bluuebunny/crossref_metadata_2025_split huggingface dataset:
Validation of an automatic tool for the measurement of brain atrophy and white matter hyperintensity in clinical routine: QyScore®
Authors: Cavedo Enrica , Tran Philippe , Thoprakarn Urielle , Martini Jean‐Baptiste , Movschin Antoine , Delmaire Christine , Gariel Florent , Heidelberg Damien , Pyatigorskaya Nadya , Ströer Sébastian , dos Santos Clarisse Longo , Dormont Didier ,   the Alzheimer’s Disease Neuroimaging Initiative,   the Frontotemporal Lobar Degeneration Neuroimaging Initiative
Published: December 2020

AbstractBackgroundBrain automatic segmentation methods have shown reliable results in measuring brain structure volumes and white matter lesions. Several studies showed that automated segmentation provides greater benefits than risks for patients affected by neurological diseases. However, few automated segmentation software are currently approved by regulatory agencies such as the US Food and Drug Administration (FDA). Here we present the methods and performance of QyScore®, an automated imaging analysis tool certified in Europe (CE marked) and US (FDA cleared) for the automatic volumetry of Grey and White Matter (GM and WM respectively) Hippocampus (HP), Amygdala (AM) and White Matter Hyperintensity (WMH).MethodA comprehensive database (N = 210) coming from several cohorts of patients with neurodegenerative diseases was established. The reliability measures considered for the validation of QyScore® imaging markers were: Dice Similarity Coefficient (DSC) and the Relative Volume Difference (RVD) for the HP, the AM, the GM and the WM volumes, DSC and the F1 metrics for the WMH. For each reliability index we identified thresholds and we hypothesized that DSC/F1 scores obtained using QyScore® markers were superior to the threshold, while RVD scores were inferior to the threshold. In addition, QyScore® performances were compared with the ones obtained from gold standard methods (manual segmentation) through regression analysis and Bland‐Altman plots.ResultComparison with reliability measures are described in Table 1. QyScore® compared with manual segmentation methods provides reliable performances for the segmentation of the grey and white matter volumes, hippocampal and amygdala volumes, as well as white matter hyperintensity volume as described in Figure 1.ConclusionQyScore® represents a reliable and user‐friendly tool, supporting the diagnosis made by clinicians for the early detection of neurological diseases such as MCI and AD dementia.
Cross‐omics studies of the role of apolipoprotein E in Alzheimer’s disease and dementia: Searching common pathways in patients, populations and cellular models
Authors: van Duijn Cornelia M. , Ahmad Shahzad , Sáez María Eugenia , Bennett Keiryn , Socorro Alfredo Cabrera , Bakker Margot H.M. , Ramirez Alfredo , Ruiz Agustín , Hankemeier Thomas 
Published: December 2020

AbstractBackgroundGenetic and transcriptomic studies in patients and cellular models are converging on a key role for lipids and the immune system. ADAPTED aimed to develop a comprehensive atlas of changes in metabolic and protein pathways in the blood and brain and determine whether these are driven by the apolipoprotein E gene (APOE). We conducted cross‐omics studies in human populations and integrated the findings with that of isogenic APOE ε2/ε2, APOE ε3/ε3, and APOE ε4/ε4 cell lines.MethodHuman studies were embedded in the Rotterdam Study and prospective studies of patients with mild cognitive impairment (MCI) in memory clinics of Fundació ACE and the Central Institute of Mental Health (Mannheim). State‐of‐the‐art RNA‐sequencing, proteomics and metabolomics were used to characterize changes in blood and cerebrospinal fluid (CSF). Metabolomics included comprehensive analysis of cholesterol subfractions, signalling lipids including lysophosphatic acids (LPA), amino acids and proteins using NMR and LC‐MS/MS. Proteomics studies are based on high‐multiplex immunoassays and LC‐MS/MS.ResultsIn blood, we identified a broad spectrum of metabolites associated with risk of AD, including HDL‐subfractions, DHA, amino acids and glycoproteins. We found systemic changes in the levels of metabolites in circulation are driven by APOE in concert with other genes implicated in AD. In blood, we found a weak correlation between LPA levels and risk of AD. However, LPA levels in CSF strongly associated with amyloid, phosphorylated and total tau, with APOE driving the profiles. LPA 16:0 and 16:1 CSF levels were associated with MCI to AD conversion. Our proteomic studies show a large number of proteins associated with amyloid, phosphorylated and total tau levels in CSF of MCI patients. However, in blood we also discovered two proteins associated with future risk of dementia: CDH6 and Hagh. Integrating the findings with RNA sequence data in iPSC based cellular models showed that CDH6 is differentially expressed across APOE genotypes in isogenic neurons but not in macrophages.ConclusionsWe show a wide range of metabolic and proteomic changes that may be relevant for the development and course of AD. The findings show the potential of cross omics‐research connecting findings in human populations and cellular models.
Hypersynchronization, a common feature along the AD process
Authors: Maestú Fernando ,   Center for Biomedical Technology
Published: December 2020

AbstractBackgroundIn the last decade there are more and more literature indicating that subjects at different stages of Alzheimer´s Disease (AD) continuum, have a disrupted organization of their anatomo‐functional networks. Neurophysiological findings with MEG have indicated an increased brain synchrony between different brain regions across different stages of the disease. In this talk we will concentrate on these neurophysiological findings in humans comparing magnetoencephalography (MEG) findings with clinical and current biomarkersMethodIn a series of studies using magnetoencephalography, we have recorded resting state activity in patients with Mild Cognitive Impairment (MCI), Subjective Cognitive Decline (SCD) and in healthy subjects at preclinical stage or at risk for developing dementia. We used functional connectivity in the source space to assess how the brain oscillatory activity synchronize across brain regions. MEG findings will be compared with clinical stages, amyloid‐PET, cerebrospinal fluid (p‐tau), or brain atrophy.ResultMCI patients and SCD participants showed an increased functional connectivity values in anterior regions of the brain in the alpha band. This was in combination with a posterior hyposynchronization which was slightly higher in MCI patients compared to SCD. MCI patients who did convert to dementia showed hypersynchronization between anterior cingulate cortex and posterior regions in the alpha band. A second MEG scan on MCI converters (when they were at the dementia stage) showed a decrease in brain synchrony in a similar region, indicating that hypersynchrony accelerate the process of network dysfunction (the “X Model”). These profiles of brain synchrony were evaluated in comparison with biomarkers. MCI patients with elevated p‐tau in the CSF showed again increased synchronization between anterior cingulate and the medial temporal lobe. Healthy subjects (no memory complaints, no brain atrophy, no hypometabolism) with a positive amyloid PET showed as well increased brain synchrony. Finally, young relatives of AD patients showed increased phase synchrony in similar brain regions than that found in MCI patients in the alpha band.ConclusionAll these findings together indicate that hypersynchronization of the brain networks could be an excellent non‐invasive biomarker for tracking the disease and evaluate interventions.
Subjective cognitive impairment differs by racial/ethnic groups and sociodemographic factors: The Multi‐Ethnic Study of Atherosclerosis and Alzheimer’s Disease (MESA‐MIND)
Authors: Hughes Timothy M. , Winkey Khadijah , Sachs Bonnie C. , Fitzpatrick Annette L. , Craft Suzanne , Baker Laura D. , Heckbert Susan , Jacobs David R. , Rapp Stephen R. , Hayden Kathleen M. , Caban‐Holt Allison M. 
Published: December 2020

AbstractBackgroundSubjective cognitive decline (SCD) is associated with objective cognitive decline, incident cognitive impairment, and AD pathology in mostly white populations. Little data are available to describe SCD and objective cognitive impairment in diverse populations.MethodThe Multi‐Ethnic Study of Atherosclerosis (MESA) began cognitive testing, including the Cognitive Abilities Screening Instrument (CASI), in 2010‐12 among four racial/ethnic groups: 38% white, 28% African‐American, 22% Hispanic, and 12% Chinese Americans across six field centers. MESA‐MIND and ancillary studies added repeated CASI by in‐person exam (2016‐2018) and the 12‐item Cognitive Change Index (CCI‐12) during the 2018 annual follow‐up call. Statistical analyses using the CCI‐12 item sum and two published thresholds (CCI‐12≥16 and CCI‐12≥23) established the point prevalence for SCD across racial/ethnic groups. Socio‐demographic factors were examined using multivariable logistic regression. Spearman correlations and general linear models related 5‐year subjective change (CCI‐12) and objective change in cognitive performance (change in CASI) over the same time period.ResultCCI‐12 data were available on 3,676 MESA participants (aged 60‐95) across all racial/ethnic groups and sites. Table 1 presents demographics, CCI‐12 scores, and CASI scores. The prevalence of SCD (CCI‐12≥16) across racial/ethnic groups ranged between 52% to 72%. There was a lower prevalence in African‐American and white and a higher prevalence in Chinese and Hispanic participants. In adjusted models, various socio‐demographic factors were significantly associated with a higher odds of reporting SCD (CCI‐12≥16), including: older age, female gender, Chinese language preference, diabetes, smoking, birth in the Western US or Mexico, and lacking health insurance coverage. African‐American ethnicity, higher education, and income greater than $75,000 were each associated with a lower reporting of SCD. CCI‐12 was weakly and inversely correlated with antecedent cognitive performance (2010‐12, n=3,200, Rho=‐0.16, p<0.01) and cognitive decline (n=1,800, Rho=‐0.06, p=0.01) over 6 years of follow‐up. In stratified analyses, associations between CCI‐12 and objective cognitive decline were observed in white participants only.ConclusionIn a large regionally and ethnically diverse cohort of older adults, SCD defined by subjective memory concerns on the CCI‐12 significantly differed by race/ethnicity and indicators of socioeconomic status, suggesting that cultural and institutional biases may influence reporting SCD in diverse populations.
Differences in the characteristics, neuropsychiatric comorbidities, and psychometric features of subjective cognitive decline in Hispanics versus non‐Hispanic whites
Authors: Faustin Arline , Masurkar Arjun V. 
Published: December 2020

AbstractBackgroundSubjective cognitive decline (SCD) is thought to be a prodromal stage of Alzheimer’s disease (AD), yet has been primarily studied in non‐Hispanic whites. This study aimed to understand the differences in SCD presentation between Hispanics (of any race) and non‐Hispanic whites.MethodA cross‐sectional analysis was performed on participants seen at the NYU Alzheimer’s Disease Center with subjective cognitive decline and who identified as Hispanic (of any race, n=52) and non‐Hispanic white (n=265). Demographics, SCD characteristics, mood/behavioral symptoms, and performance on psychometrics tests were analyzed, with statistical analysis by t‐test, ANOVA, or Fisher’s exact test where appropriate.ResultHispanic participants with SCD were younger (64.3 vs. 68.2, p=0.0008) and had less education (14.3 vs. 17.6, p<0.0001). The Cognitive Change Index (CCI), a measure of SCD, did not distinguish the two groups (total CCI score nor amnestic and non‐amnestic subgroups). In contrast, on the Brief Cognitive Rating Scale (BCRS), another SCD metric, Hispanic participants showed increased severity in concentration (2.62 vs. 1.93), praxis (2.60 vs. 2.13) and calculation (2.96 vs. 2.10), all p<0.001. Study partner observations on the Neuropsychiatric Inventory‐Questionnaire (NPIQ) revealed an increased prevalence of depression (27% vs. 14%, p<0.001) and appetite changes (10% vs. 0%, p<0.0001) in Hispanic SCD participants. When self‐rated via the Geriatric Depression Scale, there were also notable differences in the quality of depression, with increased prevalence in Hispanics of dropping activities (33% vs. 6%), emptiness (19% vs. 3%), boredom (19% vs. 3%), fear (27% vs. 6%), preference to stay home (31% vs. 8%), and helplessness (15% vs. 4%), all p<0.01. On psychometric testing there were no differences in MoCA or MMSE scores. However, Hispanic participants showed lower performance on the Digit Symbol Substitution Test (DSST) (39.2 vs. 56.1, p<0.0001), which can be influenced by mood and has previously shown to be a marker of decline in SCD.ConclusionThese findings support that the characteristics, neuropsychiatric comorbidities, and psychometric features of SCD are notably different between Hispanics and non‐Hispanic whites. In particular, depression in Hispanics warrants further study as a particularly significant variable in determining SCD conversion to AD.
“I just glove up and do what has to be done”: A mixed‐methods exploration of dementia care challenges and care management strategies
Authors: Leggett Amanda N , Connell Cathleen M , Gitlin Laura N , Kales Helen C 
Published: December 2020

AbstractBackgroundMost family caregivers for persons living with dementia (PLwD) don’t receive training for their role and therefore adopt a variety of care management strategies, some of which may be harmful. The current study utilizes a mixed‐methods design to integrate family caregiver’s qualitative and quantitative descriptions of recent care challenges (e.g. cognitive, functional, and behavioral symptoms of dementia), and the strategies utilized to manage these symptoms.MethodParticipants included 100 primary family caregivers for PLwD who were 74% female, 18% non‐White, and on average 64 years old. Participants were interviewed qualitatively about their management of a recent care challenge and with the Caregiver Assessment of Function and Upset, Neuropsychiatric Symptom Inventory, Dementia Severity Rating Scale, and Dementia Management Strategies Scale (subscales: criticism, active management, encouragement). Care challenges and care management strategies are compared across qualitative analysis and T‐tests.ResultThe most common type of qualitatively reported care challenge was BPSD (45%) followed by symptoms of cognitive decline (18%). Quantitatively caregivers reported the most stressful ADL to be toileting and BPSD as aggression. Caregivers providing ADL/IADL care (r=.34, p<.01) and with PLwDs with more severe cognitive symptoms (r=.30, p<.01) had significantly higher use of active management care strategies, relative to caregivers not assisting with those tasks. In contrast, caregivers providing care for PLwDs with greater BPSD burden (r=.34, p<.001) and particularly challenging symptoms of aggression (t=‐.4.0, p<.001), agitation (t=‐3.4, p<.001), irritability (t=‐.2.4, p<.05) and hallucinations (t=‐2.3, p<.05) reported more use of criticism as a management strategy.ConclusionMixed‐methods assessment of care challenges provides a more nuanced understanding of how caregivers manage care stressors. Active management or other straightforward assistive approaches may be required when the severity of dementia increases, yet critical strategies seem to emerge with greater severity of BPSD. Encouragement strategies, on the other hand, were independent of any care challenges and may be used to support the PLwD, not address an underlying symptom. As criticism tends to be associated with more negative care outcomes (burden, potentially harmful behavior), intervention approaches may help caregivers identify more adaptive responses to prepare for stressful challenges such as BPSD.
Defining the role of the Alzheimer disease risk factor CD2AP in brain vascular function
Authors: Vandal Milene , Gunn Colin , Bourassa Philippe , Institoris Adam , Shin Steven Seungjae , Jiang Yulan , Tremblay Cyntia , Belzil Camille , Bennett David A. , Gordon Grant , Calon Frederic , Nguyen Minh Dang 
Published: December 2020

AbstractBackgroundBrain hypoperfusion is the earliest change observed in Alzheimer’s Disease (AD) brains. Degeneration of the brain vasculature, that includes cerebral amyloid pathology, white matter hyperintensities and cortical infracts, isomnipresent in AD, and predicts the progression of cognitive decline in AD patients. CD2‐associated protein (CD2AP) functions as scaffolding protein for cytoskeletal remodeling, membrane trafficking during clathrin‐mediated receptor endocytosis and cell‐cell interactions. Interestingly, polymorphisms in CD2AP constitute one of the top 10 genetic predisposition factor to AD. Since CD2AP is enriched in brain endothelial cells (BECs) that form the brain microvessels, we reason that the protein plays a key role in BECs and therefore, defects in CD2AP may contribute to cerebrovascular dysfunction observed in AD.MethodWe use a multidisciplinary approach (culture of primary BECs and cerebral arteries, two‐photon brain imaging of awake active mice and analysis of isolated brain microvessels from human AD volunteers) to investigate the role of CD2AP in BECs and brain vascular function.ResultWe found that 1) CD2AP regulates the Apolipoprotein E receptor 2 (ApoER2) in BECs, 2) the CD2AP/ApoER2 axis is key for brain vascular function in vitro and in vivo and 3) human AD volunteers have altered the levels of CD2AP and this alteration is associated with cognitive dysfunction.ConclusionWe propose that the deregulation of the ApoER2/CD2AP axis contributes to the vascular defects observed in AD.
Age‐related resident memory CD8 T cells link amyloid to NFTs and neurodegeneration in mice and are modulated in AD and MCI blood
Authors: Wheeler Christopher J. , Panwar Akanksha , Rentsendorj Altan , Cordner Ryan , Yeager Nicole , Jin Lee‐Way , Koronyo Yosef , Koronyo‐Hamaoui Maya , Black Keith L. , Van Dam Debby , De Deyn Peter Paul , Yamamoto Vicky , Trujillo Kristina 
Published: December 2020

AbstractBackgroundWhile autosomal dominant mutations that promote amyloid deposition guarantee rare genetically‐determined Alzheimer’s disease (AD), discrete factors promoting more prominent sporadic AD have not been identified. Evidence from mice, and more recently from a patient resistant to autosomal dominant AD, suggests that an age‐sensitive factor missing from mice links amyloid deposition to NFTs and neurodegeneration in AD, and is critical for AD development. We previously engineered mice that possess human‐like predominance of an age‐related resident memory CD8 T cell population (hiTRM mice), and exhibit antigen‐specific CD8 T cell accumulation in brain, as well as sporadic amyloid deposition linked to NFT‐like structures and neurodegeneration.MethodWe used CD8 T cell antigen specificity within the hiTRM model to generate pHLA reagents that identify analogous antigen‐specific memory CD8 T cells in humans, and used them to quantify their levels in blood and/or brain of HLA‐A2+, normal aging, MCI with or without AD biomarkers (AD‐associated and non‐associated MCI, respectively), and confirmed late‐onset AD cohorts. Cognitive performance was also assessed using the MoCA test in sub‐cohorts of MCI patients.ResultWe show that antigen‐specific hiTRM analogues were increased in perivascular and cortical regions of human AD relative to normal aging brain (13 vs. 3%; P < 0.01), but decreased in blood of AD‐associated MCI and late‐onset AD patients (1.3 and 0.7%, respectively; 3.4% in normal controls; P < 0.00009), and correlated with cognitive impairment in MCI (r = 0.828; P < 0.005). Receiver operating characteristic (ROC) analysis of levels of these analogues in blood revealed area under the curve (AOC) of 0.715, 0.803, and 0.862 for non‐associated, AD‐associated, and AD, respectively.ConclusionOur results identify antigen‐specific memory CD8 T cells, a factor critically linking amyloidopathy to NFTs and which dominantly promote the development of AD‐like neurodegeneration in mice, as unique blood‐based biomarkers that accurately track the AD continuum in patients. As such, these cells may play a similar role in AD pathoetiology in mice and sporadic human AD. These cells thus represent novel biometric and therapeutic candidates for sporadic AD.
Red blood cell α‐synuclein heteroaggregates can discriminate healthy controls from cognitively impaired subjects of the AD‐LBD spectrum
Authors: Giampietri Linda , Daniele Simona , Piccarducci Rebecca , Palermo Giovanni , Manca Maria Laura , Nicoletti Valentina , Giorgi Filippo Sean , Frosini Daniela , Petrozzi Lucia , Gerfo Annalisa Lo , Pietrobono Deborah , Cavallini Chiara , Franzoni Ferdinando , Trincavelli Maria Letizia , Bonuccelli Ubaldo , Siciliano Gabriele , Tognoni Gloria , Ceravolo Roberto , Baldacci Filippo , Martini Claudia 
Published: December 2020

AbstractBackgroundα‐synuclein’s (α‐syn) pathological accumulation is involved in the development of Lewy body dementias (LBDs), namely Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB). Several autoptic series have nonetheless documented pathologic α‐syn deposits up to 30% cases of otherwise confirmed Alzheimers’s disease (AD) brains. A considerable body of evidence supports the mutual pathological interaction between α‐syn and AD’s hallmark altered proteins, namely beta‐amyloid and tau, both in AD and LBDs. Aim of this study was to explore the diagnostic potential of red blood cells (RBCs) levels of α‐syn, beta‐amyloid 1‐42 (Aβ1‐42), total‐tau (t‐tau), and their heteromers in subjects with LBDs, AD, and healthy controls (HCs).MethodTotal α‐syn, Aβ1‐42, t‐tau, α‐syn/Aβ1‐42, α‐syn/tau concentrations in RBCs were determined by means of an “in‐house” immunoenzimatic assay, and confronted in AD subjects (either AD Dementia or Prodromal‐AD, N=51), LDB subjects (either DLB or PDD, N=27), and HCs (N=60). Then, the diagnostic potential of each significant biomarker was examined calculating the area under the receiver operating characteristic curve (AUROC).ResultCompared to HCs, both AD and LBD subjects had significantly lower levels of t‐tau (4.25±4.99 and 3.19±5.13 ng/mg respectively, vs 8.43±11.52 ng/mg of HC) and α‐syn (16.46±15.85 and 15.31±18.30 ng/mg respectively, vs 39.62±57.19 ng/mg of HC) concentrations, as well α‐syn/tau heterodimers (1.04±1.54 and 0.86±0.10 ng/mg respectively, vs 2.36±1.87 ng/mg of HC), while only AD subjects showed significantly reduced levels of α‐syn/Aβ1‐42 (1.91±1.91 ng/mg vs 3.80±3.32 ng/mg in HC). Regarding t‐tau diagnostic accuracy, it turned out to be fair in differentiating LBD patients from HCs, and just poor in discriminating AD from HCs. Notably, RBCs α‐syn/tau heterodimers were able to discriminate LBD and AD subjects from HC with good and fair accuracy respectively. Similarly, α‐syn/Aβ1‐42 heterodimers concentrations were found to have fair accuracy in discriminating between AD and HCs (Table 1).ConclusionRBC α‐syn heteromers concentrations were able to discriminate HCs from AD and LBD patients, though provided no help in the differential diagnosis of LBD vs AD. The interest for these data goes beyond eventual clinical implications, supporting new perspectives on the interaction of the different pathologies in these neurodegenerative diseases.