bluuebunny/crossref_metadata_2025_split huggingface dataset:
Longitudinal changes of self‐ and informant‐reported cognitive decline in elderly with regard to clinical progression and amyloid‐status
Authors: Kuhn Elizabeth , Stark Melina , Kleineidam Luca , Wolfsgruber Steffen , Boecker Henning , Bürger Katharina , Düzel Emrah , Fliessbach Klaus , Gaertner Florian , Heneka Michael T. , Laske Christoph , Perneczky Robert , Peters Oliver , Priller Josef , Schmid Matthias , Schneider Anja , Spottke Annika , Teipel Stefan , Wiltfang Jens , Jessen Frank , Wagner Michael 
Published: December 2023

AbstractBackgroundSelf‐ and informant‐reports of cognitive decline have been previously associated with a higher risk of cognitive decline in elderly. Yet, few studies assessed their longitudinal changes over time with regard to both incident mild cognitive impairment (iMCI) and Alzheimer’s disease (AD) pathology. This study aims at describing these links to better understand which trajectories are indicative of higher AD‐risk.MethodWe used data from 501 participants followed‐up annually (2.51±1.35 years) in the DELCODE project. All were cognitively unimpaired, and had an amyloid measurement available, at inclusion. Among them, 145 were amyloid‐positive, and 65 progressed to iMCI during the follow‐up period (31 iMCI‐Aß+). The SCD‐Interview was used to measure (i) the number of cognitive domains in which the participants or its relative perceived a decline (i.e., self‐ and informant‐SCD‐I), and (ii) the number of fulfilled SCD‐plus criteria. Linear mixed‐effect models were used to assess SCD trajectories over time, according to four groups defined by amyloid status and clinical progression (Stable‐Aß‐, Stable‐Aß+, iMCI‐Aß‐ and iMCI‐Aß+). Analyses were adjusted for age, sex and education; and their interaction with time.ResultsBoth self‐SCD‐I levels and SCD‐plus scores decreased significantly over time, without significant differences between groups (Figure 1A, 1B). Conversely, informant‐SCD‐I levels did not significantly change over time in the whole sample, although slopes significantly differed between groups. Compared to the Stable‐Aß‐ group, there was a greater increase over time of informant‐SCD‐I report only in iMCI‐Aß+ [est 0.16, SE 0.05, p<.001] (Figure 1C). The resulting discrepancy score (Self‐SCD‐I minus Informant‐SCD‐I) tended to decrease over time with significant differences between groups. Compared to the Stable‐Aß‐ group, the discrepancy score showed a faster decrease over time in iMCI‐Aß+ [est ‐0.21, SE 0.056 p<.001] (Figure 1D).ConclusionLongitudinal patterns in subjective reports of cognitive decline might help identify preclinical AD subjects at higher risk of clinical progression. Specifically, an increase of informant‐reported cognitive decline over time may indicate objective cognitive decline in amyloid‐positive subjects. Conversely, the decrease of self‐reported cognitive decline over time, regardless of the group, may reflect generally reduced concerns after inclusion, or result from current limitations in longitudinal SCD assessment.
Effect of early‐ and mid‐life cognitive enrichment on Alzheimer’s disease pathology and late‐life cognition
Authors: Simone Stephanie M. , Wagner Maude , Peterson Rachel , Krasnova Anna , Andrews Ryan M , Armstrong Nicole M. , Widaman Keith F. , Zaheed Afsara B , Sol Ketlyne , Bennett David A. A , Barnes Lisa L. , Vonk Jet MJ 
Published: December 2023

AbstractBackgroundCognitive reserve and brain maintenance may explain individual differences in trajectories of cognitive and brain aging due to various life exposures (e.g., education, cognitive enrichment). Cognitive reserve refers to the advantages that life exposures exert on cognitive abilities despite brain aging or disease; brain maintenance refers to the protective effects of life exposures on the brain itself (e.g., reduced rate of neuropathology accumulation). Previous findings showed that early‐life cognitive enrichment (ELCE) was associated with slower cognitive decline, which was partially mediated through global Alzheimer’s disease pathology. Building on this work, this study investigated mediation by β‐amyloid and tau pathology (reflecting brain maintenance) as well as moderation by early‐ and mid‐life cognitive enrichment (ELCE, MLCE; reflecting cognitive reserve) on cognitive functioning at last visit proximate to death.MethodThere were 1015 community‐based participants (M baseline age = 82.57±6.35) from the Rush Memory and Aging Project (MAP) and Minority Aging Research Study (MARS) cohorts, who completed annual cognitive and clinical assessments. ELCE and MLCE composite measures were derived from z‐scored self‐reported indicators obtained at baseline (Table 1). Summary measures of β‐amyloid and tau burden were derived from immunohistochemistry at autopsy. Late‐life cognition was measured using a global composite of 19 z‐scored neuropsychological tests obtained at last visit. To test for cognitive reserve, separate linear regression models examined whether ELCE and MLCE moderated relations between β‐amyloid or tau and cognition, adjusted for age at death and sex. To test for brain maintenance, a series of mediation analyses examined whether β‐amyloid and/or tau burden mediated the relationship of ELCE and MLCE with cognition.ResultELCE (p = .005) and MLCE (p = .005) moderated the relationship between tau—but not β‐amyloid—and late‐life cognition proximate to death (Figure 1). Mediation analyses revealed an indirect effect of β‐amyloid—but not tau—on the relation between ELCE (B = 0.058, p = .004) and MLCE (B = 0.040, p = .03) and late‐life cognition (Figure 2).ConclusionELCE and MLCE improve late‐life cognition partially through reducing β‐amyloid, but not tau, accumulation (i.e., brain maintenance). In contrast, ELCE and MLCE are protective against late‐life cognitive impairment in the presence of tau pathology (i.e., cognitive reserve), but not β‐amyloid.
Associations between ASL‐derived cerebrovascular health and cognitive performance: results from the Insight 46 study
Authors: Dijsselhof Mathijs B.J. , Lu Kirsty , Lorenzini Luigi , Collij Lyduine E. , James Sarah‐Naomi , Thomas David L , Scott Catherine J , Manning Emily N , Cash David M ,   Insight 46 study Team, Hughes Alun D , Richards Marcus , Barkhof Frederik , Petr Jan , Mutsaerts Henk‐Jan 
Published: December 2023

AbstractBackgroundCardiovascular and cerebrovascular pathology may accelerate brain aging and cognitive decline. Structural cerebrovascular imaging biomarkers, such as white matter hyperintensities, reflect mostly irreversible accumulated damage. In contrast, cerebral blood flow (CBF), measured with arterial spin labelling (ASL) perfusion MRI, is a potential early haemodynamic biomarker of cognitive impairment. However, our understanding of physiological CBF variability and its relation with cognition is limited.MethodWe included 245 cognitively unimpaired participants from the Insight 46 birth cohort study, who underwent 3D T1‐weighted and pseudo‐continuous ASL‐MRI (labelling duration = 1800ms; post‐labelling delay = 1800ms) on a 3T Siemens Biograph mMR PET‐MRI scanner. Cognitive assessment included tests for logical memory (Wechsler Memory Scale‐Revised), associative memory (Face‐Name Associative Memory Exam), attention and processing speed (Digit‐symbol substitution and response inhibition test), non‐verbal reasoning (Matrix test), executive functioning (Choice Reaction Time), visuomotor integration (circle‐tracing task), and two composite scores (Mini‐Mental State Examination (MMSE) and the Preclinical Alzheimer Cognitive Composite).ResultSample characteristics are reported in Table 1. Associations were found between GM sCoV and MMSE (Male/Female ß = 0.74/‐0.75, p = 0.028, Figure 1), and GM sCoV and Logical Memory (Male/Female ß = 1.05/‐0.25, p = 0.005, Figure 2), but not between CBF and any cognitive scores (p>0.05).ConclusionIn a cognitively unimpaired population, cognitive performance was associated with GM sCoV but not with other CBF parameters. However, in males, the relationship was opposite to what we expected. Further work should investigate to what extent this indicates macrovascular change occurs before perfusion alterations and could relate to future cognitive decline, and how they differ between sex.
Impact of Stress, Loneliness and Sociodemographic Factors on Psychological Well‐Being During the COVID‐19 Pandemic
Authors: Udeogu Onyinye , Mimmack Kayden J. , Gagliardi Geoffroy Pierre , Burling Jessa , Gatchel Jennifer , Quiroz Yakeel T. , Donovan Nancy J , Amariglio Rebecca E. , Sperling Reisa A. , Marshall Gad A , Vannini Patrizia 
Published: December 2023

AbstractBackgroundPersonal and social factors have had a varied effect on older adults during the COVID‐19 pandemic. Psychosocial factors and underlying pathological changes may have influenced the mental health of these older adults. Understanding the drivers behind the mental health of older adults during the pandemic may help identify treatment targets. We aimed to understand this phenomenon by exploring the relationships between the psychosocial factors iand self‐reported experiences of psychological well‐being.MethodWe included 149 participants (mean age: 75.6) from the Harvard Aging Brain Study and Instrumental Activities of Daily Living Study who took a survey conducted during the Summer of 2021, to assess stress (Perceived Stress Scale), loneliness (UCLA Loneliness Scale. 3‐item version), resilience (Connor Davidson Resilience Scale) and psychological well‐being (PROMIS‐Global Mental), encompassing self‐reported quality of life, mood and thinking, satisfaction with social relationships and anxiety and depressive symptoms. Pre‐assessed measures of cortical amyloid (PiB; mean time difference = 1.8 years) and medial temporal tau (Flortaucipir; mean time difference = 1.7 years) were also included. We performed a hierarchal regression analysis to understand the relationships among the psychosocial factors, controlling for demographics, amyloid, and tau as predictors of well‐being.ResultDemographic and survey responses are presented in Table 1. Significant negative associations were found among perceived well‐being and pathology (amyloid and tau), stress and loneliness, such that increased pathology, increased stress and increased feelings of loneliness were related to worse mental health (Figure 1). A positive association was found between resilience and well‐being, such that increased resilience was related to higher well‐being. (Figure 1). The hierarchical regression analysis results revealed that loneliness (β = −0.32, t = −5.81, p<.001), stress (β = −0.38, t = −5.48, p<.001), and resilience (β = 0.28, t = 4.34, p<.001) uniquely accounted for a significant proportion of variance in well‐being even after controlling for demographic characteristics (age, sex, education, race) and psychosocial characteristics (marital status, living alone) (Table 2).ConclusionOur findings suggest that measuring and quantifying loneliness, stress, and resilience can help clinicians and researchers understand the potential detrimental effects of the COVID‐19 pandemic among older adults. These findings may extend to other prolonged exposures to stressful situations and uncover much needed targets for intervention.
Integration of cerebrospinal fluid pQTL and GWAS prioritizes novel causal proteins for Alzheimer’s disease
Authors: Western Daniel , Timsina Jigyasha , Wang Lihua , Wang Ciyang , Ruiz Agustin , Marquié Marta , Boada Mercè , Rojas Itziar , Alvarez Ignacio , Aguilar Miquel , Pastor Pau , Sung Yun Ju , Cruchaga Carlos 
Published: December 2023

AbstractBackgroundQuantitative trait loci (QTL) are successful at identifying the functional gene for many loci identified through GWAS. While expression QTL (eQTL) studies robustly examine tissue‐specificity, most protein QTL (pQTL) studies have been limited to plasma. We have previously demonstrated that pQTL associations are highly tissue‐specific. Given the relevance of cerebrospinal fluid (CSF) to Alzheimer’s disease (AD) and other forms of neurodegeneration, we developed a CSF‐specific pQTL atlas and integrated it with AD GWAS to identify novel causal proteins for AD.MethodWe generated CSF proteomics (Somalogic, 7,584 analytes) data for 3,107 individuals. pQTL mapping was performed using a three‐stage approach: discovery, replication, and meta‐analysis. We analyzed the tissue‐ and molecule‐specificity of our associations by comparing to plasma & brain pQTLs and various eQTLs. We performed a proteome‐wide association study (PWAS) and Mendelian randomization (MR) to prioritize proteins affecting AD. We determined shared protein‐disease genetic regulation using colocalization. Using AD‐associated proteins, we built risk models of disease status.ResultWe identified 2,316 significant pQTL (1,247 in cis and 1,069 in trans) for 1,960 proteins, of which 1,720 were novel and not reported in the largest currently available pQTL studies in plasma or brain. Through PWAS, we identified 440 proteins associated with AD risk, which show enrichment in neurons (with APOE region) or microglia/macrophages (without APOE). MR prioritized 37 proteins as causal and colocalization identified 153 proteins that share genetic etiology with AD. Seventeen of these proteins overlap between all three methods and multiple (including PILRA, PRSS8, and SIRPA) represent novel causal proteins for AD. A protein risk score using PWAS‐identified proteins outperformed a polygenic risk score (PRS) at predicting amyloid/tau positivity across ages (AUC: 0.852‐0.906 vs. 0.724‐0.806, P<0.002) and across APOE genotypes (AUC: 0.809‐0.893 vs. 0.70‐0.80, P<0.027).ConclusionWe reported the largest CSF pQTL analysis to date and confirmed that CSF pQTLs are largely tissue‐specific. We identified proteins involved in AD that confirm reported candidate genes and prioritize new ones at GWAS loci. We developed accurate prediction models using prioritized proteins. Our findings offer insights into AD biology undetected with plasma pQTL analyses, supporting proteogenomic databases in neurologically‐relevant tissues.
Biomarkers of microvascular dysfunction and cerebral white matter connectivity: The Maastricht Study
Authors: Beran Magdalena , van Gennip April C.E. , Stehouwer Coen D.A. , Jansen Jacobus F.A. , Gupta Monideepa D. , Houben Alfons J.H.M. , Berendschot Tos T.J.M. , Webers Carroll A.B. , Wesselius Anke , Schalkwijk Casper , Backes Walter H. , de Jong Joost J. , van der Kallen Carla J.H. , van Greevenbroek Marleen M.J. , Köhler Sebastian , Vonk Jet M.J. , Geerlings Mirjam I. , Schram Miranda T. , van Sloten Thomas T. 
Published: December 2023

AbstractBackgroundMicrovascular dysfunction may contribute to the development of various cerebral disorders, including cognitive dysfunction, dementia, and certain forms of depression. The suggested mechanism through which microvascular dysfunction contributes to these disorders is by disrupting white matter tracts and altering brain connectivity, but evidence is scarce. We investigated the association between multiple biomarkers of microvascular function and cerebral white matter connectivity.MethodWe used cross‐sectional data from The Maastricht Study, a Dutch population‐based cohort (n = 4,326, mean±SD age 59.4±8.6 years, 49.7% women). Measures of microvascular function included urinary albumin excretion, central retinal arteriolar and venular calibers (CRAE and CRVE), a composite score of flicker light‐induced retinal arteriolar and venular dilation response, and a composite score of plasma biomarkers of endothelial dysfunction (soluble intercellular adhesion molecule‐1 (sICAM‐1), soluble vascular cell adhesion molecule‐1 (sVCAM‐1), soluble E‐selectin (sE‐selectin) and von Willebrand factor (vWF)). White matter connectivity was calculated from 3T diffusion MRI to quantify the number (average node degree) and organization (characteristic path length, global efficiency, clustering coefficient and local efficiency) of cerebral white matter connections.ResultA higher endothelial dysfunction composite score was associated with a longer characteristic path length (beta per SD: 0.066 (95% confidence interval: 0.017; 0.114)) after adjustment for sociodemographic, lifestyle and cardiovascular factors, but not with any of the other white matter connectivity measures. All other measures of microvascular dysfunction were not associated with any of the connectivity measures after adjustments.ConclusionThe present study suggests that microvascular dysfunction, as quantified by a set of various measures, is not consistently associated with cerebral white matter connectivity. Only a composite score of plasma biomarkers of endothelial dysfunction was associated with a longer characteristic path length, with a longer characteristic path length being indicative for a topographically less integrated and less efficient cerebral network. Future cross‐sectional and longitudinal studies are needed to further understand the role of microvascular dysfunction in the development of cerebral disorders.
[18F]PI2620 tau deposition increases along the Alzheimer’s disease continuum in Down Syndrome and in presence of amyloid
Authors: Pegueroles Jordi , Camacho Valle , Montal Victor , Bejanin Alexandre , Videla Laura , Aranha Mateus Rozalem , Benejam Bessy , Morcillo‐Nieto Alejandra O. , Zsadanyi Sara E. , Barroeta Isabel , Carmona‐Iragui Maria , Lleo Alberto , Flotats Albert , Fortea Juan 
Published: December 2023

AbstractBackgroundDown’s syndrome (DS) is currently considered a genetic form of Alzheimer’s disease (AD). People with DS develop early‐onset AD due to an extra copy of the amyloid precursor protein gene, present on chromosome 21. Thus, DS is a unique model to study AD pathophysiology. We aimed to study the neurofibrillary tau burden in adults with DS using the second‐generation Tau PET tracer [18F]PI‐2620 and assess its relationship with amyloid PET.MethodCross‐sectional study. We included 46 subjects: 18 euploid subjects without cognitive impairment and 16 asymptomatic DS, 4 DS with prodromal AD and 8 DS with AD dementia. All subjects underwent dynamic [18F]PI‐2620 PET/CT, [18F]Flutemetamol amyloid PET/CT and T1w‐MRI scans. PET images were co‐registered to the corresponding T1w‐MRI and intensity normalized by the mean value in the reference region (whole cerebellum for [18F]Flutemetamol and inferior cerebellar cortex for [18F]PI‐2620). For amyloid PET, the mean of the composite region (frontal, temporal, parietal, and cingulate) was calculated and transformed into Centiloid units. [18F]PI‐2620 tracer retention was quantified in region of interest (ROIs) corresponding to individual anatomical definitions of Braak stages I‐II, III‐IV and V‐VI. ANOVA was used to test differences between clinical diagnoses. To assess the relationship between amyloid and tau, vertex‐wise analysis was performed using the PETSurfer toolbox of Freesurfer.ResultThe pattern of tau deposition in symptomatic DS included typical AD areas (i.e., temporal and parietal lobe, precuneus; Fig1). Differences in [18F]‐PI2620 uptake along the AD continuum in DS were statistically significant in the three Braak staging ROIs only between asymptomatic DS and demented DS, although a trend was observed between controls and demented DS (Fig2). The vertex‐wise regression showed a relationship between local tau burden and global amyloid deposition in widespread areas, but especially in typical AD ones (Fig3; FWE‐corrected p<0.05).Conclusion[18F]PI‐2620 PET presented high affinity to tau aggregates in symptomatic DS subjects, and presented similar deposition as in sporadic AD. Tau PET deposition measured by [18F]PI‐2620 increased along the AD continuum in DS and was mainly present in subjects with high amyloid burden.
Genomic editing of APOE4/4 to APOE3/3 in iPSCs bearing African or European local ancestry surrounding APOE
Authors: Oron Oded , DeRosa Brooke A. , Rajabli Farid , Celis Katrina , Feliciano‐Astacio Briseida E. , Silva‐Vergara Concepcion , Beecham Gary W. , Adams Larry D. , Tejada Sergio J. , Mena Pedro R. , Whitehead Patrice , Hamilton‐Nelson Kara L. , Starks Takiyah D. , Byrd Goldie S. , Cuccaro Michael L. , Young Juan I. , Pericak‐Vance Margaret A. , Vance Jeffery M. , Dykxhoorn Derek M. 
Published: December 2023

AbstractBackgroundThe APOE4 genotype is the main contributor to the risk of developing Late Onset Alzheimer’s Disease (LOAD), while the APOE3 genotype has no effect on LOAD risk. Previously our group has shown that Local Ancestry (LA) surrounding APOE4 regulates APOE expression in adult individuals. As LOAD pathology has been shown to develop decades before the onset of symptoms, we sought to explore if LA has similar or different effect in mitotic cells, and whether the APOE3 genotype modulates the effect of the LA. To answer this question, we generated APOEε3/3 and APOEε4/4 isogenic induced Pluripotent Stem Cells (iPSCs) lines from individuals with either European LA or African LA.MethodPBMCs were derived from APOEε4/4 carrying individuals with either African or European APOE LA. To generate APOE isogenic lines, we formed a ribonucleoprotein (RNP) complex using a previously published APOE sgRNA (Lin et al. 2018) and performed nucleofection using the 4D‐Nucleofector system (Lonza). Homozygous APOEε3/3 edited and APOEε4/4 unedited isogenic clones were selected, and confirmed to lack unwanted off‐target editing. Isogenic clone pluripotency was confirmed by immunocytochemistry (SOX2, NANOG and OCT4a staining). APOE expression in the isogenic clones was tested by quantitative Real‐Time PCR and significance was calculated by Student’s T‐test.ResultIsogenic clones were similar in their pluripotency and growth characteristics. Preliminary APOE expression in the iPSC line carrying the African LA was higher (p = 0.0002) in each of the individual APOEε3/3 KI clones (n = 3) compared to each of the individual unedited APOEε4/4 clones (n = 2), showing consistency within each isogenic group. In contrast, the APOE expression in the iPSC line carrying the European LA was not significant in the APOEε3/3 KI clones (n = 2) compared to the parental line.ConclusionOur data suggests that differences in local ancestry has a direct effect on the expression of APOE isoforms in iPSCs. This finding supports previous reports in frontal cortex suggesting that the regulation of APOE expression differs depending on ancestry.