bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of a retinal deep phenotyping platform to detect the likely cerebral amyloid PET status in humans
Authors: Soucy Jean‐Paul , Chevrefils Claudia , Osseiran Sam , Sylvestre Jean‐Philippe , Beaulieu Sylvain , Pascoal Tharick A , Arbour Jean Daniel , Rhéaume Marc‐André , Villeneuve Sylvia ,   Prevent‐AD Research Group, Nasreddine Ziad S , Rosa‐Neto Pedro , Gauthier Serge , Robillard Alain , Chayer Céline , Black Sandra E. , Kertes Peter J , Shahawy Hossam El , Chen John J , Knopman David S. , Lowe Val J , Lesage Frédéric 
Published: December 2020

AbstractBackgroundTranslating recent advances in the diagnosis of Alzheimer’s disease (AD) and other dementias to clinical practice using biomarker‐based approaches requires accessible, affordable biomarkers. This protocol tested the performance of a Retinal Deep Phenotyping platform for the detection of likely positron‐emission tomography (PET) amyloid status (negative or positive) in human subjects. This platform generates data rich retinal reflectance images captured non‐invasively with a Metabolic Hyperspectral Retinal Camera (MHRC) yielding specific spatial‐spectral features which are analyzed by a machine learning algorithm relatively to a recognized gold standard biomarker (in this case PET amyloid imaging).Methods134 subjects (50 years and older) from 3 clinical sites were included, 94 with normal, 40 with abnormal cognition, imaged with the MHRC and amyloid PET (unanimous visual reads from a panel of 3 expert reviewers; 42 amyloid positive, 92 negative). Over 600 spatial‐spectral features were extracted from hyperspectral retinal images obtained at 450‐900 nm. After a feature selection based on F‐score ranking, a classifier was trained on the datasets from 87 patients (2/3 of the cohort) using the most discriminating features. The classification performance was then evaluated with the datasets from the remaining 47 patients.ResultsResubstituting the training set of 87 patients into the classifier yielded sensitivity and specificity values of 88% and 91%, respectively. The training misclassification rate was predicted using the k‐fold loss metric, with a predicted error rate of 19%. To verify this performance, the test set of 47 patients was classified by the model resulting in sensitivity and specificity values of 80% and 81%, respectively.ConclusionsThe Retinal Deep Phenotyping platform shows promise for detecting the likely cerebral amyloid PET status in human subjects and could serve as a screening tool to identify subjects in the AD continuum, for instance in a clinical or drug development context. The platform could also be used for the detection of other biomarkers involved in cognitive decline.
Simvastatin maintains white matter integrity in healthy middle‐aged adults with increased risk for Alzheimer’s disease: A secondary analysis of a randomized controlled trial
Authors: Vogt Nicholas M , Hunt Jack FV , Ma Yue , Van Hulle Carol A , Adluru Nagesh , Lazar Karen K , Asthana Sanjay , Johnson Sterling C. , Bendlin Barbara B , Carlsson Cynthia M 
Published: December 2020

AbstractBackgroundThe brain is the most cholesterol‐rich organ and myelin contains 70% of total brain cholesterol. Statins are potent cholesterol‐lowing medications used by millions of adults for prevention of cerebrovascular disease, yet the effect of statins on cholesterol‐rich brain white matter (WM) is largely unknown. In this study, diffusion tensor imaging (DTI) data collected during an 18‐month randomized controlled trial in healthy middle‐aged adults with a parental family history of Alzheimer’s disease (ClinicalTrial.gov NCT00939822) was used to determine the effect of simvastatin (40mg/daily) on WM integrity.Method73 participants were randomly assigned to drug or placebo (placebo group: N=38, baseline age 55.7±8.0yrs, 76.3% female; simvastatin group: N=35, baseline age 56.7±6.3yrs, 68.6% female) and underwent MRI (T1‐weighted, T2FLAIR, and DTI at baseline, 6m, 12m, and 18m). DTI parameter maps were used for longitudinal WM microstructure and tract‐based spatial statistics analyses. Total gray matter (GM), WM, and WM hyperintensity (WMH) volumes were calculated from T1‐weighted and T2FLAIR imaging. ANCOVA models (covariates: age, sex, APOE4‐genotype) tested the effect of treatment group on percent change in neuroimaging measures at each study visit. Model‐based path analysis tested whether the effects of simvastatin on WM microstructure were mediated by change in serum total cholesterol (TC) levels.ResultThere were no differences in baseline neuroimaging measures between treatment groups. At 18 months, the simvastatin group showed significantly attenuated decline in fractional anisotropy (FA) and attenuated increase in radial diffusivity (RD) in total WM relative to the placebo group (Fig1). At 12 and 18 months, the simvastatin group showed preserved WM volume relative the placebo group, but no differences in GM or WMH volume (Fig2). Approximately 30% of the effect of simvastatin on change in WM microstructure was mediated by change in serum TC (Fig3).Conclusion18 months of simvastatin use in statin‐naïve middle‐aged adults resulted in preserved WM microstructure and volume compared to placebo, suggestive of a potential protective effect of simvastatin on WM. Changes in FA and RD (but not axial diffusivity) suggest simvastatin‐induced alterations in myelin content, and partial mediation by change in serum TC suggests pleotropic effects of simvastatin on WM.
Longitudinal inferior temporal FTP‐PET signal increase is associated with contemporaneous longitudinal temporal lobe cortical thinning in preclinical Alzheimer’s disease
Authors: Hampton Olivia L. , Buckley Rachel F. , Properzi Michael J. , Chhatwal Jasmeer P. , Johnson Keith A. , Sperling Reisa A. , Schultz Aaron P. 
Published: December 2020

AbstractBackgroundFlortaucipir (FTP)‐PET enables visualization of in vivo paired helical filament tangles, a hallmark of Alzheimer’s disease (AD) pathological progression. Due to its recent implementation, most studies have only analyzed its cross‐sectional associations. This work leverages longitudinal measurements of inferior temporal (IT)‐FTP to better understand the temporal relationship of tau accumulation and neurodegeneration through analyzing the change in IT‐FTP signal on change in contemporaneous cortical thickness across the brain in clinically‐normal (CN) older adults.MethodT1‐weighted MRI scans were processed using Freesurfer (FS) v6 longitudinal pipeline (Reuter et al., 2012) and we computed bi‐hemispheric thickness values in all 34 ROIs. 18F FTP‐PET images in 124 participants (2‐3 timepoints, range 1.21‐5.19 years; Table 1) were aligned within subject before being co‐registered to FS longitudinal base images. SUVR measures were calculated using cerebellar gray as the reference region, with IT signal used as a tau proxy for all analyses. Participants also underwent 11C Pittsburgh Compound‐B (PiB) imaging at baseline. We calculated slopes with respect to time for IT tau signal and cortical thickness in each ROI using linear regressions for each participant. For all analyses, we used IT‐FTP slope to predict thickness slope in each ROI using a linear regression covarying for sex and baseline age. We also divided our sample into PiB+ (N=41) and PiB‐ (N=83) groups based on a global 1.186 PiB DVR threshold to understand the impact of IT tau change on cortical thinning in a preclinical AD (PiB+) sample.ResultGreater IT tau slopes were associated with accelerated contemporaneous cortical thinning in temporal regions (Fig. 1A). PiB+ individuals were found to drive the IT‐FTP slope effect on temporal atrophy (ps < 0.001, Fig. 1B, 2). Particularly, the entorhinal cortex showed the strongest effect (t(37); p<0.00005; Fig. 2). No ROI in the PiB‐ group yielded a significant IT tau slope‐associated rate of atrophy (Fig. 1C).ConclusionWe found that in CNs with increasing IT‐FTP signal, temporal regions are susceptible to neurodegeneration. However, high PiB individuals drive this relationship. Our longitudinal results confirm previous research with cross‐sectional IT tau and provide evidence for contemporaneous cortical thinning in temporal regions in preclinical late onset AD.
Using linkage analysis to identify novel gene‐gene interactions in Alzheimer’s disease
Authors: Grunin Michelle , Wheeler Nicholas R. , Bush William S. , Haines Jonathan L. ,   Alzheimer’s Disease Sequencing Project
Published: December 2020

AbstractBackgroundLinkage analysis was a workhorse of disease gene mapping until the advent of more refined genomic scans through genome wide association studies (GWAS). However, GWAS’ ability to detect gene‐gene interactions is hampered by the required huge sample sizes. Whole Genome Sequencing (WGS) captures nearly all allelic variation enabling direct measurement of co‐segregation with disease for each allele in a family through linkage analysis without the need to consider recombination fractions. We developed an approach integrating co‐segregation data with extant biological interaction data to identify interacting genes involved in disease using WGS of multiplex Alzheimer’s Disease (AD) families.MethodTwo point linkage (MERLIN) was performed on WGS of 46 AD Sequencing Project (ADSP) families. Per family, an empirical maximum LOD score (MaxLOD) was calculated. Interactions between proteins were identified by querying multiple functional/pathway databases. Variants reaching a family‐specific MaxLOD were filtered by high/moderate impact (missense+stop/loss) and functional interaction. Further families from the ADSP are being analyzed using the same pipeline.ResultGenes of interest were defined as genes of known interaction where at least 2 biologically interacting loci per family reached a family‐specific MaxLOD and were found in >1 family, creating a single shared transchromosomal locus. The transchromosomal MaxLODs were combined across multiple families sharing the same biologically interacting loci. Multiple families had biologically interacting genes with individual variants attaining a MaxLOD>1.2. One interaction of shared gene pairs/family had a transchromosomal MaxLOD across 3 families of 4.05, linking variants in SLC10A6, DHCR7, SOAT1, ABCA1 and SREBF2 in the cholesterol metabolism and lipid processing pathways. An additional 5 families had MaxLOD variants in at least one of these genes. 4 families had interacting pairs with a transchromosomal MaxLOD score >2.4 unique to the family.ConclusionThis approach utilizes biological interactions to identify potential disease loci despite genomic distance, thus identifying possible epistatic effects not easily observable in case‐control datasets. It is easily applicable to any complex disorder having multiplex families.
Platelet APP levels from subjects with Alzheimer’s disease and mild cognitive impairment
Authors: Magno Augusto , Bram Jessyka Maria de França , Talib Leda Leme , Joaquim Helena Passarelli Giroud , Gattaz Wagner Farid , Forlenza Orestes Vicente 
Published: December 2020

AbstractBackgroundThe clinical diagnosis of Alzheimer’s disease (AD) is a probabilistic formulation that may lack accuracy particularly at early stages of the dementing process as Mild Cognitive Impairment (MCI). Beta‐amyloid peptide (Aβ) accumulation is one of the hallmarks of AD. It is well‐known that the main mechanism of Aβ production, whose accumulation is one of the hallmarks of AD, is from abnormalities in amyloid‐beta precursor protein (APP) metabolism. APP is an integral transmembrane protein widely expressed in neuronal and peripheral tissues and the enzymatic machinery needed to process APP in neurons is also present in platelets. The aim of the present study was to compare the protein level of APP to discriminate cases of AD and MCI from controls.MethodThe APP protein levels were measured in platelets from non‐medicated older adults with AD (n=10), MCI (n=17) and healthy elders (n=12) by western blotting. The densitometries of 130kDa and 110kDa were used to estimate the levels of APP and APP–ratio. Each sample was analyzed in duplicate and for normalization of platelet assay values we used β‐actin as loading (internal) control. All statistical analyses were performed with the aid of the software Statistical Package for the Social Sciences (SPSS) ‐ version 14. Differences in sociodemographic characteristics and platelets APP concentrations at baseline were analyzed using the Kruskal‐Wallis.ResultThere was no difference regarding gender distribution or age among the three groups (p=0.310 and p=0.088, respectively). We found a down expression of 110kDa‐APP‐fragment in AD compared to MCI and controls. In contrast, there was no difference nor in 130kDa‐APP‐fragment (p=0.212) either APPratio (p=0.736).ConclusionOur findings indicate that 110kDa‐APP‐fragment is down regulated in AD and may be a marker of altered APP metabolism in platelets since MCI state when compared to controls.
Awake two‐photon fluorescence imaging in the TgF344‐AD Alzheimer’s disease rat model
Authors: Al‐Azzawi Zaid A.M. , Joo Illsung L. , Koletar Margaret M. , Hill Mary E. , Mester James R. , Stefanovic Bojana , McLaurin JoAnne 
Published: December 2020

AbstractBackgroundInextricably linked with the manifestations of Alzheimer’s disease (AD) is vascular compromise which arises early during disease progression. Vascular compromise leads to subsequent failure in neurovascular coupling, plaque clearance, and oxygen delivery. Previous imaging studies have relied on the use of anesthetics to study vascular compromise. It is widely recognized that anesthetics have a wide range of effects on normal brain physiology including dampening neurovascular coupling, slowing neuronal responses, and decreasing brain metabolism. Therefore, there is a need for better imaging models which examine vascular responses during the early stages of AD without the confounds of anesthesia. The aim of this study is to develop the methodology for non‐anesthetized 2‐photon fluorescence imaging using the TgF344‐AD rat model to examine vascular compromise in the ‘prodromal’ phase of AD.MethodThe TgF344‐AD rat recapitulates the age‐dependent nature of AD exhibiting a ‘prodromal’ phase wherein underlying neuropathological changes are occurring without overt cognitive deficits. A prominent change during this period is vascular compromise. Recent advancements in 2‐photon fluorescence microscopy (2PFM) have allowed for high depth imaging of live tissues and has been significantly used in deciphering neuro‐vascular responses within the brains of various animals. 2PFM allows for the direct measurement of blood flow changes within blood vessels in response to neuronal activation. A cranial window is implanted into 4‐month old rats to gain optical access to the barrel cortex.ResultIn order to track vascular responses along branching points of major diving vessels within the barrel cortex, a 1.5mm microprism is implanted adjacent to the barrel cortex providing sideways visualization into the vasculature within the region. A 3D‐printed motorized treadmill was constructed in order to calm and distract the conscious animal while imaging is undertaken. Preliminary results in anesthetized animals show that qualitative images can be obtained through the prism within the barrel cortex.ConclusionThis method shows promise in providing a more naturalistic model for studying functional vascular responses over time. It provides a platform for generating novel insights into neurovascular coupling in disease and healthy conditions.
Modeling and evaluating the effects of hyaluronic acid degradation on human microglia activation using multi‐interpenetrating polymer networks (mIPNs) as 3D in vitro models
Authors: Munoz‐Pinto Dany J. , Jimenez‐Vergara Andrea C. , Cagle Tyler , Jolliffe Alyssa 
Published: December 2020

AbstractBackgroundNumerous recent studies have focused on the role of microglia in the onset and progression of neurodegenerative diseases including Alzheimer’s disease (AD) (Lee et al. 2015). One of the areas of interest is the study of the physiological changes microglia elicit in response to neural damage. Macromolecules such as collagen type IV, laminin, and hyaluronic acid (HA) characterize the extracellular matrix (ECM) landscape of the central nervous system (CNS). These components contribute to the regulation of microglia activation and phenotype modulation. In response to tissue injury or trauma, the normal composition of the ECM can be altered to induce microglia activation.MethodsIn this work, we modeled and evaluated the effects of HA molecular weight (MW) on human microglial cells (HMC3) under in vitro conditions using multi‐interpenetrating polymer networks (mIPNs). We fabricated and characterized a family of mIPNs comprised of poly(ethylene glycol) diacrylate (PEGDA), collagen type I (Col I), and HA of high (HAH, ∼1.5 MDa) or low (HAL, ∼40 kDa) MW via sequential infiltration (Van Drunnen et al. 2019). The viscoelastic properties of mIPNs were evaluated using dynamic mechanical analysis (DMA). In these scaffolds, the effects of HA MW on microglia activation were studied independently of scaffold mechanical performance. After 3 days in culture, changes in the expression of microglia pro‐inflammatory (M1) markers TNFα, IL‐1β, iNOS, and CD86, and the alternatively activated (M2) marker CD206 were measured at the protein level using immunofluorescence. Cell phenotypic expression at the protein level was quantified using confocal microscopy imaging and the ImageJ 2 (FIJI) program. Cell morphology was assessed using confocal microscopy.ResultsThe overall HMC3 viability in the mIPNs exceeded 85%. Microglia morphology appears to be modulated by HA MW. On day 3, the reduction in HA MW in the mIPN formulations promoted a significant increase in the expression of the M1 and M2 markers iNOS, IL‐1β, and CD206 respectively.ConclusionWith the proposed engineered scaffolds, we demonstrated that the reduction in the MW of HA — which is normally associated with tissue degradation — is a significant contributing factor for human microglia activation.
Microstructural alterations of regional white matter tracts predict tau deposition in the Alzheimer’s disease signature regions
Authors: Yi Dahyun , Byun Min Soo , Lee Jun Ho , Byeon Gihwan , Lee Younghwa , Ahn Hyejin , Joung Haejung , Moon Seok Woo , Kim Yu Kyeong , Lee Yun‐Sang , Kang Koung Mi , Sohn Chul‐Ho , Lee Dong Young 
Published: December 2020

AbstractBackgroundWe first aimed to investigate the association between regional white matter (WM) microstructural alterations with tau deposition in Alzheimer’s disease (AD) signature cortical regions. We also tried to develop models to predict pathological tau deposition positivity with regional WM microstructural alterations.MethodOne‐hundred nine older adults with normal cognition or mild cognitive impairment recruited from the Korean Brain Aging Study for the Early diagnosis and prediction of Alzheimer’s disease (KBASE) cohort were included in the analyses. All Participants underwent structural MRI (T1), diffusion tensor imaging, PiB‐PET and Tau‐PET (AV‐1451) scans. AD signature cortical regions for tau deposition included the angular gyrus, posterior cingulate, and inferior temporal cortical regions (Jack et al. 2017). Pathological tau positivity was determined by the presence of significantly high deposition in the Braak regions III‐VI according to the ADNI cutoff (Baker et al. 2017).ResultMean diffusivity (MD) of the posterior corona radiata, fornix, and posterior thalamic radiation were significantly associated with tau deposition in AD signature regions (F(1,107) = 13.48, p < 0.005; F(1,107) = 17.38, p < 0.001; F(1,107) = 15.92, p < 0.001, respectively) (Fig 1). Fractional anisotropy (FA) of the bilateral posterior thalamic radiation was also significantly associated with tau deposition in AD signature regions (F(1,107) = 17.14, p < 0.005) (Fig 1). Pathological tau positivity prediction model based on FA value of the posterior thalamic radiation, MD values of the posterior corona radiata and fornix had area under the curve (AUC) of receiver operating characteristics curve of 0.73 [0.62‐0.84] (Fig. 2a). With additional information on amyloid beta positivity, the AUC increased to 0.86 [0.78‐0.95] (Fig. 2b).ConclusionThe findings indicate that microstructural alterations of the specific regional WM tracts closely linked to AD‐signature cortical regions are strongly correlated with tau deposition in the same cortical regions. Moreover, the findings also support propagation of tauopathy through WM tracts. The information on regional WM alteration may be used for the prediction of pathological tau deposition.
Hippocampal subfield volumetry in subjects at high risk of dementia: The PREVENT‐Dementia study
Authors: Dounavi Maria‐Eleni , Mak Elijah , Wells Katie , Ritchie Karen , Ritchie Craig W. , Su Li , O'Brien John T. 
Published: December 2020

AbstractBackgroundIt is now well‐established that pathological brain alterations in Alzheimer’s disease (AD) patients start occurring decades before symptom onset. The earliest detectable neuroimaging finding during the disease’s preclinical stage is amyloid plaque deposition. During the disease’s prodromal period, hippocampal atrophy is observed. However, it has been suggested that individual hippocampal subfields might demonstrate atrophy at an earlier stage. Our goal in the present study was to investigate the volume of individual hippocampal subfields along with their rate of volumetric change in cognitively normal middle‐aged subjects at high risk of AD using multi‐modal MRI.MethodPREVENT‐Dementia study participants were recruited based on their dementia family history (FH). The participants’ age ranged between 40 and 59 years old and they were scanned at two time‐points (visit 1: 183 participants; visit 2: 155 participants). Hippocampal subfields were segmented using Freesurfer and information from a T1‐weighted MPRAGE scan (TR=2.3s /TE=2.98ms ,voxel size=1mm3) and a high‐resolution T2 coronal hippocampal acquisition (TR=9s/TE=94ms, voxel size=0.4x0.4x4.0mm3). The volume of the subiculum, CA1, CA2‐3, dentate gyrus & CA4, molecular layer, hippocampal fissure, hippocampal tail and the whole hippocampus were quantified and normalised to total brain volume. The volume of each subfield along with its rate of volumetric change were compared between FH positive and negative subjects and APOE ε4 carriers and non‐carriers using linear regression with age, sex and years of education as covariates.ResultAPOE ε4 carriers had a significantly decreased molecular layer volume (figure 1) compared to controls at both study time‐points (visit 1: p < 0.01; visit2: p = 0.02). There were no other differences in the examined subfields, whole hippocampal volume and the rate of volumetric change between the groups.ConclusionThe molecular layer encompasses the stratum radiatum lacunosum and moleculare which is one of the earliest regions to be influenced in AD and has demonstrated high efficiency in separating amyloid positive and negative subjects. Our results suggest that the molecular layer could be amongst the first hippocampal subfields to demonstrate an atrophic pattern in mid‐aged APOE ε4 carriers, in the absence of whole hippocampal, CA1 or subiculum atrophy.