P‐tau217 and GFAP together and with other plasma AD biomarkers (Aβ42/40, neurofilament light [NfL], total tau [T‐tau]) and age could improve their performance for identifying individuals with abnormal tau‐PET or Aβ‐PET.ResultPlasma levels of P‐tau217 were increased in Aβ‐PET‐positive tau‐PET‐positive (A+T+) DS and A+T– DS compared with A–T– DS while GFAP was only increased in A+T+ DS (Figure 1). Plasma P‐tau217 levels were also higher in A+T+ DS than A+T– DS. In participants with DS, plasma P‐tau217 and GFAP (but not plasma Aβ42/40, t‐tau and NfL) were consistently associated with abnormal tau‐PET and Aβ‐PET status in models covaried for age (ORrange, 1.59‐2.46, p<0.028). A combination of P‐tau217 and age performed best when detecting tau‐PET abnormality in the temporal and neocortical regions (AUCrange, 0.96‐98), whereas the most parsimonious model for Aβ‐PET status included P‐tau217, T‐tau and age (AUC=0.95) (Figure 2). Higher levels of plasma P‐tau217 were associated with worse performance on DS Mental Status Examination and Cued Recall tests in Aβ‐PET positive (βrange, ‐0.231–[‐0.559], p<0.036) but not in Aβ‐PET negative DS.ConclusionPlasma p‐tau217 is an accurate biomarker of both tau and Aβ pathological brain changes in DS that could facilitate inclusion of individuals with DS in future AD clinical trials, especially when combined with age as a covariate.
Prospective cohort of elderly patients after hospitalization due to COVID‐19: preliminary results
Authors: Cintra Fabiana Carla Matos da Cunha , Cintra Marco Túlio , Almeida Daniella Cristina Brites , Martins Daniel Messias , Simão Gabriel Rabelo de Barros , Filipin Carolina Sant’anna , Vasconcelos Júlia Cunha , da Cruz Victor Fonseca Alves , da Silva Maria Clara Pereira , Fortini Iza de Faria , Viana Bernardo de Mattos , Bicalho Maria Aparecida Camargos 
Published: December 2022

AbstractBackgroundPost Covid‐19 syndrome is recognized as the maintenance of disease symptoms for weeks to months after the disease has healed. It is suspected that the involvement of the ACE enzyme and IL‐6 may trigger an increased risk of dementia.MethodThis is a cohort study that is evaluating over 12 months the functional status and cognition of elderly people after hospital discharge. One group is composed of elderly people admitted to the hospital for Covid‐19 and the other group is composed of elderly people hospitalized for other clinical reasons. The groups are evaluated with The Mattis (DRS), AD8, IQCODE, ADCS‐ADL, PCL‐C, GDS‐15, FIM, COPM, CFS, FSS, mMRC and SARC‐calf. We will describe the preliminary results of the first 15 patients included in the COVID‐19 group on functional status, cognition, mood and quality of life.ResultsFifteen patients with COVID‐19 were evaluated three months after hospital discharge. One was excluded due to previous mental disorder and another due to a request to be excluded from the study. We found a mean age of 67.7 ± 7.15 years, schooling 8.7 ± 4.7 years, 61.5% female, Charlson Comorbidity Index 1.9 ± 1.4, 69.2% with smoking history had incomplete vaccine protection for COVID‐19. Considering cognition, 15.4% of the sample had no impairment, 53.9% had mild cognitive impairment (MCI) (30.8% amnestic MCI and 23.1% non‐amnesic MCI) and 30.8% had dementia. 23.1% declared their health status and quality of life as fair or poor. Median CFS was 5 (3‐5), mean GDS‐15 was 4.7 ± 2.9, FSS 32.9 ± 18.9, PCL‐c 32.6 ± 12.5, SARC‐calf 3.2 ± 4.2. All had mMRC dyspnea classified between 2 and 4.ConclusionThere was a high prevalence of mild cognitive impairment and dementia among patients after three months of discharge, with a predominance of mild frailty due to CFS and the presence of fatigue. It is noteworthy that a quarter of the sample reported low quality of life.
GMNC risk alleles in individuals with Alzheimer’s disease are associated with cerebrospinal fluid concentrations of proteins involved in neuronal plasticity and blood brain barrier function
Authors: Visser Pieter Jelle , Reus Lianne M. , Gobom Johan , Teunissen Charlotte E. , Bertram Lars , Zetterberg Henrik , Tijms Betty M. 
Published: December 2022

AbstractBackgroundGWAS studies showed that cerebrospinal fluid (CSF) levels of total‐tau in Alzheimer’s disease (AD) are associated with genetic variations in GMNC (Cruchaga,2013). GMNC is involved in neural progenitor cell differentiation and regulates the generation of multiciliated ependymal cells (Kyrousi,2015), but the precise role of GMNC in AD pathophysiology remains unclear. We investigated which processes were associated with GMNC risk alleles by studying its associations with CSF levels of 1705 proteins in AD individuals.MethodWe selected 432 individuals with abnormal CSF amyloid beta 1‐42 levels from the EMIF‐AD multimodality biomarker discovery study and ADNI. We measured 1705 proteins by untargeted mass spectrometry (EMIF‐AD), the Human DiscoveryMAP panel (ADNI) or targeted mass spectroscopy (ADNI). We correlated the number of GMNC rs9877502‐A risk alleles with protein levels in additive models. To characterise proteins associated with GMNC risk alleles, we performed pathway enrichment analyses for Gene Ontology biological processes (GO‐BP) and ChEA transcription factors.ResultAverage age was 71.2 years. At least one GMNC rs9877502‐A risk allele was present in 60% of the AD individuals. Increasing number of GMNC risk alleles was associated with increased total‐tau, as expected, and with increased levels of 591 other proteins (35% of proteins measured). These proteins were associated with neuronal plasticity related processes (table) and SUZ12 and REST transcription factors, which are neuronal transcription repressors (all p‐FDR corrected>6.34e‐18). GMNC risk alleles were further associated with decreased levels of 105 proteins, including 72 proteins associated with blood brain barrier (BBB) permeability.ConclusionWithin AD individuals, GMNC risk alleles are not only associated with increased total‐tau levels but also with increased levels of neuronal plasticity associated proteins. We also found that GMNC risk allele carriers may have less BBB dysfunction than non‐carriers. Further studies are needed to clarify the association of GMNC with neuronal plasticity and BBB function in AD.ReferencesCruchaga, Neuron 2013: 256‐268. Kyrousi, C. , Development 2015: 3661‐3674.