bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lifestyle differences modulate the effects of cognitive reserve on functional connectivity
Authors: Ersözlü Ersin , Rauchmann Boris , Peters Oliver , Priller Josef , Schneider Anja , Wiltfang Jens , Jessen Frank , Düzel Emrah , Bürger Katharina , Teipel Stefan J. , Christoph Laske , Spottke Annika , Ramirez Alfredo , Cardenas‐Blanco Arturo , Wagner Michael , Perneczky Robert 
Published: December 2020

AbstractBackgroundCognitive reserve (CR) refers to the individual differences in cognition relative to brain aging or neurodegenerative changes. Recently, various studies tried to quantify a marker that represents CR. Among others, the residual approach suggested being relatively reliable as it has been studied not only with cross‐sectional but also with longitudinal observations. However, it is unknown if brain connectivity changes in the resting‐state are related to reserve factors e.g. lifestyle factors.MethodIn the present study we defined a CR Marker based on residuals calculated through a multimodal (multi‐linear) regression model adapted from a recent study using pathological changes of AD such as atrophy, demographic and genetic information as predictors. The data of 546 participants including healthy controls, participants with subjective cognitive decline, 62 patients with MCI, and 64 patients with AD from the German multicentric DELCODE cohort was assessed. To examine neural substrates of defined CR marker, we constructed a weighted undirected partial correlation matrix in the GraphVar toolbox and analyzed graph theoretical metrics in global topography with various network thresholds. Permutation‐based FDR‐correction has been used in statistical analyses with graph measures. Then we examined the possible associations between CR and lifestyle factors specifically the Lifetime Experiences Questionnaire(LEQ).ResultCR was positively correlated (r=0.247, p=0.012) with higher scores in LEQ which includes leisure, educational and physical activities across the lifespan. We demonstrated that LEQ interacts with CR in functional connectivity changes, we used a multivariate regression model, in which LEQ was binarized using median values of total normalized scores. At the global level, interaction between CR and binarized LEQ score has been found with clustering coefficient (p=0.02), transitivity (p=0.017), but not with global efficiency(p=0.45). Moreover, component of LEQ scores corresponding to young adulthood, mid‐life, and late‐life didn’t interact with CR. However, LEQ of late‐life showed interaction at marginal level(uncorrected p=0.03).ConclusionOverall, CR and lifestyle differences appear to be reflected by changes in brain connectivity with increased global information processing capacity in participants exhibit higher CR. These findings foster understanding of early AD and will be useful to help identify individuals with vulnerability or resistance to AD pathology.
Transcriptome characterization of the motor cortex suggests microglial‐related key events due to TDP‐43 aberrant inclusions
Authors: Dols‐Icardo Oriol , Montal Victor , Dolcet Sonia Sirisi , López‐Pernas Gema , Cervera‐Carles Laura , Querol‐Vilaseca Marta , Muñoz Laia , Molina‐Porcel Laura , Pegueroles Jordi , Turón‐Sans Janina , Blesa Rafael , Lleó Alberto , Fortea Juan , Rojas‐García Ricard , Clarimon Jordi 
Published: December 2020

AbstractBackgroundTAR DNA binding protein 43 (TDP‐43) is an RNA binding protein with a central role in transcription regulation. Evaluation of the transcriptome in affected brain tissues with aggregated TDP‐43 will allow us to better understand the pathological processes occurring in a variety of neurodegenerative disorders.MethodWe performed massive RNA sequencing in the motor cortex (BA4) of amyotrophic lateral sclerosis (ALS) patients (n = 11) and controls without lesions (HC; n = 8). Differential gene and isoform expression between patients and controls were evaluated with DESeq2. Gene ontology and KEGG pathway enrichment analyses were applied using default parameters in Metascape 3.0. The Multi‐Subject Single Cell deconvolution algorithm (MuSiC) was used to perform cell‐type deconvolution of our bulk RNAseq data. Formalin‐fixed and paraffin‐embedded motor cortex sections were used for immunohistochemistry, with IBA1 and ps409/410‐TDP primary antibodies. For immunofluorescence, anti‐MHCII markers (HLA‐DP,DQ,DR) and anti‐IBA1 were employed.ResultDifferential gene expression between ALS patients and HC disclosed 108 up‐regulated and 16 down‐regulated genes in the motor cortex (Figure 1; adj. p < 0,05). Gene ontology and KEGG pathway analyses revealed an enriched involvement of the inflammatory response in ALS. The assessment of changes at the isoform expression level also pointed towards an enrichment of the immune response as a dominant pathway, but also revealed a postsynaptic involvement. Characterization of cell type variability from bulk RNA‐seq data, using available single‐nucleus RNAseq data comprising 70.634 cells from Alzheimer’s disease and HC subjects (n = 48) (Mathys et al., Nature 2019) as reference, revealed an overrepresentation of microglial cells in the ALS motor cortex as compared to HC (p = 0,025) (Figure 2). Our deconvolution analysis also showed that a specific microglial subpopulation, recognized as the recently described disease associated microglia (DAM) was disproportionately present in ALS (p = 6,6 × 10−3) (Figure 3). Immunofluorescence through the combination of IBA1 and MHC class II markers confirmed the over representation of this cell subtype in the motor area of ALS cases.ConclusionThe presence of insoluble TDP‐43 inclusions in affected brain tissue leads to RNA dyshomeostasis, with genes related to inflammation and synaptic functions as major altered transcriptome signatures. The recently described DAM play a key role in ALS and maybe other TDP‐43 related proteinopathies.
Impact of the APOE gene on amyloid deposition in participants with abnormal soluble amyloid levels
Authors: Cacciaglia Raffaele , Molinuevo Jose Luis , Salvadó Gemma , Suárez‐Calvet Marc , Fauria Karine , Minguillón Carolina , Shekari Mahnaz , Farrar Gillian , Buckley Christopher , Blennow Kaj , Zetterberg Henrik , Gispert Juan Domingo ,   the ALFA Study
Published: December 2020

AbstractBackgroundAmyloid pathology can be quantified both in the cerebro‐spinal fluid (CSF) and in positron emission tomography (PET) images, even though they measure two distinct amyloid pools. While CSF Aβ reflects the clearance of soluble amyloid species from the brain, PET imaging informs on the presence of insoluble fibrillary plaques. Many studies have shown the concordance of the two measures in individuals along the Alzheimer’s disease (AD) continuum. Here, we assessed whether APOE‐ε4, the major genetic risk factor for AD, affects the pattern of cerebral Aβ‐load as a function of CSF Aβ levels.MethodThe first consecutive 276 cognitively unimpaired (CDR=0) individuals of the ALFA+ study, aged between 48 and 74, with valid structural MRI and [18F]Flutemetamol (FTM) PET, APOE genotyping and CSF samples were included. Aβ‐40 and Aβ‐42 concentrations were determined with the NeuroToolKit (Roche Diagnostics International Ltd.) on a Elecsys cobas e‐411 instrument and parametric standardized uptake value ratio images (SUVr) were calculated with the whole cerebellum as reference region. A voxelwise regression to predict FTM uptake was performed, with the following independent variables: Age, Sex, APOE‐ε4, and CSF Aβ‐42/40. Statistical threshold was set to p<0.001 with a cluster extent correction of 100 voxels.ResultAs expected, CSF Aβ‐42/40 was strongly and negatively associated to cerebral FTM uptake (Fig. 1a‐1b). Age and APOE‐ε4 gene dose mapped onto distinct spatial patterns of FTM binding across the whole sample (Fig. 2b‐2c). Importantly, we found a significant interaction between Aβ‐42/40 and APOE‐ε4 indicating that carriers had a negative association between fluid and imaging Aβ measures in the bilateral hippocampus, as well as the bilateral middle temporal and temporo‐parietal junction (Fig. 3).ConclusionCompared to non‐carriers, APOE‐ε4 carriers show higher cerebral amyloid load for any given level of CSF Aβ 42/40 in areas which are not typically vulnerable to Aβ deposition yet undergoing neurodegeneration early in the AD continuum, such as the hippocampus. This suggests that APOE‐ε4 may influence the biological mechanisms regulating the equilibrium between soluble and deposited amyloid, which may transcend the hindering effect caused by Aβ fibrillary plaques and render medial temporal lobe structures particularly vulnerable when Aβ metabolism becomes deficient.
Dorsolateral prefrontal cortex excitability assessed using TMS‐EEG and its relationship with neuropsychiatric symptoms in Alzheimer’s dementia
Authors: Joseph Shaylyn , Zomorrodi Reza , Ghazala Zaid , Knezevic Dunja , Blumberger Daniel M. , Daskalakis Zafiris J. , Mulsant Benoit H. , Pollock Bruce G. , Rajji Tarek K. , Kumar Sanjeev 
Published: December 2020

AbstractBackgroundNeuropsychiatric symptoms (NPS) are common in patients with Alzheimer’s Dementia (AD) and cause substantial distress to patients and caregivers. Mechanisms underlying NPS are not well known. Studies have found increased cortical excitability in patients with AD. Studies in other neuropsychiatric disorders have found increased cortical excitability in association with NPS. We hypothesized that cortical excitability will be negatively associated with cognition and positively associated with NPS in AD.MethodThis cross‐sectional study included participants diagnosed with probable AD using the NIA‐AA core clinical criteria. Cognition was assessed using Montreal Cognitive Assessment (MoCA) and NPS were assessed using the Neuropsychiatric Inventory‐Questionnaire (NPI‐Q). NPIQ agitation‐hyperactivity domain scores were calculated by combining scores on agitation, aggression, anxiety, disinhibition and irritability domains. Motor threshold and Transcranial Magnetic Stimulation (TMS) intensity sufficient to induce 1 millivolt (mV) peak to peak motor evoked potential were calculated as per established methods. TMS at the 1mV intensity was applied to the dorsolateral prefrontal cortex (DLPFC) at a frequency of 0.1 Hz. Electroencephalography was collected during TMS. Cortical excitability was assessed using rectified area under the curve (AUC) for TMS‐evoked potential (TEP) during early (25‐80 ms) and late phases (80 – 200 ms). Individual TEP peak amplitudes were also calculated.ResultThe study included 25 participants (female = 17, Mean (SD) age = 74.3(7.1) Years, Mean (SD) MoCA score = 17.5 (4.6)). There was a negative correlation between MoCA and the TEP early AUC at the DLPFC site of stimulation (Spearman’s rs = ‐ 0.589, n = 24, p = 0.002). In contrast there was a positive correlation between NPI‐Q agitation ‐ hyperactivity domain scores and the TEP early AUC (Spearman’s rs = 0.422, n = 24, p = 0.04). There was also a positive correlation between total NPIQ and early TEP (P30) amplitude.ConclusionCortical excitability in the DLPFC is inversely associated with cognition and positively associated with NPS in AD. Specifically, increased excitability found during the early TEP duration suggests potential role of aberrant glutamatergic transmission and overall gamma amino butyric acid and glutamate imbalance. These findings may have important implications for developing treatment interventions targeting cortical excitability in AD.
Iatrogenic transmission of Alzheimer's disease: Evidence based on experimental inoculation of Alzheimer's brains into a primate
Authors: Dhenain Marc , Lam Suzanne , Gary Charlotte , Herard Anne‐Sophie , Koch James , Petit Fanny , Gipchtein Pauline , Sawiak Stephen , Caillierez Raphaelle , Eddarkaoui Sabiha , Colin Morvane , Aujard Fabienne , Deslys Jean‐Philippe , Duyckaerts Charles , Brouillet Emmanuel , Comoy Emmanuel , Pifferi Fabien , Picq Jean‐Luc ,   French Neuropathology Network
Published: December 2020

AbstractBackgroundEpidemiologic data suggest that, in humans, iatrogenic administration of compounds (cadaver‐sourced human growth hormone, dura mater graft) or cerebral surgeries with tools contaminated with Aβ and tau induce aggregated Aβ and possibly tau lesions. Aβ and tau lesions could thus be iatrogenically transmitted to humans. Several studies in mice have shown that experimental inoculation of amyloid and/or tau‐positive brain samples into transgenic (tg) mouse models overexpressing Aβ or tau promotes either Aβ or tau aggregation in the brain of the recipient animal. Unlike rodents, primates naturally express Aβ or tau under normal conditions and they have a biochemical and physical cerebral environment that is closer to that of humans than that of mice. The aim of this work was to evaluate the impact of human brain samples inoculations in the mouse lemur primates.Method12 adult mouse lemurs, aged from 3 to 4 years old, were included in this study. Human brain homogenates from AD patients or control (CTRL) age‐matched subject were bilaterally inoculated in the hippocampus and subjacent cortex (n = 6/group). We performed longitudinal cognitive, electroencephalography (EEG) and morphological MRI studies up to 18 months post‐inoculation followed by immunohistopathological examination of brain tissues.ResultMouse lemurs inoculated with Alzheimer brain homogenates displayed progressive cognitive impairments (clinical tests assessing cognitive and motor functions), modifications of neuronal activity (detected by electroencephalography), widespread and progressive cerebral atrophy (in vivo MRI assessing cerebral volume loss using automated voxel‐based analysis), neuronal loss in the hippocampus and entorhinal cortex (post mortem stereology). They displayed parenchymal and vascular Aβ depositions and tau lesions for some of them, in regions close to the inoculation sites.ConclusionThis study is the first one to highlight neuronal and clinical dysfunction following inoculation of Alzheimer’s disease brain homogenates in a primate. Based on controlled experiments, it suggests the possible iatrogen transmission of Alzheimer pathology. Acknowledgments: We thank the “GIE NeuroCEB” Brain Bank, the France‐Alzheimer Association, the Fondation Plan Alzheimer, and the CEA Bottom‐Up program.
Long‐chain omega‐3 polyunsaturated fatty acids, brain atrophy, cognitive decline and dementia risk
Authors: Thomas Aline , Baillet Marion , Proust‐Lima Cécile , Féart Catherine , Foubert‐Samier Alexandra , Helmer Catherine , Catheline Gwenaelle , Samieri Cécilia 
Published: December 2020

AbstractBackgroundLong‐chain omega‐3 polyunsaturated fatty acids (n‐3 PUFA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), mainly provided together by fish intake in the human diet, are important constituents of neural membranes. Epidemiological studies reported associations between long‐chain n‐3 PUFA intakes or blood concentrations, and lower risks of dementia and related outcomes (cognitive decline, brain atrophy). However, evidence has been inconsistent according to the type (e.g., EPA, DHA or total n‐3 PUFA) and/or the exposures (intake versus blood status) investigated. Moreover, previous studies displayed short follow‐up periods (generally less than 5 years). In this study, we took advantage of the long follow‐up for dementia and related outcomes in a large cohort of older persons, the Three‐City (3C) study, to look for robust associations of an omega‐3 index in plasma (EPA+DHA), with the long‐term evolution of three complementary outcomes: atrophy of the medial temporal lobe (MTL, a biomarker of dementia), cognitive decline and incidence of dementia.MethodWe included 1279 participants (aged ≥65) from the 3C study, non‐demented at the time of blood measurements at baseline. Face‐to‐face neuropsychological assessments at baseline and follow‐up visits (7 visits over 17 years) were used to evaluate global cognitive decline (n=1185), memory decline (n=1039), and for the systematic detection of incident dementia. An ancillary study included 467 participants with up to three repeated brain imaging exams over 10 years (FreeSurfer 5.1 segmentation). Linear mixed models were used to assess the associations between plasma EPA+DHA and trajectories of global cognition, memory and MTL volumes. The association between EPA+DHA and the risk of dementia was estimated by a Cox model.ResultHigher levels of plasma EPA+DHA were associated with a lower risk of dementia (HR for 1SD = 0.87 [95% CI, 0.76‐0.98]), and a lower decline in global cognition (P = .04 for change over time), memory (P = .06) and MTL volume (P = .02).ConclusionThe consistency of the long‐term associations found between higher levels of plasma EPA+DHA and three dementia related outcomes in this large cohort of older adults provides compelling evidence for the interest of long‐chain n‐3 PUFA in dementia and cognitive decline prevention.
Body & Brain Project: Effectiveness of a 6‐month multicomponent training on cognitive function, quality of life and functional capacity of older adults with dementia
Authors: Barros Duarte Gabriel Moleiro , Borges‐Machado Flávia , Bohn Lucimere , Sampaio Arnaldina , Ribeiro Oscar , Carvalho Joana 
Published: December 2020

AbstractBackgroundEvidence is warranted to attest the therapeutic role of exercise as a non‐pharmacological adjuvant treatment for dementia. Multicomponent Training (MT) characterizes exercise sessions combining two or more physical fitness components (i.e. endurance, strength, balance, and flexibility), and it has been suggested as a feasible training modality for dementia patients. This study aims to analyze the effectiveness of a MT intervention on cognitive function, quality of life and functional capacity of older adults diagnosed with dementia.MethodThis is a non‐randomized controlled trial comprising 41 participants (29 females), from hospitals, daycare centers and municipalities – and was conducted in 8 community‐based settings. Subjects were allocated in exercise group (EG; N: 22; 76.3 years ± 1.40; age range: 61‐90) and control group (CG; N:19; 82.6 years ± 1.27; age range: 73‐90). EG trained twice a week (50 min) for 6 months in a MT regime. CG had a monthly recreational session during the same period. Alzheimer’s Disease Assessment Scale – Cognitive (ADAS‐Cog), Quality of Life – Alzheimer’s Disease (QoL‐AD), and Short Performance Physical Battery (SPPB) tests were applied before and after the 6‐months intervention period.ResultBaseline medium score on Mini Mental State Examination was 21.1 (± 5.02) points. There was a significant group*time interaction on QoL‐AD total score (F (1,38) = 5.94, η2 = 0.135, p < 0.02) and on SPPB total score (F (1,37) = 14,94, η2= 0.29, p < 0.001) favorable to EG. No significant group*time interaction was depicted in cognitive function (F (1,38) = 0.467, η2= 0.012, p = 0.499). When adjusting for age, EG group maintained ADAS‐Cog score through time, and CG showed an increased score from baseline (27.97 ± 2.89) to post‐intervention time (29.34 ± 3.45), representative of decreased cognitive performance.ConclusionData suggest that a MT intervention may improve functional capacity in patients diagnosed with dementia. It may also positively influence quality of life, once CG experienced a significant decrease after 6 month, despite baseline differences between groups. Further research is necessary to confirm the MT effectiveness on preserving cognitive function. Supported by FCT: CIAFEL (FCT/UIDB/00617/2020), “Body and Brain” Project (POCI‐01‐0145‐FEDER‐031808), and PhD Grant (SFRH/BD/136635/2018); & IPDJ.
Dorsolateral prefrontal functional connectivity predicts transfer of working memory gains after cognitive training
Authors: Faraza Sofia , Waldenmaier Julia , Dyrba Martin , Wolf Dominik , Fellgiebel Andreas , Teipel Stefan J 
Published: December 2020

AbstractBackgroundNormal aging is associated with working memory decline. A decrease in working memory performance is associated with age‐related changes in functional activation patterns in the dorsolateral prefrontal cortex (DLPFC). Cognitive training can improve cognitive performance in healthy older adults. We implemented a cognitive training study to assess determinants of transfer of gains to untrained tasks, a key indicator for the effectiveness of cognitive training. We aimed to investigate the association of resting‐state functional connectivity of DLPFC with working memory performance improvement and successful transfer of gains after training.MethodA sample of 60 healthy older adults (mean age: 68 years) underwent a 4‐week cognitive training of working memory. Baseline resting‐state functional magnetic resonance imaging in order to investigate the functional connectivity of DLPFC. To evaluate transfer and training effects, participants underwent a neuropsychological assessment before and after the training. A second follow‐up assessment was applied 12 weeks after the training. We used cognitive scores of Digit span backwards and Visual block span backwards tasks representing working memory function. The training group was divided in subjects who had and who did not have successful transfer, which was defined as higher improvement in working memory tasks than the control group.ResultA high functional connectivity of DLPFC of the right hemisphere was a significantly associated with successful transfer of gains and performance improvement in the visuospatial task. Transfer effects were limited and maintenance of gains was restricted to the time period directly after the training. The training group showed performance improvement in the Digit span backwards task.ConclusionFunctional activation patterns of DLPFC during visuospatial task contribute to successful transfer and performance improvement. Even though transfer is possible in aging, it remains limited.
Assessing the reliability of reported medical history in older adults
Authors: Day Gregory S , Long Allison , Morris John C 
Published: December 2020

AbstractBackgroundA reliable history is critical to establish accurate clinical diagnoses, prioritize investigations and select appropriate treatments; yet few studies have considered the factors that influence the reliability of medical histories. Recognizing this, we determined the accuracy of medical history in community‐dwelling older adults engaged in longitudinal studies of memory and aging.MethodThe association between participant‐specific factors and accurate reporting of stroke or diabetes were evaluated using multivariable logistic regression in 1,401 participants enrolled in studies at the Knight Alzheimer Disease Research Center (Saint Louis, Missouri), including 425 participants with dementia (30.3%). History was verified with a reliable collateral source in all participants. Stroke and diabetes were selected as index variables, as gold standard measures—brain MRI for stroke and hemoglobinA1c (HbA1c) for diabetes—were routinely obtained in participants.Result25/862 (2.9%) participants endorsed a history of stroke, which was confirmed on MRI in 8/25 (positive predictive value, 17.4%). Stroke was detected on MRI in 38/837 (4.5%) of those without reported stroke (negative predictive value, 95.5%). Older age (OR per decade=1.7, 95%CI: 1.2‐2.5) and use of an unrelated collateral source (OR=2.0, 95%CI: 1.03‐3.7) were associated with greater odds of inaccurate reporting of stroke history. 190/1322 (14.4%) participants reported a history of diabetes, which was confirmed with HbA1c in 105/190 (positive predictive value, 55.3%). HbA1c 6.5% was detected in 29/1132 (2.6%) of those who denied diabetes (negative predictive value, 97.4%). African Americans (OR=1.6, 95%CI: 1.02‐2.6) and those with hypertension (OR=2.6, 95%CI: 1.5‐4.2) or HbA1c compatible with impaired glucose tolerance (OR=4.2, 95%CI: 2.7‐6.4) had greater odds of reporting a history of diabetes. Cognitive impairment was not associated with inaccurate reporting of stroke or diabetes.ConclusionThe accuracy of reported history of diabetes and stroke was low in older community‐dwelling participants, independent of cognitive status. A history of diabetes or stroke should be objectively confirmed when relevant to decision making in clinical and research settings.