bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identifying individuals with mild cognitive impairment who are at higher genetic risk of further substantial cognitive decline due to Alzheimer's disease
Authors: Pither Richard , Daunt Paula , Davidson Greg , Gibson Alex , Hill Anthony , Oshota Olusegun 
Published: December 2020

AbstractBackgroundThe development of tools to identify disease risk is critical to enable selection of suitable individuals for inclusion in clinical trials and cohort studies. The utility of Polygenic Risk Scores (PRS) is gaining increased attention for generating genetic risk profiles and subsequent estimation of future disease risk in Alzheimer’s Disease. We have previously reported on the performance of our PRS to differentiate AD cases from healthy controls in the ADNI cohort using individual's most recent diagnosis. In this work we have analysed whether the PRS is able to predict substantial cognitive decline towards an AD phenotype of individuals with MCI at the point of entering the study. The aim being to demonstrate the utility of PRS approaches in longitudinal studies and future clinical practice.MethodThis longitudinal study explored the performance of the Cytox genoSCORE™ PRS algorithm as measured using ROC, AUC analysis when predicting a change in ADAS‐Cog13 score of 5,10 and 15 points at 2, 3 and 4‐year assessment timepoints. Subjects are included in the analysis based on availability of ADAS‐Cog13 data at those timepoints and availability of genetic data in the ADNI database. Change in cognition as measured by ADAS‐Cog13 was used instead of change of diagnosis given the broad spectrum of baseline cognitive performance in those individuals with MCI.ResultIndividuals with low PRS clearly have a lower likelihood of experiencing substantial cognitive decline (>10 points on the ADAS‐Cog13 scale over 4 years) than those individuals with higher PRS. In a population of 285 individuals with an MCI diagnosis at baseline genoSCORE™ has an accuracy as measured by area under the curve of 74% in predicting those individuals who declined substantially over 4 years, with very high negative predictive values.ConclusionIdentifying individuals of higher risk for substantial cognitive decline towards AD will allow clinical trialists to enrich their studies with more appropriate patients. In addition, use of such risk evaluation techniques in clinical practice will enable clinicians to make more informed decisions on how to manage their patients. Cytox is able to provide a robust end‐to‐end process to provide this comprehensive genetic risk assessment.
Does optimal cardiovascular health protect against cognitive decline in aging?
Authors: Speh Andreja , Wang Rui , Winblad Bengt , Kramberger Milica G , Bäckman Lars , Fratiglioni Laura , Qiu Chengxuan , Laukka Erika J 
Published: December 2020

AbstractBackgroundThe presence of cardiovascular risk factors leads to negative consequences in old age. To promote the intervention of such risk factors, the American Heart Association defined a metric of ideal cardiovascular health, also referred to as Life’s Simple 7 (LS7). The adherence to the LS7 recommendations has previously been linked to a lower risk of dementia and cognitive decline. The objective of this study was to investigate the association between individual and composite cardiovascular health metrics and rate of cognitive decline in an older population‐based sample.MethodParticipants aged ≥60 years from the Swedish National Study on Aging and Care‐Kungsholmen underwent repeated neuropsychological testing across 12 years. Domain specific scores were calculated for episodic memory, semantic memory, verbal fluency, and processing speed. The LS7 score, assessed at baseline, was composed of four behavioral (smoking, body mass index, diet, and physical activity) and three biological (serum total cholesterol, plasma glucose, and blood pressure) metrics. All metrics were categorized into three levels (poor = 0, intermediate = 1, and optimal = 2), where the LS7 total score was the sum of seven metrics (range 0‐14). On the basis of tertiles, it was categorized into poor (scores 0‐6), intermediate (7‐9) and optimal (10‐14). Data were analyzed with linear mixed‐effects models.ResultAmong 1828 participants with data on LS7 (mean age 70.4; 60.8% women), nobody achieved optimal levels for all 7 metrics. The average total score was 7.7 (SD = 1.9) and participants were classified as having poor (26.3%), intermediate (55.6%), or optimal (18.2%) cardiovascular health. People belonging to the intermediate or optimal group of cardiovascular health showed higher levels of cognitive performance. Although a more ideal level on specific metrics (e.g. blood pressure) was significantly associated with slower rates of cognitive decline, we observed no significant associations of the composite cardiovascular health metric with rate of cognitive change.ConclusionIn this cohort study, a composite score of cardiovascular health (LS7) did not predict rate of cognitive decline. Ideal cardiovascular health in specific metrics, however, was associated with slower decline rates. Further analyses of subgroups and interaction effects are ongoing.
Differences in functional connectivity in mild cognitive impairment for amyloid‐positive versus SNAP
Authors: Magalhaes Thamires Naela Cardoso , Casseb Raphael Fernandes , de Campos Brunno , Teixeira Camila Vieira de Ligo , Forlenza Orestes Vicente , Talib Leda Leme , Cendes Fernando , Balthazar Marcio Luiz Figueredo 
Published: December 2020

AbstractBackgroundThe default mode network (DMN) is a neurofunctional network particularly relevant to Alzheimer's disease (AD) since its structures are vulnerable to the deposition of amyloid (Aβ) and neurofibrillary tangles [1]. Observing the more up‐to‐date classifications, we classified our patients according to AT(N) (alterations in amyloid (A), tau (T) and neurodegeneration (N)) classification: normal AD biomarkers (AD‐) (A‐T‐N‐); suspected non‐Alzheimer pathophysiology (SNAP) (A‐T+N‐, A‐T‐N+, or A‐T+N+) and AD pathophysiologic continuum (AD+) (any A+ combination) [2]. We investigated whether the activity and functional connectivity (FC) can differentiate MCI subgroups according to AD biomarkers classification.MethodWe recruited 58 mild cognitive impairment (MCI) patients who underwent: lumbar puncture to analyze Aβ1‐42, p‐Tau and t‐Tau levels; Magnetic Resonance Imaging in a 3T Philips Achieva scanner; and a broad neuropsychological evaluation. Was considered pathophysiological evidence of AD (AD continuum) low Aβ1‐42 concentrations < 416 pg/m and was considered Tau alteration: p‐Tau > 36.7 pg/mL and t‐Tau > 76.7 pg/mL [3]. To identify the DMN we used the UF2C software and seed‐based analysis using a mask of the posterior cingulate cortex to extract the reference time‐series. We obtained FC values for 8 DMN regions for each patient. We performed a general linear model to compare the groups with FC values of DMN regions.ResultThere was a statistically significant difference between groups SNAP and AD continuum and FC of left hippocampus (p = .017). AD continuum group shows more connectivity than SNAP group.ConclusionCSF protein profiles seem to be related to alterations in resting state activity. In this study we were able to differentiate clinically similar patients through neuroimaging biomarkers. With further refinement, resting‐state connectivity hold promise as non‐invasive neuroimaging markers. References: [1] Matura S, et al., doi: 10.1017/neu.2019.49; [2] Jack CR, et al., doi: 10.1016/j.jalz.2018.02.018; [3] Forlenza OV, et al., doi: 10.1016/j.dadm.2015.09.003.
Difference between Okinawan and Dutch elderly in working memory‐related brain activation
Authors: Ćurčić‐Blake Branislava , Willcox Craig D , Futenma Yuko , Ueda Yukihiko , Aleman André 
Published: December 2020

AbstractBackgroundOkinawan elderly have been reported to suffer from less age‐related diseases (including dementia) in comparison to elderly people elsewhere. However, there is a lack of research studying functional brain characteristics of succesful aging as found in Okinawan elderly. The current study is designed to take the first step in this regard. Specifically, we want to investigate brain activation during executive functioning in Okinawan elderly as compared to Western‐European elderly (in this case, Dutch elderly). We predicted that Okinawan elderly would need less prefrontal brain activation during a working memory task.MethodWe included the first data from 50 participants of the Okinawa‐Groningen study in which brain activation patterns are studied cross‐culturally in eldery subjects. The study is ongoing and aims to include N=40 at both sites. Here we present the first results based on a comparison of 34 Okinawan to 16 Dutch participants. Working memory‐related brain activation was measured using fNIRS during a visual N‐back task. 1‐back task consisted of 3 blocks (120s) including figures of objects and animals. fNIRS measurement was performed with 16 optodes (NIRx Scout, Germany) placed between Fp1 and F5 on the left and Fp2 and F6 on the right side. fNIRS data were analyzed using NIRSLab (NIRx, Germany). As groups differed slightly in level of education (higher in the Dutch sample) we included cognitive performance on a related task, verbal fluency (category and letter fluency) as covariate, to control for cognitive ability.ResultGLM analysis revealed significantly higher activation in the bilateral Inferior Frontal Gyrus (IFG) of Dutch participants. After correcting for performance on verbal fluency ANCOVA revealed significantly stronger IFG activation in the Dutch subjects, F(3, 47)=9.83 (0.003). Though in the same direction, this difference was non‐significant for the left IFG (p=0.062).ConclusionOur results reveal lower of activation of dorsolateral prefrontal cortex during working memory processing in elderly subjects from Okinawa as compared to elderly Dutch subjects. Cognitive reserve has been shown to be related to less activation during a task involving executive functioning (Oh et al. 2018). We suggest that Okinawan elderly may need less executive processing resources to perform the task.
Baseline features of the AMYPAD Diagnostic and Patient Management Study (DPMS) participants
Authors: Altomare Daniele , Collij Lyduine , Garibotto Valentina , Poitrine Léa , Moro Christian , Alves Isadora Lopes , van Maurik Ingrid S. , Berkhof Johannes , Scheltens Philip , Delrieu Julien , Molinuevo Jose Luis , Nordberg Agneta K , Jessen Frank , Walker Zuzana , Démonet Jean‐François , Gismondi Rossella , Farrar Gill , Barkhof Frederik , Stephens Andrew W , Frisoni Giovanni B ,   AMYPAD Consortium
Published: December 2020

AbstractBackgroundAMYPAD‐DPMS is the largest European, multicenter, prospective and randomized study assessing clinical utility and cost‐effectiveness of amyloid‐PET in a controlled but realistic clinical setting. In the present abstract we report preliminary results on the baseline features of the first study participants.MethodA total of 900 participants (300 with subjective cognitive decline plus [SCD+], 300 with mild cognitive impairment [MCI], and 300 with dementia) will be enrolled and randomized into 3 study arms: ARM‐1, amyloid‐PET performed early in the diagnostic workup; ARM‐2, amyloid‐PET performed late in the diagnostic work‐up; and ARM‐3, amyloid‐PET performed if and when the physician chooses to.ResultAs of January 23rd 2020, 617 participants (154 SCD+, 303 MCI, and 160 dementia) have been enrolled from 8 centers. Baseline features are reported in Table 1. SCD+ participants are younger than MCI (p=0.006) and dementia (p<0.001) participants. SCD+ are more highly educated than MCI and dementia (p<0.001), and MCI are more highly educated that dementia (p=0.008). As expected, worse global cognition is observed in dementia (p<0.001) compared to MCI and SCD+, and in MCI compared to SCD+ (p<0.001). Among those who already underwent amyloid‐PET, 34% (30/88) of SCD+, 58% (90/155) of MCI, and 74% (60/81) of dementia patients were amyloid‐positive based on visual PET scan assessment.ConclusionThe socio‐demographic and cognitive features of the first 68% of AMYPAD‐DPMS participants are as expected for a memory clinic population, confirming the inclusion/exclusion criteria resulted in a representative sample. These results support the generalizability of the final study results. The end of participants’ enrolment is expected by mid‐2020.
How dominant hand dexterity could help in characterizing different grades of cognitive decline: A motor and cognitive dual‐task study
Authors: Mancioppi Gianmaria , Fiorini Laura , Rovini Erika , Zeghari Radia , Gros Auriane , Manera Valeria , Mouton Aurelie , Philippe Robert , Cavallo Filippo 
Published: December 2020

AbstractBackgroundThe combined provision of an arising number of dementia cases, and the substantial absence of effective treatments, led the scientific community toward the identification of early phases of this condition. Such an effort aims at the recognition of therapeutic windows and the characterization of the disease’s different grades. In the last years, Motor and Cognitive Dual‐Tasks (MCDT) have been widely used to address the early diagnosis of several neurocognitive disorders, among which dementia.MethodIn this work, we presented a brand‐new sensor‐based MCDT approach, regarding the upper limb activity: the index‐tapping MCDT (FTAP). We tested this protocol on 30 subjects, among which: 10 Healthy Older Adults (HOA), 10 Subjective Cognitive Decline (SCD), and 10 Minor Neurocognitive Disorders (m‐NCD).ResultThe preliminary results suggest that the FTAP protocols seem to enlarge the possibility to differentiate among different grades of cognitive decline. The FTAP within‐group analysis revealed a low rate of task saturation if such a task is compared to the gold standard protocols. Furthermore, several motor parameter differs among the aforementioned clinical label (opening and closing velocity, tapping frequency, number of tapping, etcetera), suggesting the possibility to better discriminate among clinical condition.ConclusionThis paper presents a brand‐new application of MCDT, enlarging the literature about the motor‐cognitive interface. Moreover, FTAP protocols, differently from gait analysis, can also be easily applied in neuroimaging studies.
Differential gene expression in genetic and early‐onset Alzheimer’s disease in two biological samples: Brain tissue and lymphoblastoid cell lines
Authors: Ramos‐Campoy Oscar , Lladó Albert , Bosch Beatriz , Aldecoa Iban , Gonzalo Ricardo , Muñoz Cristina , Ximelis Teresa , Fernandez‐Villullas Guadalupe , Balasa Mircea , Sanchez‐Pla Alex , Sanchez‐Valle Raquel , Antonell Anna 
Published: December 2020

AbstractBackgroundSeveral previous studies have analyzed the genetic expression in late‐onset Alzheimer’s disease (AD). In this study, we aim to analyze the differential gene expression between sporadic early‐onset AD (sEOAD) and autosomal dominant AD due to the presence of PSEN1 mutations (PSEN1) in two type of samples, brain tissue and lymphoblastoid cell lines (LCL).MethodFrozen prefrontal cortex (5 CTRL, 4 sEOAD and 4 PSEN1) was obtained from the Neurological Tissue Bank and LCL (5 CTRL, 5 sEOAD and 5 PSEN1) from the Alzheimer’s Disease Unit, both from the Hospital Clinic of Barcelona, IDIBAPS. Gene expression was measured with microarray Clariom D (Affymetrix). Differentially expressed genes (DEG) were obtained selecting the 35% most variable genes (n = 8473) by adjusting a linear model with empirical Bayes moderation of the variance. Significance threshold was set at p.value < 0.05 and fold change in absolute value >0.5. The analysis of biological significance was based on gene set enrichment analysis on Reactome Pathway Knowledge database.Result781/355 (brain/LCL) genes were differentially expressed in the sEOAD vs CTRL comparison, 503/275 in the PSEN1 vs CTRL, and 244/115 in the PSEN1 vs EOAD. No DEG were found with a significance threshold of an adjusted p.value <0.05. Any of the DEG survived after multiple comparisons correction. The top 10 enriched pathways for each comparison, using the most significative p.value and a normalized enrichment score (NES) absolute value >1.8, were considered. Pathways involved in synapsis were found in 2 comparisons: sEOAD vs CTRL (brain) and PSEN1 vs CTRL (LCL). Pathways related to metabolism (mainly Krebs cycle) were identified in all comparisons between patients and controls in both tissues. Signal transduction pathways were found in all comparisons. Immune system was observed in all comparisons between PSEN1 and sEOAD, as well as sEOAD vs CTRL in brain.ConclusionGenes involved in the immune system and signal transduction pathways were differentially expressed in sporadic and autosomal dominant AD caused by PSEN1 mutations. The number of DEG was higher in brain tissue than in LCL comparisons. Validation of these findings by quantitative‐PCR would be necessary to discard false positive results.
Amyloid Pattern Similarity Score (AMPSS): A reference region free measure of amyloid PET deposition in Alzheimer’s disease
Authors: Prosser Lloyd , Veale Thomas , Malone Ian B , Coath William , Fox Nick C , Cash David M 
Published: December 2020

AbstractBackgroundAmyloid‐PET has high sensitivity for cerebral amyloid, a hallmark of Alzheimer’s disease (AD). Typically, a global measure of amyloid burden in used to classify individuals as amyloid positive or negative. Measures like the Standarised Uptake Value ratio (SUVr) rely on a reference region to normalise amyloid measures, but are non‐specific, sensitive to delineation errors, and reference region choice is debated. This study evaluates a summary measure based on the multivariate pattern of amyloid deposition without a reference region, named Amyloid Pattern Similarity Score (AMPSS).MethodAlzheimer’s Disease Neuroimaging initiative (ADNI) individual and volumetric T1 MRI data were co‐registered. MRI data was then spatially normalised using DARTEL. Combined, these two transforms then map PET data into common space. A support vector machine (SVM) was trained using a) age‐matched normal controls with higher CSF Aβ42, and b) individuals with clinical diagnosis of AD and lower CSF Aβ42(Table 1). Normalised grey matter voxels were used as the SVM features. Rather than conventional binary classification, the SVM generated probabilistic scores based on logistic regression (i.e. AMPSS). Three evaluations were performed: (1) a validation set (Table 1), (2) comparison with CSF determined amyloid status, and (3) initial longitudinal trajectory evaluation (Table 2).ResultThe validation set AMPSS perfectly classified AD and controls. AMPSS results did not differ depending on specific reference region or global signal normalisation (between subjects ANOVA F(2,26) = 0.65, p = 0.526, r2 .99). AMPSS showed high concordance with CSF defined amyloid status. Figure 1 highlights the strong AMPSS and CSF relationship. There was a nominal, non‐significant improvement in accuracy for this method compared to SUVr (p=.176), Figure 2. Longitudinal data highlighted that individuals with baseline AMPSS >50% tended to show increased AMPSS at follow‐up, while most individuals <50% baseline AMPSS remained stable. However, there is evidence of some individuals with subthreshold amyloid accumulation. (Table 3, Figure 3.).ConclusionThe Amyloid Pattern Similarity Score is a reference‐free summary metric of amyloid deposition that performs comparably with conventional SUVr measures. Initial validation shows high agreement with CSF and good sensitivity to increasing amyloid accumulation over time, even in early disease.
Pathways involved in the relationship between resilience and cognitive function: The Memento cohort
Authors: Grasset Leslie , Chêne Geneviève , Dubois Bruno , Vellas Bruno , Pasquier Florence , Blanc Frédéric , Paquet Claire , Hanon Olivier , Gabelle Audrey , Ceccaldi Mathieu , Annweiler Cedric , Salmon Pierre Krolak , Dufouil Carole ,   Memento Study Group
Published: December 2020

AbstractBackgroundGiven the burden related to dementia, identifying prevention targets against cognitive aging and Alzheimer’s disease (AD) and related disorders is of high interest. While factors of resilience, i.e. education, physical or cognitive activity, or social network, are thought to mitigate the effect of cerebral damage on cognition, mechanisms involved are not well understood. This work thus aims to investigate the pathways involved in the association between resilience and cognition.MethodData were collected as part of the Memento study, a French nationwide cohort including patients from 28 memory clinics with either isolated cognitive complaints or mild cognitive impairment. Factors contributing to resilience, such as education level, salary, physical activity, leisure activities, or social network, as well as MRI markers of brain health were collected at baseline. AD cerebrospinal fluid (CSF) biomarkers were assessed in a subsample (n=410). Based on resilience factors, we established a global resilience score using a latent variable from a structural equation model. Structural equation models were also used to evaluate cross‐sectional pathways between resilience, brain ageing biomarkers in relation to cognition, taking into account potential confounders (Figure). Estimates from latent variables were standardized and results reported are for one SD of resilience.ResultParticipants’ mean age was 70.9 years old, 62% were women, 28% were APOE‐ε4 carriers, and 59% had a CDR score of 0.5. Resilience score obtained for each participants, ranged from ‐2.28 to 2.73. AD CSF biomarkers were all significantly associated with worse cognition. Higher resilience was significantly associated with higher cognitive performances (total βres_cog=0.569, p<.0001). In addition to a direct effect on cognition (direct βres_cog=0.519, p<.0001), this association was partly mediated by an indirect effect of resilience on cognition (indirect βres_cog=0.050, p<.0001) through lower neurodegeneration (direct βres_nd=‐0.128, p<.0001). White matter hyperintensities volume, CSF Aβ42/Aβ40 ratio, and CSF phosphorylated tau were not involved in the association between resilience and cognition.ConclusionResilience preserves cognitive functions both directly and indirectly through an apparent protection against neurodegeneration. Beside, AD and small vessel disease markers are not associated with resilience and they do not mediate the protective effect of resilience on cognition.
Chimeric models to analyze human neuron and astroglia responses in Alzheimer's disease
Authors: Arranz Amaia M. , Preman Pranav , T.C.W. Julia , Snellinx An , Calafate Sara , Thal Dietmar Rudolf , Goate Alison M. , De Strooper Bart 
Published: December 2020

AbstractBackgroundWe have previously generated a chimeric model of Alzheimer´s disease (AD) by transplanting human pluripotent stem cell (PSC)‐derived neurons into the brain of a rodent model of AD. Remarkably, human neurons integrate efficiently into the mouse brain and show main pathological hallmarks of AD such as abnormal Tau phosphorylation, pathological Tau conformational changes and major degeneration and cell loss. However, PSC‐derived mouse neurons transplanted into the mouse brain are not able to recapitulate main AD hallmarks, which reveals a selective vulnerability of human neurons to the amyloid pathology and associated neuroinflammation.MethodOn follow‐up studies, we are generating a chimeric model of AD using a similar experimental approach and transplanting human PSC‐derived astrocytes into the brain of AD mice.ResultHuman astrocytes also integrate in the mouse host brain and mature in a cell‐autonomous way maintaining their human‐specific properties. Interestingly, human astrocytes interact with Aβ plaques showing differential morphological responses.ConclusionThis novel data highlights the importance of studying both human neurons and glia cells on the context of AD.