bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of a probiotic administration on inflammatory profile and clinical features in patients with Alzheimer’s disease
Authors: Mombelli Elisa , Lopizzo Nicola , Marizzoni Moira , Mirabelli Peppino , Luongo Delia , Salvatore Marco , Frisoni Giovanni B. , Cattaneo Annamaria 
Published: December 2020

AbstractBackgroundIncreasing evidence shows that the gut microbiota (GMB) may affect the inflammatory status and influence the pathogenesis of several brain disorders, including Alzheimer’s Disease. Moreover, it has been suggested that probiotics may have potential beneficial effects on the immune system via microbiome composition, influencing in turn also cognitive performances.MethodSixty‐two old subjects with normal cognitive performance and 37 AD patients were recruited and stool and blood samples were collected. Moreover, the group of AD patients received a probiotic administration for three months and stool and blood samples were collected again at the end of the treatment. Plasma levels of a panel of pro‐inflammatory cytokines were measured by using the High Sensitivity 9‐Plex Human ProcartaPlex™ Panel (IFN‐ϒ, IL‐1b, IL‐2, IL‐4, IL‐6, IL‐10, IL‐12p70, IL‐17A and TNFα, Thermo Fisher Scientific) on Luminex Bio‐Plex® 200™ system. Moreover, we also measured the plasma levels of C‐Reactive Protein (CRP) using the CRP Human Instant ELISA Kit (Thermo Fisher Scientific). Bacterial composition of fecal samples was inferred using 16s sequencing; the levels of the short chain fatty acids acetate, propionate, valerate and butyrate were measured by mass spectrometry and adhesion molecules by FACS.ResultWe found higher levels of the pro‐inflammatory cytokines IL‐6, IFN gamma, TNF‐alpha, IL‐1beta, and il12p70 and of IL‐2 and lower levels of the anti‐inflammatory cytokine IL‐10 in AD patients as compared to control subjects (all p<0.05). Moreover, we found a positive correlation between MMSE score and the levels of pro‐inflammatory cytokine IL‐6 (p=0.03, r=0.56). Interestingly, the three months treatment with the probiotic composition was able to significantly reduce the level of IL‐6 (p=0.03) and increase the levels of IL‐10 (p=0.023). Bioinformatic analyses on the 16s sequencing data as well as on the SCFAs and endothelial markers are ongoing.ConclusionInflammatory status is higher in AD patients as compared to control subjects and it correlates with cognitive performances. Interestingly probiotic composition is able to push down the inflammatory status in patients, possibly via changes in microbiome composition. Probiotics may be beneficial in delaying neurodegeneration and cognitive deficits in subjects at risk of developing Alzheimer Disease.
A study of alpha desynchronization, heart rate, and MRI during stroop testing unmasks pre‐symptomatic Alzheimer’s disease
Authors: Arakaki Xianghong , Hung Shao‐Min , Wei Ke , Tran Thao , Arechavala Rebecca Johnson , Kleinman Michael T. , Kloner Robert , Fonteh Alfred N. , King Kevin , Harrington Michael G. 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) studies suggested the need to detect pre‐symptomatic stage, when cognitive challenges reveal changes of alpha power (brain hyperactivity). Heart rate (HR) regulates brain oxygen supply, is regulated by the brain (eg. hippocampus and amygdala), and correlated with resting state alpha power. We aimed to compare alpha power, HR, and hippocampal and amygdala volume between pre‐symptomatic AD and normal, aging individuals.MethodWe employed quantitative electroencephalography (qEEG) to monitor brain activity during resting and during Stroop interference testing. Cognitively healthy (CH) study participants (demographically matched) were recruited from the local community, consisting of two subgroups based on cerebrospinal fluid (CSF) proteins: with normal amyloid/tau ratio (CH‐NAT, n=20) or pathological amyloid/tau ratio (CH‐PAT, equals pre‐symptomatic AD, n=21). Cognition was assessed using Montreal Cognitive Assessment (MoCA) and Mini‐Mental State Examination‐7 (MMSE‐7). Participants were presented a series of colored words and asked to respond to each word for the color of the ink, including low load (congruent trials, when color matches the word) and high load (incongruent trials, when color does not match the word). Comparisons between two groups include: alpha desynchronization and alpha spectral entropy (SE), as well as the relationships of alpha desynchronization, HR after Stroop testing, and hippocampal and amygdala volumes (1.5T MRI, demographically balanced subgroups).ResultNo alpha differences were found during the resting state. Occipital alpha desynchronization of CH‐PATs was more negative than in that of CH‐NATs (p=0.024) during the congruent trials (Figure 1), indicating hyperactivity during low load. CH‐PATs had higher alpha SE during congruent trials (p=0.042 frontal, p=0.039 occipital), and lower frontal SE change from congruent to incongruent trials (p=0.012) (Figure 2), supporting reduced functional reserve. Alpha desynchronization positively correlated with HR in CH‐PATs but not CH‐NATs; alpha desynchronization correlated with hippocampal or amygdala differently between CH‐NATs and CH‐PATs (Figure 4). Multiple spectral frequencies revealed correlations in MMSE‐7 & MoCA that differed between CH‐NATs and CH‐PATs.ConclusionThese results suggest that hyper‐excitability during low load challenge and limited brain reserve is manifest with increasing interference load in pre‐symptomatic AD. We also find brain‐heart coupling is altered in pre‐symptomatic AD.
Towards harmonizing subtyping methods for PET and MRI studies of Alzheimer’s disease
Authors: Mohanty Rosaleena , Mårtensson Gustav , Poulakis Konstantinos , Rodriguez‐Vieitez Elena , Grothe Michel , Nordberg Agneta K , Ferreira Daniel , Westman Eric 
Published: December 2020

AbstractBackgroundIdentification of biological subtypes in Alzheimer’s disease (AD) has become a growing field for understanding the heterogeneity of the disease. Subtypes, originally identified by postmortem markers (Murray et al., 2011), have been translated to utilize in vivo biomarkers such as those based on structural magnetic resonance imaging (sMRI) and positron emission tomography (PET). While there exists methodological variability across studies, comparable characteristics are reported at group‐level. However, the question that remains to be explored and the motivation for this study is: do group‐level similarities translate to individual‐level agreement across subtyping methods?MethodWe compared five subtyping methods reported in previous studies in a two‐part approach: (a) we validated the methods in 89 AD dementia patients (reference group: 70 healthy individuals; HC) from ADNI using sMRI only; (b) we extended and applied the methods to 30 AD dementia and 53 prodromal AD patients (reference group: 200 HC) from ADNI with concurrent sMRI and tau PET. All AD patients were Aβ positive while all HC were Aβ negative. Subtyping methods included four hypothesis‐driven (Byun et al, 2015; Ferreira et al., 2017; Murray et al., 2011; Risacher et al., 2017) and a data‐driven (Poulakis et al., 2018) algorithms and were implemented as outlined in each original study. Up to four subtypes were identified, namely: typical AD (TAD), limbic predominant (LP), hippocampal sparing (HS) and minimal atrophy (MA). Group‐level and individual‐level comparisons across methods were performed.ResultIn cohort (a), similar frequencies of subtypes were observed between reproduced and published values, thus, establishing proof‐of‐concept. However, comparison of individual‐level subtypes showed disagreement across methods. In the extended cohort (b), large disagreements were observed at the individual level. This is reflected by the low values of Cohen’s kappa, measuring the agreement between methods (Figure 1).ConclusionAlthough characteristics of subtypes are comparable at group‐level, there exist large disparities in individual‐level agreement across subtyping methods. Study of subtypes is growing rapidly by incorporation of multiple biomarkers and application to AD continuum. Thus, there is an urgent need for consensus and harmonization across methods to push the field forward.
Liraglutide and semaglutide: Pooled post hoc analysis to evaluate risk of dementia in patients with type 2 diabetes
Authors: Ballard Clive , Nørgaard Caroline Holm , Friedrich Sarah , Mørch Lina Steinrud , Gerds Thomas , Møller Daniel Vega , Knudsen Lotte Bjerre , Kvist Kajsa , Zinman Bernard , Holm Ellen , Torp‐Pedersen Christian , Hansen Charlotte Thim 
Published: December 2020

AbstractBackgroundGlucagon‐like peptide 1 receptor agonists (GLP‐1 RA) have previously shown improved measures of memory and reduced phospho‐tau burden in preclinical animal models relevant to progressive cognitive impairment (Hansen. J Alzheimers Dis.2015;46:877‐88; Hansen. Brain Res.2016;1634:158‐70). Liraglutide and semaglutide are structurally similar GLP‐1 RAs associated with potent glucose‐lowering effect, body weight loss and cardiovascular benefits shown in large cardiovascular outcomes trials (CVOTs) (Marso. N Engl J Med.2016;375:311‐22; Marso. N Engl J Med.2016;375:1834‐44; Husain. N Engl J Med.2019;381:841‐51). In order to investigate the potential effects of GLP‐1 RA on dementia in a clinical setting, a post‐hoc analysis was conducted based on pooled data from three CVOTs.MethodLEADER, SUSTAIN 6 and PIONEER 6 were randomised, double‐blind, multicentre, placebo‐controlled CVOTs evaluating the cardiovascular effect of liraglutide or semaglutide vs. placebo, added to standard of care. The trials included patients with type 2 diabetes and established or high risk of cardiovascular disease. A post‐hoc analysis on pooled data from the three CVOTs was considered appropriate due to the similarities in trial design, patient population and treatment effects. Across all trials 15,820 patients with median follow‐up of 3.6 years were included in this analysis. Dementia‐related adverse events (AEs) were identified using Standardised MedDRA (version 21.1) Query for “dementia” narrow search terms. AE data collection across the trials differed in line with the regulatory requirements at the time of trial conduct. In LEADER and PIONEER 6 only serious AEs were systematically collected, while all AEs were collected in SUSTAIN 6. A time‐to‐event analysis based on the Cox proportional‐hazards model using treatment as covariate was used to estimate the hazard ratio for developing dementia.ResultAcross the three CVOTs, 15 GLP‐1 RA‐treated patients and 32 placebo‐treated patients were identified with development of dementia (Figure). Post‐hoc analysis on the pooled data showed a significant estimated hazard ratio of 0.47 [0.25; 0.86]95%CI in favour of the GLP‐1 RA treatment versus placebo.Conclusion
Post‐hoc analysis based on pooled data from three double‐blinded CVOTs suggests, albeit with a low number of events, a reduced risk of dementia with liraglutide or semaglutide treatment in patients with type 2 diabetes.
Identification of clinical phenotypes of Alzheimer’s disease through the gut microbiota
Authors: Marizzoni Moira , Cattaneo Annamaria , Mirabelli Peppino , Luongo Delia , Mombelli Elisa , Salvatore Marco , Frisoni Giovanni B. 
Published: December 2020

AbstractBackgroundThe genetic, clinical and anatomical presentation of Alzheimer's disease (AD) is extremely heterogenous. Although increasing evidences show that alterations in the gut microbiota (GMB) composition are involved in AD, their contribution to AD pathology remain unclear. The aim of this study is to evaluate whether disease‐specific alterations of the microbiome are present in patients with AD pathology and can identify individuals with peculiar clinical features.MethodSixty‐two cognitive impaired subjects underwent Florbetapir amyloid PET and stool collection. Brain amyloidosis was measured with standardized uptake value ratio versus cerebellum (SUVRs) in the frontal, parietal, temporal, anterior cingulate, posterior cingulate and precuneus regions of interest. Amyloid positivity was defined as global PET florbetapir SUVR>1.11. Bacterial composition of fecal samples was inferred using 16S metagenomic sequencing, analyzed with QIIME 2 (Quantitative Insights into Microbial Ecology, https://qiime2.org/). We first compared amyloid negative (Amy‐) and positive (Amy+) patients with respect to GMB‐specific profiles. We then applied Principal Component Analysis (PCA) on those taxa found differentially abundant in Amy+ and Amy‐.ResultDespite a similar GMB structure (Unweighted and weighted Unifrac, p>0,05) of Amy+ (n=29) and Amy‐ (n=33), taxonomic comparison showed that Amy+ were mainly characterized by rare genera. PCA identified a small subgroup of 6 Amy+ with lower amyloid SUVR uptake in the temporal cortex (p=0,009) and lower cognitive deficits, as showed by better performance at MMSE, ADAScog, logical memory, Rey auditory verbal learning test, Raven’s progressive matrices test and Functional Activities Questionnaire (p<0.044) compared to the other Amy+ patients. Amyloid SUVR uptake in the temporal cortex was negatively associated with logical memory, Rey auditory verbal learning test, Raven’s progressive matrices test and Functional Activities Questionnaire (moderate: rho£0.44, p£0.047) and MMSE (weak: rho=0.36, p=0.076) as well as negatively associated with FAQ (moderate: rho=0.47, p=0.010) in the whole Amy+ group.ConclusionDespite the small sample size, this study suggests that distinctive bacterial signatures might be associated with specific clinical AD phenotypes.
The impacts in caregiver burden of getting lost events on family caregivers of patients with Alzheimer’s disease
Authors: Hong Wei‐Pin , Pai Ming‐Chyi 
Published: December 2020

AbstractBackgroundThe prevalence of Alzheimer’s disease (AD) is increasing. The caregiver burden on family caregivers also increased. Behavioral and psychological symptoms of dementia not only reduce the quality of life of patients living with AD and their family caregiver, but also increase risk of institutionalization from their originally living community. Topographical disorientation is common in patients with AD, which may result in getting lost (GL) events. GL in patients with AD is not uncommon. From previous researches, the prevalence of GL events in community are about 30%‐70%. This study will focus on the impacts of GL events on family caregivers since this kind of studies have been never conducted before.MethodIn our preliminary research, we have interviewed the family caregivers of patients with AD who experienced their first ever GL event. The most prominent events after GL was emotional stress and astonishment. In this research, we will interview the family caregivers whose patients with AD and have GL events in recent 3 months. We will divide them into two groups, one is patients with first ever GL event, the other is patients with repetitive GL events. We expect to enroll 100 pairs of patients and their family caregivers and 50/50 in each group. The patients and their family caregivers’ demographic data, patients’ cognitive function, and navigational abilities, and family caregivers’ emotional stress are collected, including Cognitive Abilities Screening Instrument (CASI), Questionnaire of Everyday Navigational Abilities (QuENA), Perceived Stress Scale (PSS) and Chinese version of Startle, Physically Upset by Reminders, Anger, and Numbness scale (SPAN‐C).ResultThe research has been ongoing. The final results will be disclosed during AAIC 2020. We hypothesis that GL events in patients with AD will make great emotional stress on their family caregivers, especially those who suffered from first GL events.ConclusionFamily caregivers of patients with AD should notice the potential risk of GL and make necessary prevention before it happened.
A comprehensive analysis of dementia cerebrospinal fluid biomarkers using GWAs, polygenic risk scores and Mendelian randomization in Parkinson’s disease
Authors: Ibanez Laura , Bahena Jorge Alberto , Dube Umber , Farias Fabiana H.G. , Yang Chengran , Harari Oscar , Cruchaga Carlos , Benitez Bruno A. 
Published: December 2020

AbstractBackgroundCerebrospinal fluid (CSF) levels of amyloid beta (Aβ), tau and p‐tau are the standard biomarkers for diagnosis and progression of Alzheimer disease (AD). CSF levels of Alpha‐synuclein (α‐Syn) have not been very informative in Parkinson’s disease (PD). The burden of Aβ plaques and Tau tangles inversely correlates with cognitive status in PD cases with dementia. However. Lewy body aggregated correlates with dementia progression in PD. A systematic study of CSF biomarkers in PD is yet to be complete, thus, we aimed to investigate the relationship between dementia biomarkers and PD using polygenic risk scores and Mendelian Randomization.MethodsGenome wide association analyses (GWAs) were performed in N = 1,960 individuals to define the genetic architecture of CSF biomarker levels (α‐syn, Aβ, tau and p‐tau). CSF values were normalized using Z‐score; linear regression was corrected by sex, age and population structure. We performed the same analyses in PD affected individuals only (N = 700) to evaluate if the signals were driven by the PD population. PD genetic architecture was obtained from the latest PD risk meta‐analysis (Nalls, et al 2019) summary statistics. .ResultsPRS analysis showed that CSF Aβ genetic architecture was correlated to that of PD (p = 2.5 × 10−11; R2 = 2.29%.), but not α‐syn, tau or p‐tau. Mendelian randomization methods found that CSF Aβ have a causal role in PD (p = 1.44 × 10−05); an effect mediated by a SNP near the APOE gene (rs769449). Additionally, a trend towards a causal association was found for α‐Syn and PD (p = 0.06). GWAs on PD only population did not reveal any new or known signal for those CSF proteins.ConclusionWe demonstrated that Aβ is involved in the causal pathway of PD, even though APOE does not seem to be related to CSF Aβ levels or PD risk in PD cohorts. α‐Syn also seems to have a causal relation with PD, but studies with a larger number of samples are needed.
Distinct neural substrates of receptive and responsive aspects of empathy in patients with neurodegenerative disease
Authors: Sollberger Marc , Toller Gianina , Miller Bruce L. , Rankin Katherine 
Published: December 2020

AbstractBackgroundThe way we interact with each other is influenced by how we perceive and evaluate socioemotional signals and adapt our interpersonal behavior to them (Lieberman, 2007). In this study, we investigated the neurostructural substrates of two key aspects of interpersonal behavior: socioemotional sensitivity and behavioral self‐management, using a neurodegenerative disease lesion model.MethodSocioemotional sensitivity and behavioral self‐management were measured by obtaining informant reports from two subscales of the Revised Self‐Monitoring Scale (RSMS)(Lennox & Wolfe, 1984). Scores were correlated with structural volume using voxel‐based morphometry. The study enrolled 360 participants, including 251 patients diagnosed with one of five neurodegenerative disease syndromes causing diverse structural brain changes (77 behavioral variant frontotemporal dementia, 30 semantic variant primary progressive aphasia, 33 non‐fluent variant primary progressive aphasia, 57 progressive supranuclear palsy, and 54 Alzheimer’s disease) and 109 neurologically healthy older controls.ResultSensitivity to others’ social cues was significantly predicted by volume in predominantly right‐hemispheric paralimbic ventro‐anterior‐ and mesio‐temporal regions, some of which are known to support auditory and visual social signal reading, while the remaining regions were part of the frontotemporal semantic appraisal network (Yeo, et al., 2011), involved in making social evaluations. In contrast, capacity to make behavioral adjustments in response to social cues was uniquely predicted by volume in predominantly right‐hemispheric neocortical frontal regions that comprise the cingulo‐opercular stable task control network (Dosenbach, et al., 2007), involved in maintaining attention during socioemotional tasks.ConclusionOur results clarify how receptive and responsive aspects of empathy rely on distinct, predominantly right‐hemispheric anterior fronto‐temporal brain regions, largely comprising two intrinsically connected networks including the semantic appraisal and cingulo‐opercular task control networks, along with right temporal structures mediating person perception. The fidelity with which this questionnaire method revealed these specific brain networks shows that standardized informant reports are valuable tools in assessing the complex socioemotional constructs involved in empathy. Lastly, the specificity of these brain‐behavior correlations provides further evidence that observable, measurable patterns of decreased empathy in patients with brain disorders can be a direct result of differently localized brain lesions.
Imaging dopamine system transporter activity and connectivity in Alzheimer’s dementia
Authors: Caminiti Silvia , Sala Arianna , Pilotto Andrea , Presotto Luca , Garibotto Valentina , D'Amelio Marcello , Liguori Claudio , Mercuri Nicola , Padovani Alessandro , Perani Daniela 
Published: December 2020

AbstractBackgroundNeuropsychiatric symptoms and cognitive deficits in Alzheimer’s Disease (AD) dementia can be related to changes in the brain dopamine (DA) system. In order to investigate whether and how the DA pathways, namely the nigrostriatal and mesocortico‐limbic, are involved in the pathophysiology of AD, we relied on imaging measures of DA transporter activity, using [123I]FP‐CIT SPECT. We tested (i) presence and degree of alterations in the ventral and dorsal dopamine structures and their major cortical targets; (ii) presence of alterations in DA molecular connectivity within the two DA pathways.MethodsSixteen amyloid‐positive subjects with amnestic mild cognitive impairment (aMCI), twenty‐two amyloid‐positive patients with probable Alzheimer’s dementia (AD) and seventy‐two healthy controls, were selected from three centres. Each subjects underwent an [123I]FP‐CIT SPECT scan. The subcortical/cortical dopaminergic structures showed significant tracer binding, as compared to the reference region, and were thus selected for further analyses, which included the assessment of regional differences in [123I]FP‐CIT bindings, via MANCOVA and differences in molecular connectivity within the dopamine pathways via partial‐correlation analysis, among the three groups. Gender, age and reconstruction method were included as nuisance covariates in all statistical analyses. Results deemed significant at p<0.05, following Bonferroni correction for multiple comparisons.ResultsThe assessment of DA transporter activity demonstrated a significant reduction in aMCI subjects and AD patients in subcortical and cortical targets of the ventro‐tegmental area, namely the ventral striatum and hippocampus, bilaterally, and the middle cingulate gyrus. Within the nigrostriatal projections, only the dorsal caudate was affected, bilaterally. Molecular connectivity measures demonstrated a widespread loss of inter‐connections among targets of the ventro‐striatal pathway only, with a sparing of the nigrostriatal projections.ConclusionsThe selective and significant decrease in dopaminergic transporter activity in the ventro‐striatal subcortical/cortical dopaminergic regions is indicative of an axonal degeneration starting from the projections arising from the dopaminergic ventro‐tegmental brainstem nuclei, and involving the mesolimbic pathways. Our data, consistent with previous post‐mortem evidence [1], support the involvement of the ventral dopaminergic system in AD, since the prodromal phases. The mesolimbic subcortical/cortical DA alterations might play a role in the pathophysiology of memory function and neuropsychiatric symptoms in AD.