bluuebunny/crossref_metadata_2025_split huggingface dataset:
A digital biomarker for remote self‐assessment of Alzheimer’s Diseases: development and validation
Authors: Watermeyer Tamlyn J , Butler Joe , Matterson Ellie , Harper Emily G , Parra‐Rodriguez Mario A 
Published: December 2022

AbstractBackgroundOnline data‐collection provide an opportunity for Alzheimer's Disease research to collect large datasets crucial for understanding important public health concerns. However, the reliability of online tasks as compared to those administered in the lab is poorly examined. Our goal is to validate an online version of the short‐term memory‐binding task (STMBT), a potential digital biomarker sensitive to Alzheimer’s Disease (Parra et al., 2010), to understand if data collected online in two environments, at‐home and in the lab, is comparable.MethodWe created an online version of the STMBT task using Psytoolkit (Stoet 2010; Stoet 2017). Development involved piloting, group and user discussions to explore how such a novel tool could be best presented for self‐assessment. Useful insights led to refinement of the online tool (i.e., instruction videos, images, and text). The validation stage involves test‐retest reliability assessment of cognitively fit participants (aged >40 years) who complete the two conditions of this paradigm (i.e., shape only and binding). Task Environment (home and in the lab) and conditions (shape and binding) were fully counterbalanced. Measures of general cognitive abilities, anxiety and at‐home environment were also taken.ResultRecruitment is on‐going, but preliminary data (n=10) has already proved informative. A repeated measures ANOVA looking at task‐accuracy with factors of Environment (home vs. lab) and Condition (shape vs. binding) revealed no significant effects of Environment: F(1, 9) = 0.308, p = .591; Condition: F(1, 9) = 2.202, p = .172); or Interaction: F(1, 9) = 0.308, p = .591). For the shape condition, all participants performed near ceiling regardless of testing environment. In the binding condition, we observed good‐to‐excellent test‐retest reliability between environments using single measures interclass correlation (ICC = 0.954, CI 0.83‐0.99, (F(9, 9) = 39.62, p <.001).ConclusionThese preliminary results indicate the STMBT can provide reliable data when self‐administered using an online version of the task which has important implications for public health researchers. For our fully powered sample, we will provide summary of other measures.
Comparison of FreeSurfer inputs on estimates and reliability of volume and thickness measures
Authors: Ferreira‐Atuesta Carolina , Binder Sarah , Piendel Lydia A , Emerson Jacqueline M , Andrew‐Jaja Nancy , Sutkowski Jonathan , Hedden Trey 
Published: December 2022

AbstractBackgroundAnatomical volume and cortical thickness are measures of neurodegeneration to track disease progression and evaluation of treatment efficacy. FreeSurfer software provides automatic structural parcellation and segmentation to estimate volume and thickness. T1‐weighted inputs are commonly used, but T2 or T2*FLAIR images can be added. This study compared FreeSurfer estimates for T1 only vs T1+T2 or T1+T2*FLAIR inputs with regard to reliability and its relation to amyloidosis.Method3‐Tesla MRI data were included for 379 scans (T1: 35%, T1+T2: 35%, T1+T2*FLAIR: 31% ‐ session 1: 39%, 2: 34%, 3: 27%) from 60 healthy older adults (mean age 71, 67% female). FreeSurfer‐derived estimates of volume and cortical thickness were obtained for T1, T1+T2, and T1+T2*FLAIR inputs. Kruskal Wallis tests followed by Dunn post hoc test were used to identify estimates that were significantly different across sequences. Two‐way mixed model analyses were performed on each estimate, including subject and session as grouping factors. Interclass correlation coefficients measured similarity and reliability. Amyloid‐PET SUVR levels were available for 54% of subjects. Bonferroni correction and estimated marginal means were used to correct for multiple comparisons.ResultFor volume estimates, 17% of pairwise combinations (7% T1+T2vsT1+T2*Flair, 6% T1vsT1+T2, and 4% T1vsT1+T2*FLAIR) showed significant differences between sequences adjusting for multiple comparisons. The cross‐sectional similarity between sequences had median ICC=0.87. Test‐retest reliability within sequences had median ICC=0.88 for T1, 0.87 for T1+T2 and 0.78 for T1+T2*FLAIR. For thickness estimates, 73% of pairwise combinations (27% T1+T2vsT1+T2*FLAIR, 23% T1vsT1+T2*FLAIR, and 22% T1vsT1+T2) showed significant differences between sequences after adjusting for multiple comparisons. The cross‐sectional similarity between sequences had median ICC=0.43. Test‐retest reliability within sequences had median ICC=0.78 for T1, 0.74 for T1+T2 and 0.30 for T1+T2*FLAIR. Amyloid SUVRs had non‐significant correlations with all ICC measures.ConclusionOverall, volumes had high similarity across sequence inputs and high test‐retest reliability. Thickness showed less reliability across sequences and sessions driven by low similarity and low reliability for T1+T2*FLAIR. Amyloid deposition did not impact reliability estimates. These results suggest that T1 only or T1+T2 inputs have high reliability across sessions and should be considered in clinical trials designs that measure change in volume or thickness.
Trajectory of Inflammatory biomarkers in the perioperative period and associations with postoperative decline in patients undergoing cardiac surgery
Authors: Evered Lisbeth A , Scott David A , Silbert Brendan S , O'Bryant Sid E. , Hall James 
Published: December 2022

AbstractBackgroundPerioperative neurocognitive disorders (PND), including postoperative delirium (POD), are the most common complications of anesthesia and surgery in those 65y or more, especially following cardiac surgery. PND are associated with increased risk of poor recovery and long‐term outcomes including increased risk of morbidity, dementia and mortality. With no therapeutic targets currently available, prevention is the key to reducing PND. Whilst the pathophysiology of POD and PND remains to be elucidated, current hypotheses highlight the impact of inflammation on these outcomes. This study aimed to identify the trajectory of biomarkers throughout the perioperative period and associations with POD and PND to identify targets for therapeutic interventions to prevent POD and other PND.MethodThe RECOGNISED trial was a prospective trial investigating PND and inflammatory biomarkers across the perioperative period in patients undergoing cardiac surgery. Neuropsychological testing occurred at baseline, and 3 and 12 months postoperatively. Blood samples for inflammatory biomarkers were collected at baseline and 30 minutes, 6, 24 and 48 hours after commencement of surgery.ResultPatients were aged 70y (6) and 24% were male. IL‐6 levels increased at every postoperative time point compared with baseline, with a maximum increase at 6h (1.6 (4.4) vs 113.8 (154.2), p<0.001). IL‐10 levels also increased at every postoperative timepoint, with maximum increase at 6h (0.32 (0.23) vs 10.5 (17.5), p < 0.001). IL‐18 levels were significantly increased at 24 and 48h, with peak increase at 24h (111.9 (51.6) vs 133.8 (54.7), p < 0.001). TNF‐α levels were significantly increased at 30 minutes and 6h postoperatively, with maximal increase at 6h (6.1 (1.7) vs 12.8 (7.9), p < 0.001). Patients with POD experienced a significantly greater increase in IL‐6 at 6h compared to patients without POD. There was no association between peak IL‐10, IL‐18 or TNF‐ α levels and POD. Associations between these biomarkers and other PND will be discussed.ConclusionThese results demonstrate significant increases in both pro‐inflammatory and anti‐inflammatory biomarkers during the perioperative period. IL‐6 levels at 6h were predictive of POD, confirming the role of inflammation in the development of POD. IL‐6 may be a useful target for therapeutic interventions to prevent POD.
Subclinical β‐amyloid peptides impair homeostatic synaptic potentiation in hippocampal neurons in 5XFAD mice
Authors: Catron Mackenzie A. , Howe Rachel K. , John Emily K. St. , Potesta Cobie Victoria , Shostak Alena , Schrag Matthew , Zhou Chengwen 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) patients exhibit early symptoms of non‐rapid eye movement sleep (NREM) reduction and relatively REM sleep increase, which influences homeostatic synaptic plasticity (HSP) in cortical and subcortical neurons. Meanwhile, β‐amyloid peptides can suppress synaptic plasticity in hippocampus to impair learning/memory in animal studies.MethodIn accordance with IACUC of Vanderbilt University Medical center, coronal brain slices were prepared from wt and hemi 5xFAD mice at postnatal days (P)30, 60‐90 and 120‐150. Whole‐cell patch‐clamp recordings were made from hippocampal CA1 pyramidal neurons to record spontaneous excitatory synaptic currents (sEPSCs) at 32°C (clamped at ‐55.8mV, chloride reversal potentials). Slow‐wave oscillations (SWOs, 0.5 Hz, 10 min) were induced by injecting sinusoidal currents into neurons to simulate neuronal activity (up/down state) during NREM sleep. 200 µM β‐amyloid peptides were used in ACSF for this study.ResultCompared with age‐matched wt littermates at P30 and P60‐90, sEPSCs in hippocampal neurons from hemi 5xFAD mice (n = 4 mice) exhibited larger amplitudes and higher frequency. However, at P120‐150, sEPSCs in neurons from hemi 5xFAD mice (n = 5 mice) became smaller than wt littermates (n = 4 mice), suggesting that excitatory synapses in hemi 5xFAD mice may be altered along the ageing course. Moreover, following SWO induction, HSP could be induced in neurons from wt littermates at all postnatal ages (n = 5 mice) and post‐SWO sEPSCs in neurons were increased. However, HSP could not be induced in neurons from hemi 5xFAD mice at P120‐150, except P30 and P60‐90. Moreover, 200 µM β‐amyloid peptides can suppress this synaptic potentiation in neurons from hemi 5XFAD mice at P90 (n = 4 mice).ConclusionReduced NREM sleep activity in hemi 5xFAD mice can impair sEPSCs and HSP in hippocampal CA1 neurons along the ageing course, and subclinical β‐amyloid peptides can suppress this sleep‐related homeostatic synaptic potentiation, which contributes to cognitive deficits in AD patients.
Childhood measures of socioeconomic status and cognitive decline in the LifeAfter90 Study
Authors: Peterson Rachel L. , Gilsanz Paola , George Kristen M. , Meunier Claire C. , Soh Yenee , Corrada Maria M. , Glymour M. Maria , Whitmer Rachel A. , Lor Yi 
Published: December 2022

AbstractBackgroundChildhood socioeconomic status (SES) is associated with cognitive functioning in adulthood. It is not known if this relationship endures in the oldest old. We examined the associations of subjective and objective childhood SES with baseline cognition and cognitive decline in the LifeAfter90 (LA90) cohort.MethodLA90 is an ongoing diverse cohort of individuals aged 90+ without dementia diagnoses at recruitment. In our analytic sample (n = 341), we operationalized objective childhood SES as maternal education (range 0‐20 years); paternal education was substituted in 14% of cases missing maternal education. Subjective childhood SES was assessed using the MacArthur Scale of Subjective Social Status in which participants ranked their childhood SES using an unnumbered 10‐rung ladder picture (coded continuously with 1 = lowest SES and 10 = highest SES). Executive function (EF), semantic memory (SM), and verbal episodic memory (VEM) were assessed using the Spanish and English Neuropsychological Assessment Scales and z‐standardized to baseline. Mixed effects models estimated the associations between each childhood SES marker and level and change in each cognitive domain, adjusting for baseline age, time since baseline, gender, race and ethnicity, practice effects, and interview mode (phone vs. in‐person). We tested for the association between childhood SES measures and cognitive change by interacting SES measures with time.ResultParticipants completed an average of 3 visits (range 1‐6) each 6 months apart. On average, participants were about 93 years old (SD = 2.2), and 63% were female (Table 1). Mean parental education was 9.8 years (SD = 4.6; range = 0‐20); mean ladder score was 7.1 (SD = 2.4). Higher objective childhood SES was associated with better baseline EF (Figure 1: β = 0.03; 95% CI = 0.02, 0.05) and SM (β = 0.03; 95% CI = 0.02, 0.05). Having higher subjective childhood SES was associated with a slower decline in EF (Table 2: β = 0.02; 95% CI = 0.01, 0.04).ConclusionObjective measures of childhood SES were associated with baseline cognition and subjective childhood SES was associated with slower EF decline among the oldest‐old. High childhood SES may increase chances of surviving past age 90, a selection bias which would attenuate the associations we observed. Our results suggest the long arm of childhood may extend throughout the first century of life.
BIN1 K358R variant in 5xFAD mice ameliorates AB pathology and microgliosis
Authors: Tran Katelynn , Milinkeviciute Giedre , Tran Kristine M , Phan Jimmy , Da Cunha Celia , Javonillo Dominic I , Kawauchi Shimako , Tenner Andrea J , LaFerla Frank , MacGregor Grant R , Green Kim N 
Published: December 2022

AbstractBackgroundGenome‐Wide Association Studies (GWAS) identified bridging integrator 1 (BIN1) as the most important susceptibility loci for late‐onset Alzheimer's disease (LOAD), second to apolipoprotein E (APOE). BIN1 is an important regulator of endocytosis and membrane dynamics. Neuronal BIN1 localizes to pre‐synaptic termini where it functions in excitatory synaptic transmission via regulation of neurotransmitter vesicle dynamics. In humans, the gene produces multiple isoforms with 7 brain specific isoforms. A missense variant in Bin1 (K358R) has been linked to increased risk of development of LOAD. Here, we introduced this variant in mice and evaluated its effects on plaque genesis and subsequent damage.MethodTo create the Bin1K358R allele, CRISPR/Cas9 endonuclease‐mediated genome editing of Bin1 was used to introduce a K426R mutation. This mutant allele models a SNP (rs138047593) found in human BIN1 that encodes a missense mutation associated with increased risk of sporadic Alzheimer's disease. The K358R variant in human BIN1 (K542R in the BIN1‐202 isoform) is located within the C‐terminal SH3 domain. Generated BIN1 K358R mice were crossed with 5xFAD mouse models, creating four groups (wild type (WT), BIN1K358R homozygous (HO), 5xFAD, and 5xFAD/BIN1 K358R HO), then aged to 4 months for analysis of AD‐related pathology. Coronal brain sections were immunolabeled to visualize dense‐core plaques (Thioflavin‐S), microglia (IBA1), reactive astrocytes (GFAP), axonal and neuritic damage (neurofilament light chain (NfL) and LAMP1, respectively). Confocal images of hippocampal and cortical regions were analyzed using Imaris software. In addition, Aβ and NfL levels were quantified in the brain tissue and plasma NfL measured using Meso Scale Discovery technology.ResultBIN1 K358R introduced in the 5xFAD background significantly reduces plaque densities and associated microgliosis in the hippocampal region, which matches insoluble Aβ42 levels. In contrast, GFAP levels are significantly increased in 5xFAD/BIN1 K358R mice compared to 5xFAD mice. Despite reduced plaque densities, dystrophic neurite area as measured by LAMP1 staining, as well as plasma NfL, are equivalent between 5xFAD/BIN1 K358R and 5xFAD mice, suggesting increased damage per plaque.ConclusionBIN1 K358R reduces Aβ plaque deposition, but exacerbates the damage caused by those plaques, as determined by the surrounding halo of dystrophic neurites, and plasma NfL.
The WW‐FINGERS‐SARS‐CoV‐2 initiative: a multinational survey to assess the effects of the COVID‐19 Pandemic on Lifestyle and Psychosocial factors relevant to Brain Health
Authors: Mangialasche Francesca , Rocha Ana Sabsil Lopez , Lehtisalo Jenni , Solomon Alina , Middleton Lefkos T , Thunborg Charlotta , Levak Nicholas , de Jager Celeste A , Price Geraint J , Rydström Anders , Ngandu Tiia , Kivipelto Miia ,   WW‐FINGERS‐SARS‐CoV‐2 initiative
Published: December 2022

AbstractBackgroundglobal population aging and forecasted trends of modifiable risk factors for dementia and Alzheimer’s disease (AD) make prevention of these conditions an urgent priority. The World‐Wide FINGERS (WW‐FINGERS) global network of multidomain trials for dementia risk reduction and prevention is at the forefront of efforts to find effective and sustainable solutions for diverse population. The COVID‐19 pandemic has caused changes in the mental and physical health of older adults, which can influence dementia risk and prevention opportunities.MethodsThe WW‐FINGERS‐SARS‐CoV‐2 survey was developed to assess direct and indirect effects of the COVID‐19 pandemic in older adults. The questionnaire measures changes in lifestyle factors (e.g., diet, physical activity), management of chronic noncommunicable diseases (e.g., diabetes, hypertension), and psychosocial factors ‐including depressive symptoms, sleep disorders, social isolation‐ that are relevant to cognition. Both a pen‐and‐paper and a digital version of the survey have been developed in several languages. The digital version is supported through REDCap (Research Electronic Data Capture), which is used also for harmonized data collection.Results30 countries are participating in the survey. As for January 2022, data have been collected from 20 countries, with 23000+ participants. Local adaptations and piloting were done to optimize implementation in clinical‐based and population‐based settings. Participants are in the at‐risk spectrum for dementia: from normal cognition to pre‐dementia cognitive symptoms. Timing of the survey implementation varies across populations, allowing to capture short, medium and long‐term effects of the pandemic and restrictions measures. Some countries have used the survey to recruit participants in multimodal prevention trials. An updated report of the survey status and main results will be presented.ConclusionThe WW‐FINGERS‐SARS‐CoV2 survey is a joint global action of the WW‐FINGERS network which can inform better care of older adults in the context of a pandemic. The survey is also a valuable tool for pre‐screening of participants for prevention trials, and results can inform adaptions to ensure successful recruitment and adherence in forthcoming multidomain trials for dementia prevention in older adults.
The COVID‐19 pandemic on Patients With Dementia and Family Caregivers‐report from the Memory clinic
Authors: Stefanova Elka , Šarčević Maksim , Aleksić Predrag , Živković Aleksa , Despotović Jelica , Jezdić Filip , Matijaš Kristina , Stojkovic Tanja , Stojmenovic Gorana Mandic , Kostic Vladimir S 
Published: December 2022

AbstractBackgroundThe aim of the present study was to examine cognitive‐behavioral changes that may be related to the lockdown and the quarantine during the COVID‐19 pandemic in Serbian patients with mild cognitive impairment (MCI), and Alzheimer dementia (AD). The caregivers’ distress was also evaluated.MethodThe 2089 registered patients with cognitive deficits, between December 2018 until January 2020 in Belgrade Memory clinic registry, University Clinical Center was contacted by telephone within the survey, 2 months after the lockdown declaration. Either the patients or their caregivers were asked to answer on: Caregiver Questionnaire, the Kingston Caregiver Stress Scale, Patient Questionnaire, Neuropsychiatric Questionnaire, and Clinical Dementia rating scale for caregiver and patients.ResultThe study included 1002 (females 56.%) patients either with AD (n = 389) or MCI (n = 604) who have got completed data set for analyses. Unfortunately, 74 patients died in the pandemic time, and 225 subjects rejected to participate, and the rest were not reached due to wrong phone number, or missed contact record. Caregivers reported a worsening in cognitive functions in 55.1% of AD patients, and increased neuropsychiatric symptoms were reported in 59.8% as worsening of preexisting symptoms (41.9%) or as new onset (21%). The most common were depression, apathy, sleep disorders and anxiety. The prevalence of these symptoms was the same as before the pandemic, but there was a change in their frequency and intensity. Approximately 15.9% of patients with MCI showed the onset of new behavioral symptoms, sleep disorder and anxiety were the predominant new symptoms. The transition from MCI to dementia was recorded in 24%. Due to increased patients’ neuropsychiatric burden stress‐related symptoms were experienced by two‐thirds of caregivers.ConclusionPandemic quarantine induces a significant increase of neuropsychiatric symptoms in approximately half of patients and stress‐related symptoms in two‐thirds of caregivers. Health services need to plan a post‐pandemic strategy in order to address these emerging needs.
Digital Cognitive Training in MCI and Early AD: Real World Evidence and Insights from a Large Online Cohort
Authors: Schafer Robert J , Osman Allen M , Jaffe Paul I , Kerlan Kelsey , Ng Nicole F , Offidani Emanuela , Doraiswamy P. Murali 
Published: December 2022

AbstractBackgroundThe 21st Century Cures Act highlights the value of evidence obtained outside of traditional clinical trials (real world evidence, RWE) to enhance trial design and support health care decision making. Increasing use of computers and smartphones has accelerated the generation of RWE and enabled digital therapies including computerized cognitive training (CCT). CCT offers promise for improving cognitive outcomes in MCI and AD, but its effectiveness has not been fully established. Toward this end, we examined RWE on the effectiveness of CCT in MCI/AD using a large online dataset.MethodWe analyzed de‐identified data from a cohort of 82,984 individuals who participated in an online CCT program (Lumosity). Of these, 3514 reported a diagnosis of MCI or AD while the rest served as controls (N = 79,470). Participants completed the NeuroCognitive Performance Test (NCPT), a validated, computerized, online neuropsychological battery. A subset also completed a survey assessing real‐world cognitive functioning (RWC survey). Measures on both instruments were examined at baseline and after varying doses of CCT.ResultAt baseline, the MCI/AD cohort was significantly impaired on all eight NCPT cognitive subtests and the NCPT composite measure of global cognition compared to demographics‐matched controls (p<0.0001, N = 3514 MCI/AD, 79,470 healthy). The MCI/AD cohort was also impaired on the RWC survey (p<0.0001 for the composite score), particularly on items related to concentration or forgetfulness. Engagement with CCT varied among MCI/AD subjects with 2+ assessment timepoints (N = 1934), with an average of 340 CCT games played (SD = 482) over 112 days between assessments (SD = 104). The change from baseline in the NCPT composite measure increased with amount of CCT (p<0.0001, Cohen’s d = 0.31). RWC survey items also improved with training in a subset who completed them at multiple timepoints (p = 0.0530, N = 162).ConclusionThis study provides RWE for the efficacy of CCT in MCI/AD on both objective and patient rated cognitive outcomes. The study also provides insights into dose effects. Such RWE will help optimize CCT interventions to improve cognitive symptoms of MCI and AD.