bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel digital cognitive biomarker for mild cognitive impairment and Alzheimer’s disease
Authors: Fernández Gerardo , Schumacher Marcela , Orozco David , Sgrilli Gustavo , Echeverria Gustavo , Linares Ramiro , Parra Mario A. 
Published: December 2021

AbstractBackgroundRecent evidence suggests that oculomotor behaviours linked to cognitive performance can be a biomarker of Alzheimer’s disease (AD). Short‐Term Memory Binding (STMB) declines in patients with AD dementia and in those at risk of dementia. STMB relies on brain regions relevant to visual processing which are known to support oculomotor behaviours. Viewmind is proposed as a novel “cognitive digital biomarker” with the potential of revealing phenotypic features of AD in the pre‐dementia stage of the pathology. Viewmind applies artificial intelligence to analyse eye movements and pupil responses during the performance of STMBT.MethodSTMBT assesses the ability to temporarily hold bicoloured objects whose colours had to be remembered either as individual features (baseline) or integrated within unified representations (binding). Viewmind’s technology powered by Artificial Intelligence improved STMBT for identifying MCI patients and their potential conversion to AD.ResultThe 3 years Longitudinal Study involved 42 healthy older adults and 61 patients with Mild Cognitive Impairment (MCI). Viewmind retrospectively classified 91% of the MCI patients who later converted to AD as AD patients. From those MCI patients that Viewmind predicted as no AD, none later converted to AD but they progressed to Fronto‐temporal or Parkinson’s Disease.ConclusionTaken together, the results above suggest that Viewmind can (1) unveil novel features of AD dementia unknown to date, and (2) provide a more sensitive tool which can detect and trace aspects of such phenotype in people at risk, thus helping to ascertain the presence of the prodromal stages of the disease.
Evaluating a system to promote timely detection of cognitive impairment in primary care practice
Authors: Fitzpatrick Annette L , Belza Basia , Raetz Jacqueline G. , Suchsland Monica Zigman , Illes Judit , Gaster Barak 
Published: December 2021

AbstractBackgroundDementia and mild cognitive impairment (MCI) are underdiagnosed with evidence indicating that clinical diagnoses frequently occur late in the process of cognitive decline. Increasing evidence that dementia may be preventable or delayed has led to an international focus on earlier evaluation, diagnosis and intervention.MethodUsing the impetus of “Memory Brain Wellness” as a priority growth program at University of Washington (UW) Medicine, we are developing synergistic strategies to improve timely detection of cognitive impairment across primary care in 15 neighborhood clinics in the Pacific Northwest. This presentation will describe current quality‐improvement efforts to promote engagement across multiple stakeholders including health‐care system leadership, practice care management, primary care providers (PCPs) and clinic staff. This lifespan approach is based on the KAER (Kickstart‐Assess‐Evaluate and Refer) Model and Toolkit (2020 Edition) developed by the Gerontological Society of America (GSA).ResultsProgram activities to be described include 1) results of interviews with the primary care team to determine acceptability and support needed to implement timely cognitive evaluation; 2) implementation of a training intervention to initiate discussions, conduct cognitive assessment, and manage care; and 3) identification of support services and resources to be used in provider consultation. Input from a Technical Advisory Committee and local Community Advisory Board were incorporated into the training and resource inventory for patient/caregiver support. Topics in the training include normalizing the conversation, team approach, moving toward evaluation, assessment tools, alternate diagnoses/modifiable risk factors, multi‐disciplinary and community referrals, patient counseling, long‐term management, and advance care planning. Changes in practice patterns of PCPs will be reviewed using extracted data from the electronic health record (EHR). Details of each strategy will be provided to explain system‐wide decisions, pragmatic applications, results of trainings held to‐date and feed‐back from the primary care team.ConclusionThis is the first study to refine and utilize the GSA KAER toolkit addressing change in practice patterns in a large multi‐clinic primary care system. Results of this program will be used to extend efforts beyond the Seattle region to address timely cognitive evaluation across the 5‐state WWAMI region (Washington, Wyoming, Alaska. Montana and Idaho) served by UW Medicine.
Residual approaches to capture resilience and resistance in aging and Alzheimer’s disease: A meta‐analysis
Authors: Bocancea Diana I. , van Loenhoud Anna C. , Groot Colin , Barkhof Frederik , van der Flier Wiesje M. , Ossenkoppele Rik 
Published: December 2021

AbstractBackgroundThere is currently no consensus on how to optimally define and measure resistance and resilience in aging and Alzheimer´s disease (AD). Residuals from regression analyses can be used to quantify whether an individual´s capacity to avoid (resistance) or cope with (resilience) cerebral damage is higher or lower than expected. We aggregated the rapidly‐growing literature on neuroimaging‐based residual methods in the context of aging and AD into a meta‐analysis in order to investigate associations of residual measures of resilience and resistance with longitudinal cognitive and clinical outcomes.MethodA systematic literature search of PubMed and Web‐of‐Science databases (consulted until March 2020) and subsequent screening led to 10 studies eligible for the meta‐analysis. The included studies employed a residual measure to investigate associations between either resistance or resilience and rate of cognitive decline or clinical progression (i.e., conversion to MCI or dementia). We extracted standardized regression coefficients for the former and hazard ratios (HRs) for the latter, and assessed overall effects using random‐effects models in the R(v3.6.1) metafor package(v2.4‐0).ResultResistance was most commonly measured with age‐based residuals (also known as “brain age” methods) that capture the extent to which an individual preserves brain integrity despite chronological aging. Cognitive resilience residuals quantified deviations in cognition from expected levels based on the amount of neurodegeneration [Figure 1]. There is considerable methodological variability in how the residual measures were derived and validated. Despite these methodological differences across studies (reflected in the moderate to high heterogeneity estimates), our meta‐analysis showed significant associations between resistance and risk of dementia/AD (HR[95%CI]=1.12[1.07‐ 1.17], p<0.0001, I2
=70.2%), with a lower level of resistance indicating a higher risk of progression. Cognitive resilience was significantly associated with risk of progression (HR[95%CI]=0.46[0.32‐0.68], p<0.001, I2
=94.2%) and also with rate of cognitive decline (β[95%CI]=0.05[0.01‐0.08], p<0.01, I2
=80.3%), suggesting an overall protective role of resilience across studies (i.e. a lower level of resilience is associated with an increased risk of dementia and a faster decline) [Figure 2].ConclusionThis meta‐analysis supports the validity of residual measures to quantify resilience and resistance, as they capture clinically meaningful information in aging and AD.
Association of sleep duration at age 50, 60 and 70 with incidence of dementia
Authors: Sabia Séverine 
Published: December 2021

AbstractBackgroundSleep dysregulation is a feature of dementia but whether sleep duration prior to old age is also associated with incidence of dementia remains unclear. We examined the association of sleep duration in midlife with risk of late‐life dementia.MethodData were drawn from 7959 participants (women=33.0%) of the Whitehall II cohort study, established in 1985‐1988, from which self‐reported sleep duration at age 50, 60, and 70 was extracted and categorized as “short: ≤6 hours per night”, “normal: 7 hours per night”, “long: ≥8 hours per night”. Incident dementia (N=521) cases were identified through electronic health registers until March 2019.ResultCompared to normal sleep duration, higher risk of incident dementia was observed among those with short sleep duration at ages 50 and 60 (mean follow‐up 25 and 15 years, respectively), although not significantly at age 70 (hazard ratio 1.22 (95% confidence interval 1.01‐1.48), 1.37 (1.10‐1.72), and 1.24 (0.98‐1.57), respectively). Persistent short sleep duration at age 50, 60, and 70 compared to persistent normal sleep duration was also associated with a 32% (hazard ratio 1.32 (1.02‐1.72)) increased risk of dementia independently of sociodemographic, behavioural, cardiometabolic, and mental health factors. These associations were also evidence when analyses were restricted to participants without a history of mental illness before age 65 years. In a subsample with objective measure of sleep (accelerometer data, N=3888), the association of short sleep duration with increased risk of dementia was confirmed.ConclusionThis study paying attention to both age at sleep duration and length of follow‐up along with inclusion of a wide array of covariates shows that short sleep duration in midlife is associated with an increased risk of dementia. Public health messages to encourage good sleep hygiene, may be particularly important for people at higher risk of dementia.
Study design of FINGER‐NL: A multidomain lifestyle intervention in Dutch older adults to prevent cognitive decline
Authors: Zwan Marissa D. , Deckers Kay , Claassen Jurgen A.H.R. , Oosterman Joukje M. , de Heus Rianne A.A. , van de Rest Ondine , de Groot Lisette C.P.G.M. , Smidt Nynke , Broersen Laus M. , Counotte Danielle , Sikkes Sietske A.M. , van Boxtel Martin P.J. , Aarts Esther , van der Flier Wiesje M , Koehler Sebastian 
Published: December 2021

AbstractBackgroundPrevious multidomain lifestyle intervention trials to prevent cognitive decline in non‐demented elderly have found conflicting effects, with positive findings including the multidomain FINnish GERiatric intervention (FINGER) study (Ngandu T, Lehtisalo J, Solomon A, et al. Lancet 2015), and in specific at‐risk subgroups in other trials (Moll van Charante EP, Richard E, Eurelings LS, et al. Lancet 2016; Andrieu S, Guyonnet S, Coley N, et al. Lancet Neurol. 2017). As part of a world‐wide effort to replicate and build on these results, FINGER‐NL aims to investigate the effectivity of a 2‐year multidomain lifestyle intervention in Dutch older adults to prevent cognitive decline.MethodFINGER‐NL is a Dutch multi‐center, randomized, controlled, multidomain lifestyle intervention trial among 1,206 adults at risk for cognitive decline with a duration of 24 months. Inclusion criteria are 60‐80 years of age and presence of both modifiable (based on LIfestyle for BRAin health (LIBRA) score) and non‐modifiable (family history, worries about subjective cognitive decline) dementia risk factors. Participants will be randomized in a 1:1 ratio to the structured intervention group or the self‐guided control group. The multidomain lifestyle intervention comprises 8 modules, namely physical exercise, cognitive training, management of metabolic and vascular risk factors, nutritional counseling, Souvenaid®, sleep counseling, stress management, and social activities. The structured intervention group receives a personalized, supervised and hybrid (both online and at study site) intervention consisting of group meetings and individual sessions. The self‐guided control group receives online lifestyle‐related health education. Primary outcome is 2‐year change from baseline on a cognitive composite score covering processing speed, executive function and memory. Secondary outcomes including changes in specific cognitive domains, Amsterdam Instrumental Activity of Daily Living Questionnaire (A‐IADL‐Q), LIBRA score, EQ‐5D‐5L, lifestyle component specific outcomes. Participant recruitment will start in June 2021 and FINGER‐NL is expected to be completed in 2024.ResultResults of FINGER‐NL will provide further insight in the effectivity and feasibility of a multidomain lifestyle intervention to prevent cognitive decline in older adults.ConclusionGiven the current lack of curative treatment options and the growing prevalence of cognitive impairment and dementia, lifestyle interventions may play an important role in preventing or delaying disease onset.
Lower cognitive resilience against brain atrophy in cognitively unimpaired elderly is partly explained by Alzheimer's disease pathology
Authors: Svenningsson Anna L , Ossenkoppele Rik , Stomrud Erik , Palmqvist Sebastian , Hansson Oskar 
Published: December 2021

AbstractBackgroundCognitive resilience refers to processes involved in coping with effects of brain pathology on cognition. Factors contributing to cognitive resilience against brain atrophy are unclear, as there have been few longitudinal studies investigating this. Therefore we aimed to identify factors explaining the discrepancy between brain atrophy and longitudinal cognitive decline. One proposed method of investigating cognitive resilience is a residual approach, which suggests using the variance in cognition not explained by a specified predictor as a measure of resilience.MethodCognitively unimpaired subjects (n=406) from The Swedish BioFINDER Study with magnetic resonance imaging (MRI) and cognitive test results from at least two time points were included. Using FreeSurfer, global cortical thickness was calculated. A cognitive composite score was calculated from Mini Mental State Examination, Alzheimer´s Disease Assessment Scale – Cognitive Subscale delayed word recall, Trail Making Test B, and Animal fluency. For each subject, the beta coefficients for change in cortical thickness and change in cognition over time were calculated. Linear regression was performed between the two beta coefficients, and the residuals were used as a measure of cognitive resilience. Associations were calculated between this resilience measure and baseline demographics, biomarkers of amyloid (cerebrospinal fluid (CSF) β‐amyloid (Aβ) 42/40 ratio), tau (CSF phosphorylated tau (p‐tau)), and vascular (MRI white matter lesion (WML) volume) pathology as well as neurodegeneration (CSF neurofilament light (NfL)). For dichotomous variables (sex and pathologic Aβ42/40 ratio) independent samples t‐tests, and for continuous variables (all other variables) Pearson correlations, were performed.ResultIn univariate models, lower age at baseline, female sex, higher cortical thickness and better cognitive results at baseline were associated with higher cognitive resilience against cortical atrophy, while education was not. Further, pathological Aβ42/40 ratio and higher levels of p‐tau, NfL, and WMLs at baseline were negatively associated with cognitive resilience in univariate analyses. In a multivariable linear regression model, lower baseline cortical thickness, a pathological Aβ42/40 ratio, and higher NfL were significantly associated with worse cognitive resilience (Figure 1, Table 1).ConclusionMarkers of Alzheimer´s disease pathology and neurodegeneration are associated with worse than expected cognitive decline at a given rate of brain atrophy.
Amyloid discordance analysis in cognitively normal monozygotic twins demonstrates that the memory domain is affected first in preclinical AD
Authors: Tomassen Jori , den Braber Anouk , Van Berckel Bart N.M. , Yaqub Maqsood , Boomsma Dorret I , Scheltens Philip , Tijms Betty M. , Visser Pieter Jelle 
Published: December 2021

AbstractBackgroundThe earliest cognitive changes in Alzheimer’s disease (AD), even before amyloid‐beta (Aβ) is abnormal, remain largely unclear. We recently observed in a cohort of cognitively normal older monozygotic twins that 15% of twin‐pairs were discordant for Aβ status (Fig. 1). In this cohort, we investigated early cognitive changes by comparing cognitive decline over 4 years among twin‐pairs discordant for Aβ status (one twin normal Aβ and co‐twin abnormal Aβ), twin‐pairs with both normal Aβ (concordant Aβ‐), and twin‐pairs with both abnormal Aβ (concordant Aβ+). We expected the rate of cognitive decline to depend on baseline Aβ status with the least decline in concordant Aβ‐ twins and increasing decline from discordant Aβ‐, discordant Aβ+ to concordant Aβ+ twins.MethodFrom the EMIF‐AD PreclinAD study we selected monozygotic twins with normal cognition at baseline who had a [18F]flutemetamol PET scan and at least one cognitive follow‐up available (n=188; 90 twin‐pairs) (Table 1). We defined Aβ group status using visual read of dynamic [18F]flutemetamol PET images. We tested whether twin Aβ concordance status at baseline was associated with cognitive performance at baseline and over 4 years time with two repeated measures in memory, attention, executive function (EF) and language domains using linear mixed models adjusted for age, sex, education and genetic relatedness.ResultAt baseline concordant Aβ+ twins showed impaired performance in all domains (Fig. 2). Discordant Aβ+ and concordant Aβ+ twins showed lower memory scores compared to concordant Aβ‐ twins (discordant Aβ+, p=0.02; concordant Aβ+, p=0.04). Over time, we found that for concordant Aβ‐ twins memory improved over time (p=0.002), discordant Aβ‐ twins did not change over time (p=0.15), while discordant Aβ+ and concordant Aβ+ twins declined on memory (concordant Aβ+, p=0.03; discordant Aβ+, p=0.07). No significant changes over time were observed in the other domains.ConclusionOur findings provide further support that the earliest cognitive changes in AD are found in the memory domain and that subtle memory changes may already by present before amyloid pathology can be detected on a PET scan.
Long‐term cognitive and motor decline across the spectrum of Lewy body disease
Authors: Gonzalez Maria Camila , Maple‐Grødem Jodi , Tovar Diego , Williams‐Gray Caroline H. , Camacho Marta , Forsgren Lars , Bäckström David , Lawson Rachael A , Macleod Angus D. , Counsell Carl E. , Paquet Claire , Falup‐Pecurariu Cristian , Blanc Frédéric , Padovani Alessandro , de Lena Carlo , D'Antonio Fabrizia , Alves Guido , Aarsland Dag 
Published: December 2021

AbstractBackgroundThis study aims to compare the progression of motor and cognitive decline in dementia with Lewy bodies (DLB) compared with Parkinson’s disease (PD) using a large multicentre international consortium with up to 15 years of follow‐up.MethodLongitudinal data from 12 cohorts of patients with PD and DLB were included. The PD cohort (n=1108) included newly diagnosed patients from large, on‐going studies. The DLB cohort (n=290) included patients with probable DLB from the European DLB consortium (Table 1). The Mini Mental State Examination (MMSE) was used to explore cognitive functioning and UPDRS‐III for motor impairment. The differences in the rate of progression of MMSE and UPDRS‐III were analyzed with Linear Mixed Effects Model (LMEM) adjusted for baseline variables, with interactions for time. We used square root transformation of the number of errors to obtain an MMSE variable with normal distribution.ResultBoth DLB and PD groups presented motor and cognitive decline. The MMSE (figure 1A) showed a mean annual worsening of 2.35 points (95% CI 1.67‐3.03) for DLB patients and 1.05 points (95% CI 0.62‐1.47) for PD patients (P <0.001). In PD the rate of decline increased with time and from the tenth year, the annual rate of decline of the transformed MMSE scores matched the rate in the DLB group. While DLB patients had lower UPDRS‐III scores at baseline, the rate of decline in UPDRS‐III (figure 1B) scores was faster in DLB compared to PD (P <0.001). The annual increase in UPDRS III in DLB was 5.8 points (95% CI 5.71‐5.90), while in PD it was 1.9 points (95% CI 1.76‐1.97).ConclusionOur findings suggest that patients with DLB experience not only more rapid cognitive decline, but also accelerated motor deterioration compared to patients with PD. After ten years of follow‐up (and 12.9 years from the onset of symptoms), PD patients reach DLB's degree of yearly cognitive decline. This is the first large study to compare the natural history of PD and DLB and provides important information about the prognosis of these diseases.
The neuroinflammation signatures in different stages of the Alzheimer’s disease continuum
Authors: Wang Yi‐Ting , Benedet Andréa Lessa , Tissot Cécile , Lussier Firoza Z. , Bezgin Gleb , Therriault Joseph , Servaes Stijn , Arias Jaime Fernandez , Gauthier Serge , Rosa‐Neto Pedro 
Published: December 2021

AbstractBackgroundThe natural history of Alzheimer’s disease (AD) comprises a long preclinical stage characterized by pathological changes that start decades before symptoms arise. Despite that AD is defined based on the presence of amyloid‐β (Aβ) and tau pathology, increasing evidence supports neuroinflammation as one of the earliest pathomechanistic alterations throughout the AD continuum. Microglia and astrocytes are key cellular drivers and regulators of neuroinflammation. However, it remains unclear if there are patterns of spatial and temporal susceptibility to neuroinflammatory processes in the brain that may synergize with Aβ and tau accumulation, which drives neurodegeneration in a self‐reinforcing manner.MethodThis was a cross‐sectional study examining a total number of 283 subjects from the TRIAD cohort at McGill University Research Centre for Studies in Aging, Canada. Cerebral amyloid and tau neurofibrillary tangles were assessed using positron emission tomography (PET) radiopharmaceuticals [18F]AZD4694 ([18F]NAV4694) and [18F]MK6240 respectively. Cerebrospinal fluid (CSF) biomarkers including Aβ42, Aβ40, phosphorylated tau (p‐tau), total tau (t‐tau), neurofilament light (NfL), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), YKL40 and glial fibrillary acidic protein (GFAP) were also measured. Voxelwise analyses were performed to evaluate the relationships between cerebral amyloid load, tau burden and neuroinflammation biomarkers.ResultWe modelled biomarker changes as a function of amyloid PET standardized uptake value ratio (SUVR) and tau PET SUVR as proxies of disease progression. The earliest changes observed in the AD continuum were the decrease in the Aβ42/40 ratio and the increases in astrocytic biomarkers CSF YKL40 and CSF GFAP. This is followed by a steep increase in CSF pTau231 and, to a lesser extent, CSF pTau217 and CSF pTau181. Voxelwise analyses revealed that YKL40 and GFAP are associated with amyloid and tau load in the brain, after accounting for age, sex, education and pathological status.ConclusionNeuroinflammation involving astrocytic activation is altered very early in the Alzheimer’s continuum and could be targeted as a promising biomarker.