bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effect of age on tau burden is dependent on amyloid status in late‐onset Alzheimer's disease
Authors: Ottoy Julie , Kang Min Su , Savard Melissa , Mathotaarachchi Sulantha , Pascoal Tharick A. , Chamoun Mira , Soucy Jean‐Paul , Gauthier Serge , Rosa‐Neto Pedro 
Published: December 2020

AbstractBackgroundGrowing evidence suggests that middle‐aged subjects with early‐onset AD show higher tau burden and more rapid tau accumulation compared to elderly. Here, we aim to investigate the effects of age, the greatest risk factor in AD, on amyloid, tau, and neuroinflammation in late‐onset AD. We hypothesized the independent effect of age on amyloid and neuroinflammation. However, the effect of age on tau would depend on amyloid load in AD.MethodA total of 106 participants (66 A‐T‐, age 20‐86y; 40 A+T‐/A+T+, age 65‐84y) from the TRIAD cohort underwent static 40‐60min 18F‐AZD4694, 90‐110min 18F‐MK620, and 60‐90min 11C‐PBR28 SUVR, as well as MOCA and CDR‐SOB cognitive testing. All images were normalized to the ADNI template, and used cerebellar gray matter as the reference region. The effects of age on amyloid, tau, or neuroinflammation, as well as the interactive effect between age and AT status based on linear regression models. Last, the age‐dependent effect of amyloid, tau, or neuroinflammation on cognition is investigated. All models were corrected for sex, APOE, education, and remaining PET variables.ResultWe showed a positive main effect of age on amyloid (p<0.001) or neuroinflammation (p=0.05) while no interactive effect between age and AT status was observed. However, a significant interaction between age and AT status on tau in Braakstage1‐2 (p=0.01), Braakstage3‐4 (p=0.001), and Braakstage5‐6 (p=0.002) were observed (Figure1). In relation to cognition, younger subjects with higher tau load performed worse on cognitive testing as shown by a significant negative interaction between age and tau on MOCA. In contrast, age and amyloid showed a positive interactive effect on cognition.ConclusionOur study demonstrated that the age and amyloid or neuroinflammation have a positive association irrespective of the disease status. However, the effect of age on tau deposition depends on the amyloid load such that the presence of pathologic Ab leads to greater tau burden at younger age and worse cognition in late‐onset AD. This supports the framework where tau burden depends on amyloid load following the Ab cascade hypothesis.
Prevalence of subjective cognitive decline higher among transgender and gender nonbinary adults in the U.S., 2016‐2018
Authors: Lambrou Nickolas H , Gleason Carey E , Cicero Ethan , Flatt Jason D 
Published: December 2020

AbstractBackgroundSubjective cognitive decline (SCD), or self‐reported cognitive problems may represent an early sign of Alzheimer’s disease. Little is known about SCD prevalence among gender minorities (GM), or those who do not identify as cisgender (e.g., transgender and gender nonbinary people). The term cisgender refers to individuals whose gender identity is aligned with the sex they were assigned at birth.MethodsWe examined data from 11 U.S. states administering both optional SCD and GM modules of the Behavioral Risk Factor Surveillance System (BRFSS) between 2016‐2018. The annual BRFSS survey used random digit dialing via cellphones and landlines to assess the health and health behaviors of U.S. adults. Of those aged ≥45 years (N=59,690), 408 respondents identified as a GM. SCD represented reports of confusion or memory loss happening more often or worsening during the previous 12 months. Multivariable logistic regression was used to examine associations between GM identity and SCD adjusting for demographic characteristics.ResultsGM adults were more likely to report SCD (15%) compared to cisgender adults (10%; p < 0.001). Among GMs, 14% of transgender adults and nearly 17% of gender nonbinary adults reported SCD. After accounting for demographic characteristics, GMs were 37% more likely to report SCD compared to cisgender adults (Adjusted Odds Ratio = 1.37; 95% Confidence Interval = 1.04, 1.80). GMs with SCD were significantly more likely to report giving up day‐to‐day activities (50% vs. 34%), needing assistance with day‐to‐day activities (50% vs. 30%), and being unable to work or participate in social activities (42% vs. 31%) compared to cisgender adults. In addition, GMs with SCD were significantly more likely to report difficulties in obtaining caregiving or help with day‐to‐day activities (22% vs. 13%) compared to cisgender adults.ConclusionsThis is among the first population‐based studies to explore SCD with transgender and gender nonbinary adults. Given the higher rates of SCD in GM adults compared to their cisgender counterparts; additional research specifically focused on GM identities, psychosocial factors, and cognitive health is recommended. Efforts aimed at screening for Alzheimer’s and developing tailored interventions and care services should be considered.
Clostridium shows a higher abundance in less neurovascular and neurodegenerative changes: A microbiome‐wide association study
Authors: Karamujić‐Čomić Hata , Ahmad Shahzad , Radjabzadeh Djawad , Bonnechere Bruno , Kaddurah‐Daouk Rima F. , Kraaij Robert , Ikram M. Arfan , Amin Najaf , van Duijn Cornelia M. 
Published: December 2020

AbstractBackgroundThere is an important interplay between the gut microbiome and brain, commonly known as the gut‐brain‐axis. Several studies addressed the role of the microbiome in neurologic diseases. Here, we studied the role of microbiota in cognitive function, neurovascular changes, and neurodegenerative changes in the general population.MethodIn the population‐based Rotterdam Study, we studied the association between microbial taxa and cognitive function in 1,184 participants and the association between microbial taxa and neurovascular and neurodegenerative traits, measured on brain magnetic resonance imaging, in 1,241 participants. Gut microbiota were profiled using 16 s rRNA gene sequencing. We used linear regression analysis to study these associations and adjusted for major confounders, i.e., age, sex, technical covariates, medication use, alcohol, smoking, body mass index, and hypertension.ResultWe found that the genus Clostridium sensu stricto 1 showed a higher abundance in participants with better cognitive function (beta(β)(standard error(SE)) 0.023(0.01), p = 3.22 × 10−2), larger global brain volume (β(SE) 0.0019(0.0006), p = 1.83 × 10−3), less white matter hyperintensities (β(SE) ‐0.024(0.007), p = 5.38 × 10−4), and smaller lateral ventricular volume (β(SE) ‐0.013(0.005), p = 1.81 × 10−2). The family Clostridiaceae 1 also showed a higher abundance in these traits, with the same direction of effect and very similar effect estimates. The class Clostridia, order Clostridiales, family Christensenellaceae, and genus Christensenellaceae R7 group showed a higher abundance in better cognition. Of note is that the agreement of our findings with those of studies of Alzheimer’s disease is high.Conclusion
Clostridium shows a higher abundance in less neurovascular changes, in less neurodegenerative changes, and in better cognition. We find that different microbiota are associated to neurovascular and neurodegenerative pathology.
Cerebral microbleeds on 7 Tesla MRI in preclinical Alzheimer’s disease: The Medea‐7T study
Authors: Zwartbol Maarten H.T. , Ghaznawi Rashid , Blom Kim , Kuijf Hugo J. , Witkamp Theo , Hendrikse Jeroen , Geerlings Mirjam I. 
Published: December 2020

AbstractBackgroundSubjective cognitive decline is increasingly being viewed as an early cognitive marker of preclinical Alzheimer’s disease (AD). Studies have recommended including AD biomarkers to increase the specificity of subjective cognitive decline, because of its etiological heterogeneity. We studied the prevalence and burden of cerebral microbleeds in persons with normal cognition, subjective memory impairment, cognitive impairment, and a clinical diagnosis mild cognitive impairment (MCI) or AD.MethodsData are from 386 participants (68±9 years, 30% women) included in the Medea‐7T cohort, a diverse cohort of persons with normal cognition, patients with a history of vascular disease, and memory clinic patients. A 7T brain MRI was performed in all participants. Four cognitive stages were defined: 1) normal cognition (n=196); 2) subjective memory impairment (n=78); 3) cognitive impairment (defined as <1.5 SD below age, sex, and education adjusted Z‐scores in any cognitive domain within the study sample) (n=57); 4) MCI/AD diagnosed according to international criteria (n=36). CMBs were visually rated on 7T MRI according to established criteria. Age‐ and sex‐adjusted log‐binomial regression was performed to examine the association between the cognitive stages and presence of CMBs (yes vs. no).ResultsOverall microbleed prevalence was 61%, with estimates per cognitive stage: normal cognitive function 60%, SCD 73%, cognitive impairment 55%, MCI and AD 47% (Figure 1). Age‐ and sex‐adjusted log‐binomial regression showed that—compared with the normal group—differences in microbleed prevalence were not statistically significant. Nonetheless, SCD showed an increased risk of CMBs (RR=1.18; 95% CI, 0.99‐1.41; p=0.06), whereas MCI/AD showed a decreased risk (RR=0.68; 95% CI, 0.45‐1.02; p=0.06), both approaching statistical significance.ConclusionIn this study, cerebral microbleeds on 7T MRI were highly prevalent in older persons with normal cognition, subjective memory impairment, and MCI/AD. Differences observed between groups may reflect differences in underlying dominant etiology.
Transcutaneous vagus nerve stimulation increases locus coeruleus function and memory performance in older individuals
Authors: Jacobs Heidi I.L. , Priovoulos Nikos , Riphagen Joost M , Poser Benedikt A. , Napadow Vitaly , Uludag Kamil , Sclocco Roberta , Ivanov Dimo , Verhey Frans R.J. 
Published: December 2020

AbstractBackgroundAnimal studies reported that vagus nerve stimulation increases noradrenalin release in target areas of the locus coeruleus (LC). Furthermore, after stimulation, animals exhibited improved retention performance. Evidence for memory improvement using transcutaneous vagus nerve stimulation (tVNS), a non‐invasive alternative, is scarce. Given that the LC is affected by tau pathology early in life, we aimed to examine 1) whether tVNS can improve memory performance in older individuals and 2) whether tVNS targets the LC in older individuals.MethodTwo separate cross‐over single‐blind randomized studies were performed. In study one, 30 healthy older individuals (Mean age:60.57 years, 50% male) underwent tVNS and Sham during face‐name learning. Bias‐corrected scores across the experimental conditions were analyzed using a repeated measures ANOVA. In study two, 16 older individuals (median age:71.15 years, 56% male) underwent respiratory‐gated tVNS and Sham during 2 sessions of 7T fMRI involving a face‐name learning task. The bias‐corrected behavioral scores were compared using LME. The BOLD data were motion, distortion and ICA‐FIX denoised and we fitted a GLM for stimulation on> stimulation off within session, within participant (tVNS>Sham). The group‐average tVNS effect was estimated. For the LC, we performed analyses within a small volume search space at p<0.05. For the rest of the brain, cluster‐wise correction was applied.ResultBoth studies demonstrated higher scores on the memory task during tVNS as compared to the sham condition (tVNS versus Sham, p=0.037, Cohen’s d=0.35) but effect sizes were greater for the respiratory gated tVNS experiment (tVNS versus Sham: p=0.04, Cohen’s d=0.55). The BOLD map showed bilateral activation of the caudal LC during tVNS compared to Sham (peak z‐value=3.44). Positive clusters (tVNS>Sham) were also observed in several regions, including the prefrontal and temporal cortex, insula, thalamus, hippocampus and putamen. Negative clusters were observed in the basolateral amygdala and cornu ammonis 1.ConclusionIn older individuals, alterations in the functioning of the locus coeruleus network may mediate the positive effects of tVNS on memory performance in older individuals. Our previous work demonstrated that noradrenalin‐dysregulation was associated with greater tau. Future work will explore the efficacy and disease‐modifying potential of tVNS in cognitively impaired individuals.
Trajectories of decline in cognitively complex everyday activities across the Alzheimer’s disease continuum
Authors: Dubbelman Mark A. , Jutten Roos J. , Farias Sarah Tomaszewski , Amariglio Rebecca , Buckley Rachel F. , Visser Pieter Jelle , Rentz Dorene M. , Johnson Keith A. , Properzi Michael J. , Schultz Aaron P. , Donovan Nancy , Gatchel Jennifer R. , Teunissen Charlotte E. , Van Berckel Bart N.M. , van Der Flier Wiesje , Sperling Reisa A. , Papp Kathryn V. , Scheltens Philip , Marshall Gad A. , Sikkes Sietske A.M. 
Published: December 2020

AbstractBackgroundAssessment of daily functioning may be used to capture clinically meaningful decline in Alzheimer’s disease (AD). In this multi‐center study, we aimed to investigate ‘instrumental activities of daily living’ (IADL) trajectories along the AD disease continuum from no symptoms to overt dementia, as defined in the 2018 National Institute on Aging – Alzheimer’s Association research framework (Jack et al., 2018).MethodA total of 1,557 individuals with longitudinal IADL data (72.1±8 years; 41% female; mean follow‐up 2.4±2 years) were selected from memory clinics and community‐based cohorts (Harvard Aging Brain Study, ADNI, National Alzheimer’s Coordinating Center, Amsterdam Dementia Cohort and EMIF‐AD PreclinAD and 90+). Amyloid positivity was determined at baseline using positron emission tomography or cerebrospinal fluid. Amyloid positive individuals (n=980) were classified into four NIA‐AA clinical stages based on cut‐offs on measures of subjective cognitive decline and cognitive functioning (Table 1, independent of IADL measures). Amyloid negative individuals without memory impairment or complaints (n=577) served as a control group. Everyday functioning was assessed using study‐partner‐based questionnaires as available in the different cohorts: the Everyday Cognition, Functional Activities Questionnaire and Amsterdam IADL Questionnaire. To allow comparison between the instruments, scores were standardized into Z‐scores using baseline means and standard deviations in the control group. Changes over time were analyzed using linear mixed models with random intercepts and slopes.ResultBaseline characteristics and distribution of individuals across stages can be found in Table 2. Baseline Z‐scores did not differ between amyloid negatives and stage 1; baseline Z‐scores were significantly lower in each following stage. A decline in function was found across the AD continuum, which accelerated along the clinical stages (Figure 1 and Table 3). From stage 2 onwards, IADL decline was faster compared to controls (β=‐0.085, 95% confidence interval = [‐0.116, ‐0.053], adjusted for age, sex, and education; Table 3).ConclusionOur results suggest that AD‐related functional decline accelerates along the AD continuum, as shown by steeper rates of decline in each successive stage in people with amyloid pathology. These findings were robust across different cohorts, and can be used to inform participant selection and trial design for AD clinical trials.
Mild behavioral impairment is associated with atrophy in Alzheimer's disease‐related regions in non‐demented older adults
Authors: Matuskova Veronika , Ismail Zahinoor , Nikolai Tomas , Markova Hana , Cechova Katerina , Laczó Jan , Nedelska Zuzana , Lerch Ondrej , Hort Jakub , Vyhnalek Martin 
Published: December 2020

AbstractBackgroundMild behavioral impairment (MBI) is a recently developed diagnostic concept describing late‐onset persistent neuropsychiatric symptoms (NPS) in older adults without dementia. Few studies to date investigated associations of MBI with structural brain changes. Our aim was to explore structural correlates of NPS in a non‐demented memory clinic sample using the Mild Behavioral Impairment Checklist (MBI‐C) that has been developed to measure MBI.Method116 non‐demented older adults from the Czech Brain Aging Study presenting with subjective cognitive concerns underwent a neurological, comprehensive neuropsychological examination and brain MRI and were classified as subjective cognitive decline (n=37, MMSE=29.30±0.88) or mild cognitive impairment (n=79, MMSE=26.82±2.51). The Czech version of MBI‐C was administered to participants´ informants. 1.5T MRI with T1‐weighted 3‐dimensional images and FreeSurfer 5.3. algorithm was used to measure a priori selected brain regions: thicknesses of the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), posterior cingulate cortex (PCC) and entorhinal cortex (ERC) and hippocampal volume (HV) adjusted for total intracranial volume. The volumetric measures were averaged between the two hemispheres. The associations of the MBI‐C total score and five domain scores with the aforementioned regions were assessed within the whole sample using covariate‐adjusted Spearman Rank correlations.ResultSignificant associations of MBI‐C total score were found with HV (rho=‐.225, p=.016), ERC (rho=‐.284, p=.002) and OFC (rho=‐.214, p=.023) while controlling for sex, age and education. Both latter associations remained significant after controlling also for MMSE. We found associations of HV with both motivation (rho=‐.248, p=.008) and impulse dyscontrol scores (rho=‐.240, p=.011), ERC with impulse dyscontrol (rho=‐.368, p<.001) and OFC with motivation score (rho=‐.201, p=.033). No other associations were observed.ConclusionNPS (particularly in motivation and impulse dyscontrol domains) detected by the MBI‐C in non‐demented older adults are associated with structural changes in typical Alzheimer´s disease‐related regions. This provides supportive evidence for MBI as an early manifestation of AD.
Baseline characteristics from TANGO: Phase 2 study to evaluate gosuranemab (BIIB092) in patients with early Alzheimer’s disease
Authors: Ratti Elena , Kong Jessica , O'Gorman John , Rajagovindan Raj , Racine Annie , Graham Danielle , Schrempp Daniela Ramirez , Viollet Louis , Jones Stephanie , Mirabile Tracy , Walsh Dominic M. , von Rosenstiel Philipp , Shulman Melanie 
Published: December 2020

AbstractBackgroundGosuranemab is a humanized monoclonal antibody binding tau at the N‐terminal domain. The TANGO study is a randomized, placebo‐controlled, global Phase 2 Study evaluating safety and clinical efficacy of gosuranemab in patients diagnosed with mild cognitive impairment (MCI) due to AD or mild AD dementia. We describe baseline characteristics from the TANGO study, the first evaluation of gosuranemab in AD.MethodRandomized, double‐blind, placebo‐controlled, parallel‐group Phase 2 study (TANGO) enrolled globally over 600 individuals aged 50‐80 years, diagnosed with MCI due to AD or mild AD, Clinical Dementia Rating (CDR) global score 0.5‐1, CDR Memory Box score of ≥0.5, Mini‐Mental State Examination (MMSE) score 22‐30, objective evidence of cognitive impairment at Screening and elevated brain amyloid as assessed by PET or cerebrospinal fluid (CSF) levels. Participants were randomized 1:1:2:2 to monthly intravenous low, medium, high dose of gosuranemab or placebo during the 76‐week treatment period. After completion of the placebo‐controlled period, patients may enter a long‐term extension during which all patients receive gosuranemab. The primary endpoints included incidences of adverse events, serious adverse events, abnormalities in safety assessments. The secondary endpoints included change from baseline in CDR‐Sum of Boxes score and incidence of anti‐gosuranemab antibodies in serum. Key exploratory endpoints included change from baseline in MMSE, AD Cooperative Study‐Activities of Daily Living, Functional Activities Questionnaire, AD Assessment Scale‐Cognitive Subscale, tau levels in CSF and/or in brain measured by 18F‐MK6240 PET and pharmacokinetic parameters.ResultTANGO is now fully enrolled and ongoing; over 600 patients were randomized and have received ≥1 dose of study medication. Approximately half of the patients were enrolled in either the CSF or tau PET sub‐studies. Approximately half of the patients are women (50.5%). The percentage of patients diagnosed with Mild AD at baseline is 53%. MMSE mean (standard deviation [SD]) score at baseline was 25 (2.3).ConclusionTANGO will assess the safety profile, tolerability and clinical efficacy of gosuranemab in individuals who, per baseline characteristics, are representative of patients with early AD. Study Support: funded by Biogen.
Spatial navigation and verbal memory are influenced by the combined effects of APOE and BDNF Val66Met polymorphisms in mild cognitive impairment
Authors: Laczó Jan , Cechova Katerina , Parizkova Martina , Matoska Vaclav , Kaplan Vojtech , Matuskova Veronika , Markova Hana , Vyhnalek Martin , Hort Jakub 
Published: December 2020

AbstractBackgroundThe apolipoprotein E (APOE) ɛ4 allele is associated with an increased risk of Alzheimer’s disease (AD), episodic memory deficits and less accurate spatial navigation in non‐demented older adults. The brain‐derived neurotrophic factor (BDNF) Val66Met polymorphism is also related to the increased risk of AD and more pronounced memory impairment but its role in APOE ɛ4‐related spatial navigation deficits has not been established. Our aim was to examine the influence of combination of APOE and BDNF Val66Met polymorphisms on spatial navigation and other cognitive functions in individuals with amnestic mild cognitive impairment (aMCI).MethodIn total, 116 older adults with aMCI from the Czech Brain Aging Study were stratified based on APOE and BDNF Val66Met polymorphisms into four groups: ɛ4–/BDNF
Val/Val (n = 29), ɛ4–/BDNF
Met (n = 11), ɛ4+/BDNF
Val/Val (n = 52), and ɛ4+/BDNF
Met (n = 24). All participants underwent comprehensive neuropsychological examination, brain MRI and spatial navigation testing of egocentric (body‐centred), allocentric (world‐centred), and allocentric delayed navigation in a real‐space human analogue of the Morris water maze.ResultThe ɛ4+/BDNF
Met group although similar to other groups in age, gender, education, depressive symptoms and global cognitive function had less accurate egocentric navigation performance (ps ≤ .045). The differences in allocentric and allocentric delayed navigation performance were not significant (ps ≥ .651). The ɛ4+/BDNFMet group had lower verbal memory performance than the ɛ4–/BDNF
Val/Val group (p = .007) and similar performance to the ɛ4–/BDNF
Met (p = .071) and ɛ4+/BDNF
Val/Val (p = .240) groups. There were no between‐group differences in other cognitive domains including attention and working memory, nonverbal memory, executive function, language and visuospatial function (ps ≥ .268).ConclusionThe aMCI carriers with the most risky combination of APOE ɛ4 and BDNF
Met polymorphisms had more pronounced egocentric spatial navigation impairment than the other polymorphism groups and more pronounced memory deficits than the carriers with the least risky combination of APOE ɛ3 and BDNF
Val/Val polymorphisms. These findings indicate that aMCI individuals with two risky gene polymorphisms are particularly susceptible to hippocampus‐dependent episodic memory deficits and even more to non‐hippocampus‐dependent egocentric spatial navigation impairment that may reflect more advanced underlying pathological changes.