bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcriptomic correlates of neurite degeneration due to human brain‐derived Aβ and protection by clinical anti‐Aβ antibodies
Authors: Stern Andrew , Liu Wen , Jin Ming , Walsh Dominic M. , Selkoe Dennis J. 
Published: December 2020

AbstractBackgroundThe proximate cause of dementia in Alzheimer disease (AD) is the dystrophy and loss of synapses and neurites, and the eventual death of neurons. Upstream events include hyperphosphorylation and aggregation of tau, and further upstream is the formation of soluble oligomers of Aβ. The molecular details which link these three and other events within the “amyloid cascade” remain murky, but elucidating them will likely reveal new therapeutic targets.MethodTo dissect early steps in the Aβ oligomer‐driven neuritotoxicity, we recently developed an in vitro system in which human brain‐derived soluble Aβ is applied to iPSC‐derived human neurons (iNs) to induce neurite degeneration (Jin et al, Nat Commun. 2018; 9(1):2676). Soluble extracts from AD brain were either immunodepleted of Aβ with a polyclonal antiserum or mock‐immunodepleted with rabbit IgG, then applied at 21 DIV to iPSC‐derived neurons that had been induced by Neurogenin‐2 expression. Neurite integrity was tracked using the NeuroTrack module of the IncuCyte ZOOM system for live‐cell analysis. Various humanized anti‐Aβ antibodies were added at concentrations from 0.5 to 3 ug/mL along with the control antibody bevacizumab (Avastin).ResultImmunodepletion with the polyclonal antibody resulted in efficient removal of Aβ. Mock‐immunodepleted, but not immunodepleted, human soluble brain extracts caused quantifiable neuritotoxicity using this unbiased, automated imaging system. These effects were rescued to different degrees by different anti‐Aβ antibodies but not by Avastin.ConclusionHuman AD brain‐derived soluble extracts cause neuritotoxicity to human neurons in an Aβ oligomer‐dependent manner. This effect can be decreased by anti‐Aβ antibodies currently in clinical trials, including aducanumab and BAN2401. We are now performing unbiased transcriptomic and proteomic profiling of the iNs after treatment with human‐derived soluble Aβ oligomers to determine the immediate molecular events that precede and accompany Aβ‐dependent neuritotoxicity. These results will be compared with recently‐published single‐cell transcriptomic data from AD brain to identify potential therapeutic targets.
Navigation ability before and after menopause
Authors: Chapin Benjamin Albert , Khondoker Mizanur , Coughlan Gillian , Spiers Hugo , Hornberger Michael 
Published: December 2020

AbstractBackgroundCognitive decline is a common complaint in menopause. Alzheimer disease(AD) has higher incidence in women and early menopause increases risk for AD. Studies of cognitive change at menopause have had mixed results. Navigational ability declines early in the course of AD. No studies have looked at changes in navigational ability around menopause. Objective: Determine the effect of menopause on navigation.MethodParticipants were 200,999 persons aged 35‐65 who downloaded the Sea Hero Quest app and completed enough levels to analyze navigation. Measures of navigation examined included distance traveled and time spent to complete levels as well as accuracy in determining one’s starting point after completing a maze. These scores were normalized based on early, simple levels in order to control for video game ability. Each measure was analyzed by splitting male and female participants into ages 35‐45 and ages 55‐65 in order to look at persons before and after menopause. Groups were analyzed using a 2‐way ANOVA with gender and age as independent variables. Additionally, piecewise linear modeling was applied to the entire population aged 35 to 65 to test whether there was a significant change in the slope of decline in navigational ability at age 51, the average age of menopause.ResultFemale gender and advancing age were both predictive of worse performance on all measures. ANOVA found significant(p<0.001) but small effect sizes for an age by gender interaction with partial eta2 for distance = 0.002, duration < 0.001 and flare accuracy <0.001. Piecewise linear modeling found small but significant (p<0.001) changes in slope of worsening scores in distance, duration and flare accuracy at age 51. The increased rate of worsening performance was actually greater in men than women.ConclusionWhile men had better navigational performance than women at all ages, there is not a substantial change in this gap following menopause. Additionally, the relative rate of decline in female performance actually decreased relative to males at the typical age of menopause. This study suggests that natural menopause is unlikely to have a significant negative effect on navigational ability.
Throughput optimized immuno‐infrared‐assay for Alzheimer’s disease diagnosis
Authors: Budde Brian , Mann Marvin , Woitzik Nathalie , Güldenhaupt Jörn , Kötting Carsten , Gerwert Klaus Bernhard 
Published: December 2020

AbstractBackgroundIt is believed, that one of the first events in the progression of Alzheimer’s Disease is the misfolding of the Amyloid Beta (Aβ) Peptide. This event takes place up to 20 years before the clinical onset of the disease. Therefore, biosensors detecting the misfolding of Aβ are especially useful for the early and specific detection of Alzheimer’s Disease. In recent studies, our biosensor based on ATR‐FTIR spectroscopy performed with an overall accuracy of 86% [1,2,3]. This system is robust and reliable but the user input required is very high because each sensor can only be used once. To overcome these issues and increase the automation capacity, a regenerative system is urgently needed.MethodTo achieve higher throughput of this system, we introduced immunoglobulin binding proteins (Protein A and Protein G) as capture for antibody immobilization. Protein A and Protein G are able to recognize and bind the constant region of different IgG antibodies in a non‐covlant manner. This allows multiple measurements within the same system by performing multiple binding and elution cycles.ResultProtein A and Protein G can be attached covalently to the sensor without losing its ability to bind IgG antibodies [4]. The antibody binding and elution is monitored by ATR‐FTIR spectroscopy and validated using fluorescence spectroscopy. It is possible to perform at least 35 cycles of antibody binding and elution over 7 days without loss in diagnostic accuracy. The sensor is still able to extract different biomarkers like Aβ and the Tau Protein from CSF with highly comparable results compared to the recently used system.ConclusionThe development of a regenerative immuno‐infrared‐sensor is crucial to reduce the user input and to increase the throughput of this method. Compared to assays where the capture antibody is covalently immobilized, the regenerative system has a factor 6 increased thoughput. References: (1) Nabers, A. et al. (2016) J. Biophotonics, 9. 224‐234. (2) Nabers, A. et al. (2018) EMBO Mol. Med. 10, e8763. (3) Nabers, A et al. (2019) Alzheimer’s Dement. Diagnosis, Assess. Dis. Monit., 11, 257‐263. (4) Budde, B. et al. (2019) ACS Sens. 4, 1851‐1856.
A cohort study to identify predictors for the clinical progression to mild cognitive impairment or dementia from subjective cognitive decline
Authors: Yang Dong Won , Hong Yun Jeong , Ho Seong Hee , Jeong Jee Hyang , Park Kee Hyung , Kim Sang Yun , Wang Minjung , Choi Seong Hye , Han SeungHyun , Kang Seung Wan 
Published: December 2020

AbstractBackgroundSubjective cognitive decline(SCD) has been considered as at risk state to progress to mild cognitive impairment(MCI) or Alzheimer's disease(AD) dementia. The purpose of this study is to set up cohort and to identify risk factors for the progression to MCI or dementia from amnestic SCDMethodWe enrolled subjects aged 60 years or older complaining of persistent cognitive decline. To include higher risk SCD patients with rapidly progression, subjects needs to have 7% to 50% of the verbal memory and over 7% of the rest subtests of comprehensive neuropsychological battery. We named this state of SCD as an amnestic SCD. Brain magnetic resonance imaging (MRI) volumetry, visual and standardized uptake value ratio (SUVR) analysis of 18F‐Florbetaben brain amyloid‐beta Positron Emission Tomography (PET) were. Blood amyloid oligomerization was measured by the Multimer Detection System‐Oligomeric Aβ (MDS‐OAβ) method. Quantitative EEG were also analyzed. Sleep time and physical activity were collected with wearable device (Fitbit alta). Gait speed, body mass index, and muscle strength were measured.ResultWe analyzed 120 SCD subjects (male 53, female 67). Mean age and education were 70.9 and 11.2 years. 25 (20.8%) showed amyloid positive PET and 26(21.6%) had APOE ε4 allele. Positive amyloid PET SCD had higher frequency of APOE ε4 (48%) compared to amyloid negative SCD (14%). Positive amyloid PET SCD also had lower delayed verbal memory score and lower frontal inferior, anterior, medial and lateral temporal and lateral parietal regional brain volume ratio. Power spectral analysis of EEG showed increased relative theta /alpha ratio in the bilateral frontal regions. sLORETA showed increased theta spectrum in the left superior temporal, transverse temporal and fusiform area in amyloid positive SCD. MDS‐OAβ was positive in 55.1% which was not associated with SUVR value of amyloid PET.ConclusionAmnestic SCD with amyloid PET positive showed higher APOE ε4 allele, lower regional brain volume in AD related areas, lower verbal memory score and higher relative theta/alpha ratio in the frontal area. Longitudinal follow‐up for the next 3 years will identify risk factors for the progression to MCI or dementia and clinical significance of blood MDS‐OAβ value.
Distinctive roles of estrone and estradiol in shaping verbal memory circuitry in postmenopausal women
Authors: Schroeder Rachel A , Thurston Rebecca C , Wu Minjie , Aizenstein Howard J , Derby Carol A , Maki Pauline M 
Published: December 2020

AbstractBackgroundDeclining levels of estrogen have been implicated as a key mechanism contributing to declines in verbal memory that occur with menopause and as a potential factor contributing to risk of AD in women. We examined the association of two estrogens in postmenopausal women ‐ estradiol (E2), secreted by the ovary, and estrone (E1), secreted by peripheral tissues and the dominant estrogen in postmenopause – with functional connectivity during performance of verbal encoding and recognition tasks. We hypothesized that higher estrogen would be associated with greater functional connectivity between the hippocampus and prefrontal cortex (PFC) and between the left and right hippocampus.MethodParticipants were enrolled in MsBrain, a cross sectional investigation of postmenopausal women (n=98, mean age 59.2 +/‐ 4.2 years, 78.6% White). Serum E1 and E2 were assessed using liquid chromatography‐tandem mass spectrometry. Verbal memory was assessed using the California Verbal Learning Test (CVLT) and a functional MRI verbal memory task using a block design with two phases: encoding and recognition. A generalized psychophysiological interaction (gPPI) analysis estimated task‐based hippocampal‐whole brain functional connectivity using SPM12. Principal time series of the seed region (left or right hippocampus), task conditions (novel words, familiar words), interaction variables (seed times series × task condition), and motion parameters were included in the design matrix.ResultE1 was positively associated with connectivity between the hippocampus and rostral anterior cingulate cortex (ACC), mid cingulate, dorsal ACC, and left insula during verbal encoding. E2 was positively associated with connectivity with rostral ACC/medial PFC and left orbital inferior frontal cortex during encoding and connectivity with rostral ACC, bilateral orbital PFC, bilateral middle temporal cortex, precuneus and posterior cingulate cortex during retrieval. All results survived multiple comparison at corrected p < 0.05. No associations were found between estrogen levels and verbal memory performance.ConclusionEstrogen levels in postmenopause may play a significant role in functional connections between the hippocampus and key nodes of the salience network via E1 and cognitive control network via E2. Results suggest that estrogens enhance the ability to attend to stimuli and engage neural resources required for encoding and recognizing verbal information.
Success of referring participants to the Generation program and lessons learned for future enrollment into Alzheimer’s disease prevention trials
Authors: Gordon David , Salata Hayley , Walsh Trisha L. , High Nellie M. , Kettenhoven Cassandra L. , Reiman Eric M. , Tariot Pierre N. , Langbaum Jessica B. 
Published: December 2020

AbstractBackgroundWe developed GeneMatch in 2015 to assist enrollment into Alzheimer’s disease (AD) prevention studies by enriching referrals based in part on APOE4 genotype. The API Generation Program, which enrolled cognitively unimpaired (CU) APOE4 carriers ages 60‐75 was the first multisite clinical trial to use GeneMatch as a recruitment source.MethodGeneMatch is a US‐based, trial‐independent recruitment program of the Alzheimer’s Prevention Registry (APR), conducting APOE testing in CU individuals aged 55‐75. GeneMatch does not disclose APOE results to participants directly, however, results are used to match participants to enrolling studies in a manner that does not inadvertently disclose genotype. Participants are notified by email when they have been invited to a study. A reminder email is sent 7 days later, a letter is mailed to the participant’s home 2mo after if no response is received. Once a participant accepts his/her invitation, their contact information is shared with their preferred study site through an online portal. In July 2016, GeneMatch began inviting participants to the Generation Program.ResultTo date, >90,000 people have joined GeneMatch, > 30% are APOE4 carriers. Recruitment in the Generation Program and treatment with umibecestat was terminated in July 2019 after an early signal of mild worsening in some measures of cognitive function. At that time, 16,521 GeneMatch participants had been invited to the Generation Program, 33% (5,461) of whom accepted their invitations. Of those who accepted, 2,202 consented to the Generation Program (randomization data not yet available), 292 were scheduled for screening, 511 were awaiting scheduling for screening, 242 were waiting to be contacted by their selected study site, 1,209 were found to be ineligible after a phone screen by sites, 695 were no longer interested, and 310 were lost to follow‐up.ConclusionThe Generation Program was on track to complete enrollment in 2019 and GeneMatch was a successful program in helping to recruit APOE4 carriers. Lessons learned include the importance for GeneMatch to coordinate with study sites to ensure they are prepared to receive referrals Future analyses will examine success of GeneMatch (vs. other recruitment sources) for randomization.
Public libraries' involvement in creating a dementia friendly society
Authors: Jensen Anders Møller , Gregersen Rikke 
Published: December 2020

AbstractBackgroundThe WHO recommendations on creating dementia friendly society that helps combat stigma, and improve quality of life for people with dementia, has many parties involved. Over the years the free public libraries in the Scandinavian welfare model has developed interventions towards groups with special needs, but little is known about the needs and wishes of people with dementia. In collaboration, three libraries in Denmark has explored how they can contributed to fulfilling the national goal of creating a dementia friendly society. The aim was to investigate how special programmes towards people with dementia, and their relatives, were received by the target group, and employees at the libraries.MethodThree public libraries in Denmark developed activities based on oral text‐reading supported by pictures and/or visits to relevant museums, in order to create stimulating cultural input covering different literary genres. Between five and nine group activity’s were performed at the libraries, having 15 persons with dementia – some with the assistance of relatives – participated in the program. The sessions lasted one and a half hour. The participants lived at home with support primarily from their spouse. The participants were interviewed no later than one week after the last activity about their experiences participating in the program, and recommendation for the library sectors involvement in creating a dementia friendly society. In addition, staff involved in the activities were interviewed to document their experiences of working with people with dementia. The interviews were recorded, transcribed verbatim, and analysed using thematic analyses.ResultThe programs activities were well received and dropout rate was low. The activities helped the persons with dementia re‐experience the joy of literature, and stimulated them culturally, as well as intellectually. The staff was supportive of the library sectors involvement in creating a dementia friendly society, but pointed out that knowledge about dementia and the organisation in small groups were barriers for further deployment of the program.ConclusionThe results showed promising results regarding public libraries involvement in creating a dementia friendly society.
Disruption of concordance among spontaneous measures of intrinsic brain connectivity in Alzheimer’s disease
Authors: Chen Xiangliang , Dronse Julian , Richter Nils , Fassbender Ronja V. , Reutern Boris , Dillen Kim , Jacobs Heidi I. L. , Fink Gereon R. , Kukolja Juraj , Onur Oezguer A. 
Published: December 2020

AbstractBackgroundIn the last years, several voxel‐wise data‐driven metrics gained attention to study resting‐state connectivity in healthy aging and various pathological states. More recently, a new measure assessing the interaction between the commonly used metrics has been proposed and made widely available via the DPABI toolbox: the so‐called concordance index (CI). This index reflects the coupling of different metrics. The value of this new measure in Alzheimer's disease (AD) research is yet unclear.MethodHealthy young controls (YC, n=26), healthy senior controls (SC, n=29), and patients diagnosed with AD (n=35) underwent 3T resting‐state fMRI. First, the fractional amplitude of low frequency fluctuations (fALFF), regional homogeneity (ReHo), and degree centrality (DC) were calculated. Next, the CI among these measures was determined for each time window and each brain voxel across time by using Kendall's W. Differences in the CI between groups were examined on a whole brain, voxel‐wise, and network‐level using masks of seven of the most prominent intrinsic brain networks, with age, sex, head motion and gray matter volume as covariates.ResultThe whole‐brain CI was significantly lower in AD patients as compared to YC and SC, which is in line with results from analyzing the single metrics. Reductions of the CI in AD was consistently observed in all networks investigated except for the limbic network. In SC compared to YC, no network‐level CI differences were detectable. On the voxel level, AD patients compared to SC showed lower CI in the right middle temporal gyrus, and SC compared to YC revealed lower CI in the left middle frontal gyrus. Analyzing the single metrics for their own, we observed a lower fALFF in the right angular gyrus in AD compared to SC, but no differences were detected for ReHo and DC.ConclusionThe newly proposed CI based on resting‐state connectivity may serve as a more sensitive imaging marker in AD than single metrics. The data suggest that this index distinguishes well between neurodegeneration and healthy aging.
Effect of molecular chaperone network modulators treatment on energy and tau metabolism in human cells
Authors: Pavlov Pavel , Wang Lisha , Kumar Rajnish , Winblad Bengt 
Published: December 2020

AbstractBackgroundAlzheimer disease (AD) is a complex multifactorial disease representing >60 % cases of dementia with no disease modifying therapies available in clinics largely due to its poorly understood pathology. One of the new proteins that recently emerged as a promising target in AD therapy is FKBP51, or FK506‐binding protein 51 kDa. FKBP51, together with its partner, a molecular chaperone heat shock protein 90 kDa (Hsp90), have been found to play an important role in metabolism of tau promoting its accumulation and aggregation. In vitro, in vivo and epidemiological studies also suggest an important role of FKBP51 in control of body weight and insulin resistance.MethodRecently, we have successfully obtained several active compounds able to inhibit FKBP51‐Hsp90 interactions both in in vitro assays and in human cell lines. SH‐SY5Y cells, differentiated human adipocytes were treated with FKBP51‐Hsp90 interaction inhibitors. Effect of compounds on energy metabolism, lipid metabolism as well on tau accumulation was analyzed. Using RNAseq we have analyzed transcriptome changes upon compound treatment.ResultAddition of compounds resulted in profound stimulation of energy metabolism both in SH‐SY5Y cells and differentiated adipocytes. Significant increase in mitochondrial membrane potential was also observed. Dramatic decrease in size and number of lipid droplets was observed in differentiated adipocytes upon compound treatment. RNAseq results show increased expression of genes involved in lipid catabolism, beta‐oxidation and thermogenesis. We have also observed decreased tau levels in the treated SH‐SY5Y cells.ConclusionOur data implicate FKBP51 as a possible target for AD treatment affecting cell energy metabolism and tau accumulation.
Cell‐type specific selective vulnerability to pathological tau in Alzheimer's disease
Authors: Turkes Emir , Duff Karen E. 
Published: December 2020

AbstractBackgroundRegion‐specific neuronal subpopulations known to be selectively vulnerable to Tau pathology, as characterized in our previous work (Fu et al., 2019), were identified across several public single‐nucleus RNA sequencing datasets from non‐diseased human in order to derive putative properties and mechanisms that drive vulnerability.MethodsWe analyzed datasets from the Allen Brain Institute (Hodge et al., 2019), Broad Institute (Habib et al., 2017), and Polo group (Grubman et al., 2019). After QC, dimensionality reduction, and clustering, vulnerable and invulnerable neuronal subpopulations were identified using anatomical metadata and marker genes. Differential expression between subpopulations were performed using the Wilcoxon test, while differential pathway analysis was carried out using the GSVA algorithm.ResultWe were able to identify putative subpopulations across a range of presumed vulnerability as defined by classical pathological staging. Several themes emerge from differential pathway analysis of these subpopulations in various comparisons, including those related to vesicle‐mediated exocytosis activity and synaptic plasticity. Following further drilling down of these pathways for their association with vulnerability, pathways will be systematically screened in a model system measuring Tau aggregation.ConclusionExtensive pathway analysis of neuronal subpopulations selectively vulnerable to Tau pathology in human single‐nucleus RNA sequencing data reveal significant heterogeneity between neurons that may be responsible for driving pathological status.