bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Israel Registry for Alzheimer's Prevention (IRAP) study of middle‐aged offspring of Alzheimer’s disease patients
Authors: Ravona‐Springer Ramit , Sharvit‐Ginon Inbal , Heymann Anthony , Beeri Michal Schnaider 
Published: December 2020

AbstractBackgroundParental family history of AD is a well‐established risk factor for late onset AD (LOAD). Since AD‐related neuropathology starts decades prior to dementia onset, studying middle‐aged asymptomatic offspring of LOAD patients provides an opportunity to assess the role of genetic, health related, lifestyle and environmental factors in the very earliest stages of the disease course.MethodThe Israel Registry for Alzheimer’s Prevention (IRAP) study follows a cohort of middle‐aged offspring of AD patients (FH+; n=409) and controls (FH‐, i.e. offspring of non‐demented parents; n=104). The study collects detailed cognitive, health‐related, genetic, lifestyle and brain imaging data. Follow‐up waves will be every 3 years. All participants are members of the Israeli HMO‐ Maccabi Health Services, so detailed medical information is available on them since 1998. Here we compare baseline socio‐demographic, lifestyle, health‐related and cognitive data of FH+ vs. FH‐ participants. Comparisons between groups were done using χ2 for categorical variables, ANCOVAs for continuous variables (laboratory and lifestyle) adjusting for age, sex and education, and MANCOVAs for cognitive scores done separately for tests of episodic memory, working memory, executive functions, and language.ResultParticipants characteristics by family history status are presented in Table 1. Mean subjects' age is 54.83 (SD=6.7), 16.47 (SD=3.06) years of education; 35.7% are men; 69% of FH+ have maternal AD. Compared to FH‐, FH+ were younger (p=0.007), more often men (p=0.003) and with higher rates of the Apo E4 allele (p=0.036). Groups did not differ in other laboratory, medical and lifestyle (exercise, alcohol consumption, smoking) variables, depression scores (CES‐D) or rates of subjective memory complaints. FH+ performed worse in episodic memory (F=2.224; p=0.025) and in executive functions (F=2.850; p=0.015) but not in working memory (F=1.172; p=0.322) and language (F=1.210; p=0.303) (Table 2). Additional adjustment for APOE‐4 resulted in loss of significance for episodic memory (F=1.830; p=0.070), while executive functions remained significant (F=2.462; p=0.032).ConclusionAsymptomatic middle‐aged offspring of AD patients perform worse on tests of episodic memory and executive functions consistent with a decades‐long prodromal course of disease. APOE4 mediates the association of FH with episodic memory but not with executive functions.
Cerebrospinal fluid proteomic profiles predict progression to dementia in prodromal AD
Authors: Tijms Betty M. , Del Campo Marta , Tomassen Jori , den Braber Anouk , Scheltens Philip , Teunissen Charlotte E. , Visser Pieter Jelle 
Published: December 2020

AbstractBackgroundIndividuals with mild cognitive impairment (MCI) and abnormal amyloid are at increased risk to develop dementia and are considered to have prodromal Alzheimer’s disease (AD). Still, the precise pathophysiological processes that lead to dementia remain unclear. We studied in prodromal AD whether alterations can be detected in cerebrospinal fluid (CSF) proteomics that are related to progression to dementia.MethodWe selected from the Amsterdam Dementia Cohort 44 individuals with prodromal AD (67±7 years old, 22(44%) female), who had CSF proteomic data measured with Olink multiplex panels. Of 1010 proteins available, 501 (49%) were detected in at least 10 individuals per group and considered for further analyses. To aid interpretation, protein concentrations were Z transformed according to a normal control group (from the EMIF preclinAD study: 56 individuals with normal cognition and normal CSF amyloid and tau (68±6 years old, 28(50%) female) measured within the same experiment. Within prodromal AD, associations of protein levels with progression to dementia were tested with Cox proportional Hazard models, adjusting for p‐tau levels, age and sex. ClueGO was used for biological pathway enrichment analyses.ResultFourteen (33%) individuals with prodromal AD developed dementia over 2.6±1.4 years. In total 49 of the 501 proteins were associated with progression to dementia: for 90% of proteins a standard deviation lower concentration was associated with a 2 to 9‐fold increased risk to develop dementia (Figure 1a). Figure 1b shows a progression curve for individuals labelled according to tertiles of a protein summary score combining these proteins, with individuals having low concentrations showing an 4‐fold increased risk to progress to dementia compared to individuals with high concentrations (p<.01). Proteins associated with progression showed enrichment for several biological pathways that clustered together into 6 groups and were associated with regulation of MAPK cascade, angiogenesis, leukocyte activation in immune response, extracellular matrix organisation and regulation of neuronal death (Figure 1c; all pfdr <.05).ConclusionNeurodevelopmental pathways, angiogenesis and the leukocyte activation in immune response are involved in early AD pathophysiology and related to subsequent progression to dementia. Furthermore, CSF proteomics may have potential as a stratification tool to select fast decliners within prodromal AD.
Validation and replication of a prognostic machine learning model for enrichment of cognitive decliners in clinical trials
Authors: Dansereau Christian , Laurent César , Tam Angela 
Published: December 2020

AbstractBackgroundIdentifying individuals who will experience cognitive decline is paramount to evaluating novel treatments in Alzheimer’s clinical trials. We propose to use highly specific neuroimaging and genetic signatures that are indicative of the risk of cognitive decline in individuals with mild Alzheimer’s disease and mild cognitive impairment.MethodBaseline measurements of gray matter volumes, from structural magnetic resonance imaging, APOE4 status, age and sex were provided to a machine learning prognostic enrichment solution Cog‐Foresight from Perceiv Research Inc. Canada to identify signatures of individuals at risk of cognitive decline up to two years of follow‐up. The resulting three cohorts of individuals were: (a) low‐risk, (b) moderate‐risk, (c) high‐risk of decline according to the enrichment tool. ADAS‐cog11, CDR‐SB and MMSE were used as clinical endpoints to evaluate the trajectory of each cohort. The prognostic tool was evaluated on three independent datasets: ADNI1 (n=345), ADNI2 (n=238) [1], and the placebo arm of an 18‐month Phase 3 study in mild AD (n=110).ResultFrom the 693 individuals selected from the three datasets, 40% were deemed low‐risk and 23% were deemed high‐risk. In ADNI1, the mean rate of change at 18 months from baseline for the CDR‐SB for the low‐, moderate‐, and high‐risk groups were 0.51 points, 1.08 points, and 1.83 points, respectively. In ADNI2, the mean rate of change at 18 months from baseline for the CDR‐SB for the low‐, moderate‐, and high‐risk groups were 0.09 points, 0.57 points, and 1.79 points, respectively. In the Phase 3 study, the mean rate of change at 18 months for the CDR‐SB for the low‐, moderate‐, and high‐risk groups were 0.5 points, 0.88 points, and 2.04 points, respectively. Similar trajectories and conclusions were found for all other endpoints.ConclusionThe use of multimodal biomarkers with a machine learning‐based targeted selection was successful in identifying a sub‐cohort that will, on average, have a higher rate of decline than the rest. The proposed identification of decliners has the potential of reducing trial costs by minimizing the enrolment of cognitively stable individuals into trials. Reference: (1) The ADNI1 and ADNI2 datasets were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu).
Between‐country harmonization and differences of the Lifetime of Experiences Questionnaire (LEQ) for lifespan complex mental activity assessment
Authors: Ourry Valentin , Marchant Natalie L , Schild Ann‐Katrin , Wirth Miranka , Coll‐Padros Nina , Reyrolle Leslie , Bachelet Romain , Whitfield Tim , Demnitz‐King Harriet , Boton Maëlle , Lebahar Julie , Gonneaud Julie , Molinuevo Jose Luis , Rauchs Géraldine , Vivien Denis , Sayette Vincent De , Valenzuela Michael , Chetelat Gael , Arenaza‐Urquijo Eider M. ,   Medit‐Ageing Research Group
Published: December 2020

AbstractBackgroundThe Lifetime of Experiences questionnaire (LEQ, Valenzuela and Sachdev, 2007) is an instrument that comprehensively assesses mental activity (education/occupation and leisure activities) across the lifespan (13‐30, 30‐65, 65‐present). The LEQ has been associated with brain health outcomes and cognitive decline. Challenges for the use of this questionnaire across countries include the different education systems and occupation classifications. The objectives of this study were to (1) harmonize the LEQ across Spain, United Kingdom (UK), France and Germany, (2) assess its correlation with a similar tool and (3) assess between‐country differences.MethodThe LEQ was administered to 359 cognitively unimpaired older adults (age: 71.2 ± 6 years, education: 13.2 ± 3.5 years) from IMAP+ and Medit‐Ageing European projects. The original scale was translated from English to Spanish, French and German by a professional translation service and iteratively edited by native speakers. Education systems and classification of occupations were harmonized considering between‐country differences and in line with international guidelines. Scoring guidelines were adapted to allow between‐country comparison. We performed Pearson correlations with a similar instrument, the Cognitive Activities Questionnaire (CAQ, Wilson et al., 2003). Between‐country differences were assessed using ANOVA models.ResultThere were no between‐country differences in participant’s age and education (p>0.1). Between and within countries, the total LEQ score showed moderate to strong associations with the total CAQ score (full sample: r=0.48, Spain: r=0.74, UK: r=0.56, France: r=0.46, all p<0.001; Germany: r=0.41, p<0.05) (Figure 1). Correlation coefficients between the CAQ and LEQ were stronger within (all r>0.35) than between (all r≤0.35) periods. We observed between‐countries differences in lifespan mental activities (p=0.019, Spain > France and Germany > France), notably, during young adulthood (p=0.01, Germany > France) and late life (p=0.01, Spain > UK, Spain > France) (Figure 2). These differences were explained by leisure activities engagement rather than by differences in education and occupation (p<0.001, Young adulthood and Midlife: Spain > UK & France, Germany > France; Late life: Spain > UK & France & Germany) (Figure 3).ConclusionThe harmonized LEQ allowed comparison of complex mental activities ‐ including education and occupation ‐ across countries and was related to another questionnaire measuring mental activity across the lifespan.
Sex and sex hormones largely explain associations between glucose levels and brain atrophy in AD‐sensitive regions
Authors: Pappas Colleen , Wang Qian , Klinedinst Brandon S. , Le Scott T. , Pollpeter Amy , Larsen Brittany , Willette Auriel A. 
Published: December 2020

AbstractBackgroundHigh glucose levels are related to worse cognitive performance and brain health in AD‐sensitive regions. Sex hormones are thought to be a protective factor against hyperglycemia and many of its sequelae, where menopause and andropause in mid‐life lead to pronounced decreases in sex hormone secretion. It is unknown if sex and sex hormones modulate relationships between high glucose and regional brain atrophy or cognitive performance.MethodThe study consisted of 15,506 participants from the UK Biobank with complete brain volume, blood glucose measures, and demographic data. Multiple linear regression models tested relationships between fasting serum glucose and key brain regions of interest. Covariates included age, sex, intracranial volume, white matter hyperintensity load, and education in lieu of intracranial volume for cognition outcomes. To examine sex differences, moderation analyses were conducted. The sample was also separated by sex to test sex hormone by blood glucose interactions for the brain volume and fluid intelligence measures.ResultFor the overall sample, higher glucose or glycated hemoglobin (Hba1c) levels were associated with less total grey matter and regional grey matter in amygdala and parahippocampus. Higher Hba1c levels also predicted poorer fluid intelligence performance. Sex interactions indicated that higher HbA1c levels were related to relatively more brain atrophy among men in the hippocampus and amygdala. Due to these observations, testosterone and oestradiol levels were tested as moderators in a subset of participants with available data (n=13,858). Hormone levels only among women impacted blood glucose and brain volume relationships. Higher oestradiol and testosterone levels led to more atrophy in hippocampus and amygdala per unit increase in glucose levels.ConclusionIn general, higher glucose levels were associated with poorer neural and cognitive outcomes. Men showed this relationship more strongly, but not due to sex hormone levels. Comparatively, sex hormones in women largely accounted for detrimental glucose associations with AD‐sensitive brain regions. Future research should examine other mechanisms that may explain sex differences observed with glucoregulatory function and brain health.
Plasma levels of an N‐terminal tau fragment are highly associated with future cognitive decline and neurodegeneration in clinically normal elderly
Authors: Chhatwal Jasmeer P. , Schultz Aaron P. , Dang Yifan , Ostaszewski Beth , Liu Lei , Yang Hyun‐Sik , Johnson Keith A. , Sperling Reisa A. , Selkoe Dennis J 
Published: December 2020

AbstractBackgroundAdvances in high‐sensitivity biofluid assays have accelerated the development of novel tools to study Alzheimer's disease (AD) pathobiology. Recent work demonstrates levels of an N‐terminal fragment of tau (NT1), measured in cerebrospinal fluid or plasma, can differentiate clinically‐normal people from those with clinically‐evident AD with high sensitivity and specificity. However, the potential of plasma NT1 to capture the earliest, preclinical signs of AD remains unclear. Accordingly, we examined the potential for plasma NT1 to predict prospective cognitive decline and neurodegeneration in a large, longitudinal cohort of clinically‐unimpaired elderly at‐risk of future cognitive decline.MethodBaseline plasma samples from participants in the Harvard Aging Brain Study (n=236) were assayed for NT1 and neurofilament light (NfL) using single‐molecule array (Quanterix Simoa). Baseline NT1 and NfL were assessed alone or interactively with β‐amyloid (11C‐Pittsburgh C‐mpound‐B PET; PiB‐PET) as predictors of longitudinal cognitive decline (Preclinical Alzheimer's Cognitive Composite; PACC) and neurodegeneration (vMRI) using linear mixed effects models. In participants with available longitudinal 18F‐Flortaucipir PET (FTP‐PET), we assessed plasma NT1 as a potential predictor of tau neurofibrillary tangle accumulation.ResultGreater plasma NT1 at baseline was highly predictive of greater cognitive decline during longitudinal follow‐up (median 5.04+/‐0.99 yr; p<0.0001; Figure 1). This effect was synergistic with baseline β‐amyloid burden (p<0.005). Greater NT1 was also associated with greater decreases in cortical gray matter and hippocampal volumes. In the subset of participants with longitudinal tau PET, plasma NT1 levels at the time of initial tau PET were predictive of increases in temporal tau PET signal over time in people with high b‐amyloid burden. Baseline plasma NT1 levels were strongly associated with neurofilament light chain (NfL) levels, but NfL was a much weaker predictor of future cognitive decline in this preclinical cohort.ConclusionThese results suggest plasma NT1 may be a novel, non‐invasive, and inexpensive biomarker that captures risk of imminent cognitive decline and neurodegeneration even in unimpaired, at‐risk elderly. The pattern of results further suggests NT1 may be a powerful compliment to existing biomarkers of β‐amyloid burden, as we observed synergistic associations between NT1 and β‐amyloid PET in predicting neurodegeneration, cognitive decline, and tau accumulation.
Human brain and serum advanced glycation end products are highly correlated: Preliminary results of their role in Alzheimer’s disease and type 2 diabetes
Authors: Uribarri Jaime , Buchman Aron S , Cai Weijing , Haroutunian Vahram , Beeri Michal Schnaider 
Published: December 2020

AbstractBackgroundSerum levels of advanced glycation end products (AGEs), a large group of pro‐oxidant and pro‐inflammatory compounds, particularly carboxymethyl lysine (CML) and methylglyoxal (MG), are generated endogenously and by dietary consumption2. Accumulating evidence suggests that modifying dietary AGEs consumption might affect the accumulation of AD pathology and dementia especially those with type 2 diabetes (T2D). However, there is a paucity of human data about the relationship of serum and brain levels of AGEs in older adults.MethodAGE levels were measured in serum and tissue from superior temporal gyrus of four groups of decedents: T2D+AD (N=6); T2D/no AD (N=10); no T2D+AD (N=10), and no T2D/no AD (N=10). T2D was defined by medical records (diagnosis of T2D or use of T2D medications). CERAD criteria classified pathologic diagnosis of AD. Participants with stroke were excluded. Diagnoses of hypertension and myocardial infarction were defined by ICD9. Frozen brain samples were thawed and AGE protein content was determined by competitive ELISA for MG‐H1 (3D11 mab) and CML (4G9 mab).ResultAnalyses of variance demonstrated that adults with AD were older but postmortem interval and sex were similar in all four groups (see Table). The groups significantly differed in levels of serum MG, brain MG, and serum CML such that consistently the T2D+AD group had the highest levels of AGEs while the no T2D/no AD group had the lowest. There were strong correlations between serum and brain CML levels (r=0.64; p<0.0001) and MG levels (r=0.59; p<0.0001)‐See Figure; higher levels in serum were associated with higher levels in the brain. Adjusting for each of the demographic or cardiovascular variables did not alter the results.ConclusionThis study demonstrates strong and significant relationships between serum and brain AGE levels; the highest brain levels of AGEs were found in participants who had both T2D and AD. We have previously shown similar findings in mice, but we believe this is the first demonstration of such associations in humans. This was a small cross‐sectional study and the findings need to be replicated in a larger clinico‐pathological longitudinal study, which is currently ongoing, and will provide new data at AAIC2020.
Incidence of subjective cognitive decline is associated with amyloid‐β pathology, whereas stability relates to neurodegeneration
Authors: Sánchez‐Benavides Gonzalo , Grau‐Rivera Oriol , Suárez‐Calvet Marc , Milà‐Alomà Marta , Niñerola‐Baizán Aida , Perissinotti Andrés , Salvadó Gemma , Arenaza‐Urquijo Eider M. , Gispert Juan Domingo , Vilor‐Tejedor Natalia , Sala‐Vila Aleix , Crous‐Bou Marta , González‐de‐Echávarri José Maria , Minguillón Carolina , Fauria Karine , Cacciaglia Raffaele , Operto Greg , Falcon Carles , Kollmorgen Gwendlyn , Zetterberg Henrik , Blennow Kaj , Molinuevo Jose Luis ,   ALFA Study
Published: December 2020

AbstractBackgroundSubjective Cognitive Decline (SCD) is a risk factor for cognitive decline and increases the likelihood of abnormal Alzheimer’s disease (AD) biomarkers. A set of SCD features (SCDplus) has been proposed to be more strongly related with AD pathology, like onset within 5 years. Limited evidence suggest that there is an association between recent SCD onset and amyloid‐β (Aβ) levels but longitudinal studies exploring this association are lacking. Our objective was to explore the association between incidence and stability of SCD and biomarkers of AD pathology, synaptic dysfunction and neurodegeneration.MethodWe analyzed clinical, neuroimaging and cerebrospinal fluid (CSF)‐biomarkers data from 261 cognitively unimpaired individuals from the ALFA+ study [mean age 57(5) at baseline]. SCD status was recorded at baseline and follow‐up [mean interval 48.5(8.6) months, 80% before 60 months] using the SCD‐Q question: Do you perceive memory or cognitive difficulties? Individuals were classified as Stable‐SCD [SCD at both visits (n=28)], Incident‐SCD [SCD only at follow‐up (n=44)], Unstable‐SCD [SCD only at baseline (n=21)], and non‐SCD [no SCD at any visit (n=168)]. All remained cognitively unimpaired at follow‐up. We defined amyloid status by visual reads (Aβ+/Aβ‐) from [18F]flutemetamol PET scans. Aβ40, Aβ42, p‐tau, t‐tau, neurogranin and Neurofilament Light (NfL) were measured with Roche NeuroToolKit and Elecsys® immunoassays (Roche Diagnostics). Logistic regression models were used to predict Aβ status and ANCOVA models to explore differences in biomarkers, adjusting for age, sex and interval between visits.ResultThe proportion of Aβ+ individuals was higher in Incident‐SCD as compared to non‐SCD (OR=2.5, p=0.04, Table 1). Further, Incident‐SCD group displayed lower Aβ42/Aβ40 than non‐SCD (p=0.02, partial Eta2=0.02). While Stable‐SCD did not show differences in amyloid measures as compared to controls, NfL was significantly increased (p<0.0001, p‐Eta2=0.08) and t‐tau approached significance (p=0.08).ConclusionRecent SCD onset was associated with amyloid‐β pathology, while stable SCD, even without clinical progression, was associated to biomarkers of neurodegeneration but not to amyloid pathology. These results support the usefulness of the onset in the last 5 years as SCDplus feature to detect amyloid pathology, while also highlights the role of neurodegeneration in SCD maintenance.