bluuebunny/crossref_metadata_2025_split huggingface dataset:
CSF apolipoprotein B is associated with early tau pathology and selective activation of a cytokine cascade in cognitively unaffected subjects with a parental history of Alzheimer’s disease
Authors: Labonte Anne , Picard Cynthia , Nilsson Nathalie I.V. , Rosa‐Neto Pedro , Breitner John , Villeneuve Sylvia , Poirier Judes ,   Prevent‐AD Research Group
Published: December 2021

AbstractBackgroundWe examine the role of CSF apolipoprotein B (apoB) as a putative indicator of early tau pathology in pre‐symptomatic Alzheimer’s disease (AD).MethodAmong 129 cognitively unimpaired elderly at increased risk of AD (PREVENT‐AD cohort), we assessed blood and cerebrospinal fluid apoB, apoC3 and apoE protein levels using the the Milliplex APOMAG‐62k human apolipoprotein cardiovascular disease multiplex kit (EMD‐Millipore, MA, USA) with those of amyloid β42, total tau and phosphorylated tau (the Innotest enzyme‐linked immunosorbent assay kit (Fujirebio, Ghent, Belgium). We contrasted results with alterations in several inflammation biomarkers using Luminex’s Milliplex HCYTMAG60PMX29BK xMap technology ((EMD‐Millipore, USA).ResultAmong cognitively unimpaired participants, we observed significant correlations between baseline CSF, but not blood, apoB levels and both CSF t‐tau (R2 = 0.23, P < 0.0001) and P‐tau (R2 = 0.28, P < 0.0001). No association was detected between CSF apoB and CSF Aβ42 levels. Using multiple brain blood barrier permeability assays, we found that the contribution from peripheral apoB to be negligible. Concomitant analyses of several key cytokines and chemokines in the CSF failed to show any association following FDR correction, except for IL‐15 (R2: 0.38, p < 0.001). IL‐15, a potent inducer of reactive gliosis in both astrocytes and microglia, is normally synthesized by compromised neurons in the CNS.ConclusionCSF apoB, which is normally produced by microglia, markedly associates with early tau dysregulation and the activation of select cytokines in asymptomatic subjects, years before the onset of symptoms.
Analysis of brain structural connectivity networks and white matter integrity in patients with mild cognitive impairment
Authors: Bergamino Maurizio , Walsh Ryan R. , Stokes Ashley M. 
Published: December 2021

AbstractBackgroundMild cognitive impairment (MCI) is considered a prodromal phase of Alzheimer’s disease (AD) and patients with MCI convert to AD at a rate of about 10–15% per year. Because of this high conversion rate to AD, studies of MCI may yield insight into early pathological changes in AD. Here, we used a novel approach to analyze structural connectivity and white matter (WM) integrity using fractional anisotropy (FA), intra‐cellular (IC), extra‐cellular (EC), and isotropic (ISO) maps between patients with MCI and healthy controls (HC).MethodThirty‐two HC (age mean ± S.D. = 69 ± 6 years; 22 females) and 20 MCI (71 ± 9 years; 7 females) were included in this study. All subjects completed the Mini‐Mental State Exam (MMSE) and the Montreal Cognitive Assessment (MoCA). Multi‐shell DTI were download from ADNI (http://adni.loni.usc.edu/). Pre‐processing was performed by Mrtrix3, FSL, and ANTs. Tractography was performed with 5 million seeds using the iFOD2 algorithm. Connectome was generated from the Desikan‐Killiany parcellation file and was subsequently filtered using the COMMIT2 algorithm. A three‐compartment Stick‐Zeppelin‐Ball model was used to create the IC, the EC, and the ISO compartments, respectively. Statistical analyses (ANCOVA) were performed by connectomestats (Mrtrix3), randomise (FLS), and by an in‐house Matlab script for Spearman’s correlations.ResultThe two groups did differ in MMSE and MoCA (Mann–Whitney U test: Z=2.031; p=0.021; Z=1.683; p=0.046, respectively). Differences between HC and MCI were found principally in the fornix for FA and in several WM areas for IC and ISO (Figure 1, Table 1). Connectometry analysis found differences between groups in two distinct tracts: Tract#1 between the left‐lateraloccipital and the left‐insula (t=4.25, p=0.023) and Tract#2 between the left‐middletemporal and the left‐parsopercularis (t=3.34, p=0.013) (Figure 2). Figure 3 and Table 2 show the results for the correlations between DTI metrics and the neurological scores.ConclusionIn this study, by using a multi‐shell diffusion MRI acquisition and robust processing of DTI data, we detected alterations in WM integrity and structural connectivity in MCI subjects. Our results demonstrate the potential of these advanced diffusion MRI methods as biomarkers to distinguish MCI and HC.
EEG biomarkers differentiate Lewy body dementia from Alzheimer’s disease
Authors: Meghdadi Amir H. , Karic Marija Stevanovic , Richard Christian , Waninger Shani , Mcconnell Marissa , Poole Jared , Rupp Greg , Hamilton Joanne M. , Boeve Bradley F. , St. Louis Erik K. , Berka Chris 
Published: December 2021

AbstractBackgroundResting state electroencephalography (rsEEG) is a neurophysiologic Alzheimer disease (AD) and alpha‐synucleinopathy (dementia with Lewy body (DLB) and Parkinson disease (PDD)) biomarker [1]–[5]. Background slowing (increased low frequency power, dominant rhythm (DR) slowing) is frequent in AD and DLB, more so in DLB. We sought to identify distinguishing rsEEG signatures between DLB and AD.MethodParticipants included dementia patients [AD (n=26), DLB (n=12), PD (PDD; n=5)] and controls (HC; n=56). 20‐channel rsEEG was collected in eyes‐closed/eyes‐open conditions (5‐min each). Power spectral densities and coherences were measured using established methods [6]. Individual rsEEG power (delta, 1‐3 Hz; theta, 3‐7 Hz; alpha, 8‐13 Hz), theta/alpha ratio (TAR), dominant rhythm (DR), and DR frequency domain prominence were measured and averaged across groups, and effect sizes were determined and compared using Hedges g.ResultAD, DLB, and PDD groups exhibited increased low frequency (delta‐theta, 1‐5 Hz) power and TAR compared to controls (p<4x10‐4), with higher effect sizes in the DLB and PDD groups compared to AD. DR frequency was also decreased in all patient groups (DLB>PDD>AD) compared to controls (p=3x10‐9, p=3x10‐5, p=4x10‐4).AD alpha power and DR frequency domain prominence were reduced compared to controls and PDD/DLB groups (p<0.003). Both AD patients and controls had comparable posterior power distribution predominance of DR, while DLB power of DR was more anteriorly distributed. Compared to controls, delta coherence was higher in AD, but lower in DLB. Delta power was positively correlated with cognitive fluctuation (CAF) in DLB (r(8)=+0.67, p=0.03), while negatively correlated with MMSE in AD (r(24)=‐0.64, p=10‐5).ConclusionDLB and AD had both common and distinct rsEEG signatures. Both had DR slowing and background slowing that was more severe in DLB than AD. Distinctive DLB findings included reduced posterior DR spatial dominance and decreased delta coherence. Conversely, distinct AD features were increased delta coherence, decreased alpha power, and decreased DR frequency prominence. Finally, the DLB and PDD groups had a similar magnitude of DR slowing, consistent with posteriorly dominant functional impairment in synucleinopathy reflected by corresponding regional rsEEG slowing, although future longitudinal prospective sequential rsEEG analyses are necessary to confirm these findings.
Genome‐wide association study of mild cognitive impairment in diverse Hispanic/Latinos identifies novel loci and reveals heterogeneous associations across genetic backgrounds
Authors: Yang Yunju , Sofer Tamar , Tarraf Wassim , DeCarli Charles S , Gonzalez Hector M , Fornage Myriam 
Published: December 2021

AbstractBackgroundMild cognitive impairment (MCI) is considered a prodromal phase to Alzheimer’s disease and related dementias (ADRD) that appear to disproportionally affect Hispanics/Latinos, the largest ethnic minority in the US. The genetic architecture of MCI is poorly understood especially among Hispanics/Latinos. We performed a genome‐wide association analyses in Hispanincs/Latinos to identify genetic loci associated with MCI with consideration of genetic background.MethodGenome‐wide association studies of MCI were performed in 4,981 participants in the Hispanic Community Health Study/Study of Latinos‐Investigation of Neurocognitive Aging (SOL‐INCA), distributed among six genetic background groups (backgrounds; Central American, Cuban, Dominican, Mexican, Puerto Rican and South American). MCI was defined according to the National Institute on Aging‐Alzheimer’s Association (NIA‐AA) criteria. Participants with severe CI were also included (n=68). Genetic associations were estimated using mixed effects models adjusted for age, sex, recruitment center, sampling weight, top 5 principal components, and background as fixed effects, and for kinship, household, and block group as random effects. A subgroup analysis in subjects aged 60 and above was also performed. To account for heterogeneity among Latino backgrounds, stratified analyses by background were performed and results were combined using fixed‐ and a random‐effect based methods.ResultWe identified a novel genome‐wide significant association for MCI at rs141694916 in SLC25A21 (p=2.17x10‐8). In analyses excluding cases with severe CI, its association was less significant (p=1.22x10‐6) but two novel loci were identified: rs75090804 in DAB1 (p=1.10x10‐9) and rs112528434 in APOC1 (p=3.66x10‐8). In the aged group, we identified an association for MCI in CADM2 (rs148903011, p=1.41x10‐9). Fixed‐effect meta‐analysis of background‐stratified GWAS identified two additional loci, rs144595178 near GCNT3 (p=1.37x10‐8) and rs16974577 near KC6 (p=3.51x10‐8), while random effect meta‐analysis identified 8 additional loci showing evidence of heterogeneity (heterogeneity p<0.05) by background. These included rs543428512 in STARD13 (p=5.07x10
‐9) and rs962088 near CDH10 (p=4.14x10‐8). The identified loci showed gene expression enrichment in the hippocampus and amygdala and were enriched in gene sets implicated in the regulation of plasma amyloid beta levels.ConclusionGWAS of MCI in diverse Hispanics/Latinos identified several novel loci with functional relevance to ADRD. Examining heterogeneity by background allowed us to detect additional loci.
Is there a relationship between periodontitis and Alzheimer's disease? Systematic review and comparative analysis
Authors: Torrealba‐García Daniela , Garcia‐Morales Pilar , Torrealba Eduardo , Cejudo Juan Carlos , Silvestre‐Rangil Javier 
Published: December 2021

AbstractBackgroundAlzheimer’s disease is a neurodegenerative disease with unknown cause, being the first cause of dementia affecting 24 million people, which is set to double by 2040. Periodontitis is a multifactorial, inflammatory and chronic disease that causes the loss of the tooth’s support system; being the number one cause of tooth loss in adults. Both diseases are highly prevalent, making them an important public health issue. New studies have shown that there might be a relation between them.MethodSystematic review and comparative analysis of studies through a bibliographic search that included clinical trials, case‐control and cohort studies in humans, with objective tests for the diagnosis of both diseases. Excluding: descriptive studies or studies that didn’t focus on Alzheimer’s; studies that didn’t diagnose periodontitis clinically; sigle case studies; based on patients with syndromes; or evaluated exclusively the quality of life of the patients. From the 473 articles found only 9 fulfilled the inclusion and exclusion criteria.ResultOut of the 9 articles selected, 7 found a statistically significant difference between people with Alzheimer’s and without it in relation to periodontitis (Choi S et al, Ide M et al, de Suza T et al, Martande SS et al, Holmer J et al, Cestari JA at al, Aragón F et al). Chen CK et al didn’t find a statistical significance at the beginning (p=0.0547) but did in the 10 years follow‐up (p=0.00264). Tiisanoja A et al didn’t find a statistic significance (RR=1.54; IC=0.52‐4.56). However, when subjecting the article’s results to CI for the proportion analysis we discovered that only one study found this difference significant out of the 6 included.ConclusionThe most common oral problems in patients with Alzheimer’s were gingivitis, periodontitis, tooth loss, candidiasis, calculus. Although there seems to be a relationship between the two, further studies with larger populations and a better screening process for participants, are needed in order to truly assess whether there is a causal relationship between the two pathologies or not. One of the greatest limitations we encountered was the lack of homogeneity between the studies statistical tools, making it impossible to do a meta‐analysis.
Impact of Alzheimer’s disease and related disorders neuropathology on neuropsychiatric symptoms during life
Authors: Devanand Davangere P , Lee Seonjoo , Huey Edward D. , Goldberg Terry E. 
Published: December 2021

AbstractBackgroundThere is limited information on the impact of specific neuropathologies on neuropsychiatric symptoms (NPS). We evaluated the impact of neuropathologically defined subtypes of Alzheimer’s Disease and Related Dementias (ADRD) on neuropsychiatric symptoms (NPS) during life.MethodThe study design used a direct and unbiased approach that did not consider clinical diagnoses and included all brains with neuropathological diagnoses in the V.10 collection of the National Alzheimer’s Coordinating Center (NACC) database that also had Neuropsychiatric Interview‐Questionnaire (NPI‐Q) data collected during life. Data from 1,808 patients from 39 sites were examined. We utilized pairwise, ordinal and multiple logistic regression analyses to assess the effects of 8 neuropathological diagnoses on 12 domains in the Neuropsychiatric Inventory Questionnaire (NPI‐Q), correcting for multiple statistical comparisons. For NPS, average NPI‐Q domain scores during annual follow‐ups was the primary measure and NPI‐Q domain ever present/always absent was the secondary measure.ResultThe neuropathological diagnosis of Alzheimer’s disease (AD) using ABC criteria showed moderate associations with increased delusions, agitation/aggression and hallucinations. Cerebral amyloid angiopathy showed associations with NPS that were similar to AD. Lewy Body Disease (LBD) showed increased hallucinations. Infarcts/lacunes and microinfarcts showed weak associations with mood and motivational symptoms. Frontotemporal Dementia (FTD) was associated with marked increase in apathy and significantly decreased psychotic features and agitation. Hippocampal sclerosis was associated with less depression and increased apathy and disinhibition; these associations persisted after controlling for vascular neuropathology and FTD. In multiple regression analyses that controlled for other neuropathologies, the main findings were not altered.ConclusionThe associations of ADRD neuropathologies with specific NPS support current diagnostic criteria for behavioral symptoms in specific disorders. The findings on apathy and disinhibition in hippocampal sclerosis are novel and unique, and may explain inconsistent findings for depression treatment in dementia. Further investigation is needed to clarify the impact of hippocampal sclerosis on medial temporal lobe function and NPS, which may help eventually with diagnosis and clinical management.
The APP669‐711/Aβ1‐40 ratio as a plasma biomarker specific for the brain Aβ deposition in APP/PS1 mouse
Authors: Kaneko Naoki , Matsuzaki Masaya , Yokoyama Miyabishara , Korenaga Akihito , Sekiya Sadanori , Iwamoto Shinichi , Tanaka Koichi , Tomita Taisuke 
Published: December 2021

AbstractBackgroundWe have previously identified APP669‐711 (a.k.a. Aβ(‐3)‐40) in human plasma using immunoprecipitation combined with matrix‐assisted laser desorption ionization time‐of‐flight mass spectrometry (IP‐MALDI‐MS) (Kaneko et al., Proc Jpn Acad Ser B Phys Biol Sci. 2014). Our assay has revealed that the composite biomarker, which is a combination of APP669‐711/Aβ1‐42 ratio and Aβ1‐40/ Aβ1‐42 ratio in human plasma, correlates with amyloid PET status (Nakamura et al., Nature 2018). However, the significance of these peptide ratios in an APP/PS1 mouse model of Alzheimer's disease has been unclear. In this study, we investigated the levels of Aβ‐related peptides including APP669‐711 in plasma samples from the model mouse.MethodWe prepared plasma samples from young (2 months of age) and old (23–25 months of age) APP/PS1 mice expressing both APP bearing the Swedish mutation and PSEN1 harboring ΔE9 mutation, and cultured supernatants of HEK293 cells. Mouse plasma samples and cultured supernatants were measured by IP‐MALDI‐MS.ResultHuman APP669‐711 was detected in cultured supernatant of HEK293 cells overexpressing human wild‐type APP but not human APP with the Swedish mutation. This result indicated that two amino acid substitutions (i.e., Swedish mutation) near the APP669 site inhibited the APP669 cleavage and the production of APP669‐711 from the transgene of APP/PS1 mice. Then we focused on mouse endogenous murine Aβ‐related peptides in the evaluation of plasma biomarker for the amyloid deposition in the brains of APP/PS1 mice. The analysis of APP/PS1 mouse plasma showed that murine APP669‐711/Aβ1‐42 and APP669‐711/Aβ1‐40 ratios were increased in old mice with plaques compared to young mice without them. However, the murine Aβ1‐40/Aβ1‐42 ratio was not changed between old and young mice.ConclusionThese results suggested that the APP669‐711/Aβ1‐42 ratio is a common biomarker for the amyloid plaque pathology in humans and APP/PS1 mice. Also, we revealed the possibility that the APP669‐711/Aβ1‐40 ratio is a biomarker specific for the brain Aβ deposition in APP/PS1 mice. These biomarkers can be useful tools to study lifestyle intervention and drug development for the prevention of amyloid deposition using the model mouse.
Higher coffee consumption is associated with slower cognitive decline and Aβ‐amyloid accumulation over 126 months: Data from the AIBL study
Authors: Gardener Samantha L , Rainey‐Smith Stephanie R , Villemagne Victor LL , Fripp Jurgen , Dore Vincent , Bourgeat Pierrick , Taddei Kevin , Masters Colin L , Maruff Paul T , Rowe Christopher C , Ames David , Martins Ralph N ,   AIBL Research Group
Published: December 2021

AbstractBackgroundWorldwide, coffee is one of the most popular beverages consumed. Several studies have suggested a protective role of coffee, including reduced risk of Alzheimer’s disease (AD). However, there is limited longitudinal data available in cohorts of older adults reporting associations of coffee intake with cognitive decline, in distinct domains, and investigating the neuropathological mechanisms underpinning these associations.MethodThe aim of the current study was to investigate the relationship between self‐reported baseline coffee intake (mean = 280 ± 323 g/day) and cognitive decline assessed using a comprehensive neuropsychological battery, over 126 months, in 227 cognitively normal individuals from the Australian Imaging, Biomarkers, and Lifestyle (AIBL) study. We also sought to investigate the relationship between coffee intake and cerebral Aβ‐amyloid accumulation and brain volumes in a subset of individuals (n=60; and n=51, respectively) over 126 months.ResultHigher baseline coffee consumption was associated with slower cognitive decline in executive function, attention, and the AIBL Preclinical AD Cognitive Composite (PACC; shown to reliably measure the first signs of cognitive decline in at‐risk cognitively normal populations) over 126 months. Higher baseline coffee consumption was also associated with slower Aβ‐amyloid accumulation over 126 months, and lower risk of transitioning from ‘negative’ Aβ‐amyloid status to ‘moderate’, and ‘very high’ Aβ‐amyloid burden over the same time period. There were no associations between coffee intake and atrophy in total grey matter, white matter, or hippocampal volume.ConclusionOur results further support the hypothesis that coffee intake may be a protective factor against AD, with increased coffee consumption reducing cognitive decline potentially by slowing cerebral Aβ‐amyloid accumulation, and thus attenuating the associated neurotoxicity from Aβ‐amyloid‐mediated oxidative stress and inflammatory processes. Further investigation is required to evaluate how coffee intake could be incorporated as one modifiable lifestyle factor aimed at delaying AD onset.
The diagnostic significance of the chemokine CXCL12 in Alzheimer's disease
Authors: Mroczko Barbara , Kulczynska‐Przybik Agnieszka , Borawska Renata , Dulewicz Maciej , Doroszkiewicz Julia , Slowik Agnieszka 
Published: December 2021

AbstractBackgroundA complex relationship between the stromal cell‐derived factor 1 (CXCL12) and dementia, including mild cognitive impairment (MCI) and Alzheimer's disease (AD) has been described in the literature. The chemokine CXCL12 regulates many functions of bone marrow‐derived stem cells and has been implicated in neurogenesis as well as with the recruitment of brain resident and non‐resident circulating cells towards sites of a lesion in the central nervous system. It has been suggested that dysregulation of the CXCL12/CXCR4 signaling pathway is involved in the pathologic process of cognitive impairment. Moreover, significantly changed expressions of the CXCL12 and CXCR4 were observed in AD patients' brains compared to the normal brain tissues of the healthy non‐demented subjects. The purpose of the study was to evaluate the concentration of the CXCL12 in patients with early stage of dementia (MCI) and compare it with classical biomarkers for AD.MethodThe study group included 34 subjects: 18 patients with AD and 16 controls without cognitive impairments. The cerebrospinal fluid (CSF) concentrations of tested proteins were measured with the use of ELISA method.ResultThe CSF concentrations of CXCL12 were elevated in AD patients in comparison to non‐demented controls. The increased levels of CXCL12 correlated with all CSF biomarkers (Aβ‐42, Aβ‐42/Aβ‐40, Tau, pTau181), age and MMSE in the whole study group. Moreover, significant negative correlation between CXCL12 and MMSE in AD and control group was observed.ConclusionIt was established that CXCL12 might play role in the development of AD, although the question, whether this protein can be useful in diagnostic of dementia requires further examination on larger study group. Acknowledgment: The study was conducted with the use of equipment purchased by Medical University of Białystok as part of the RPOWP 2007‐2013 funding, Priority I, Axis 1.1, contract No. UDA‐RPPD.01.01.00‐20‐001/15‐00 dated 26.06.2015.