bluuebunny/crossref_metadata_2025_split huggingface dataset:
Longitudinal assessment of neuroinflammation and axonal loss in white matter tracts in Alzheimer’s disease
Authors: Roy Maggie , Dumont Matthieu , Houde Jean‐Christophe , Morency Félix , Descoteaux Maxime 
Published: December 2020

AbstractBackgroundFree‐water fraction (FW), proxy to neuroinflammation, and apparent fiber density (AFD) are two recently developed diffusion MRI (DMRI) white matter (WM) measures.MethodsWe aimed to longitudinally assess FW (24 months) and AFD (12 months) in specific WM tracts in normal controls (NC) (n = 27), MCI (n = 50) and Alzheimer’s disease (AD) (n = 16) selected from the ADNI2 database. The FW and AFD maps were computed and tractography was used to automatically extract 6 WM tracts: cingulum (CG), uncinate, inferior fronto‐occipital and inferior longitudinal fasciculi (UF, IFOF, ILF), and genu/splenium of the corpus callosum (CC2/CC7). Correlations were also performed to assess association between the changes of the FW and cortical b‐amyloid (18F‐AV45‐PET), as well as between the AFD and plasma neurofilament light chain (NfL).ResultsThe FW significantly increased after 2 years in the CC2, CC7, UF and CG in AD (4‐11%), with no change in MCI and NC. For the AD group, the change of cortical b‐amyloid over 2 years was positively correlated with the change of FW in the ILF, CC2, CC7, UF and CG (r = 0.31 ‐ 0.57; P = 0.02 ‐ 0.05; Fig. 1). The AFD significantly decreased after 1 year in the CG, ILF, and IFOF in AD (7‐8%), and MCI (3‐5%), with no change in NC. Only for the AD group, the change of AFD over 1 year was negatively correlated with the change of plasma NfL in the 6 tracts of interest (r = ‐0.56 ‐ ‐0.67; P = 0.01 ‐ 0.03; Fig. 2) and in the whole white matter (r = ‐0.61; P = 0.009).ConclusionsThe longitudinal assessment of FW shows increase only in AD, while the decrease of AFD is similar in MCI and AD, hence the loss of axonal density seems to appear in earlier stages. These results may also reinforce the link between: i) cortical b‐amyloid accumulation and neuroinflammation, and ii) plasma Nfl and loss of axonal density, both shown for the first time with in‐vivo imaging biomarkers: FreeWater and Apparent Fiber Density.
Activity‐dependent reconnection of adult‐born dentate granule cells in a mouse model of frontotemporal dementia
Authors: Moreno‐Jiménez Elena P , Terreros‐Roncal Julia , Flor‐García Miguel , Llorens‐Martin María 
Published: December 2020

AbstractBackgroundFrontotemporal dementia (FTD) is a neurodegenerative disorder characterized by a loss of neurons in the frontal and temporal lobes of the brain. Tau protein is encoded by MAPT gene and its mutations cause FTD‐Tau, FTD variant. TauVLW mice carries three mutations, G272V (V), P301L (L), and R406W (W) on MAPT, increasing the susceptibility of Tau to be phosphorylated. TauVLW mice show anatomical alterations in the hippocampus as well as behavioural impairments. Importantly, the hippocampus gives rise to new neurons throughout life. This process, named adult hippocampal neurogenesis (AHN), converges in the functional integration of mature dentate granule cells (DGCs) into the trisynaptic hippocampal circuit. AHN is altered in patients with Alzheimer´s disease and in animal models of distinct neurodegenerative diseases, including FTD.MethodsTo perform an in‐depth characterization of newborn DGCs of TauVLW mice we used a combination of trail‐blazing retroviral approaches. We used Red‐Green‐Blue (RGB) retroviruses to address the morphological maturation of these neurons. We also used retroviruses that encode either PSD95:GFP or Synaptophysin (Syn):GFP, together with monosynaptic retrograde rabies virus tracing to study the connectivity of these cells. Finally, we tested the effects of the selective chemoactivation of newborn DGCs using a retrovirus that encodes the excitatory Designer Receptor Exclusively Activated by Designer Drugs (DREADDs) H3Dmq, as modulator to counteract the alterations.ResultsThese innovative approaches revealed that the newborn DGCs of TauVLW mice exhibit marked morphological and functional alterations. Importantly, similar morphological alterations are observed in DGCs of FTD patients. Newborn DGCs of TauVLW mice show impaired afferent and efferent connectivity. Moreover, they are disconnected from distal brain regions and exhibited a predominance of local inhibitory innervation. Therefore, a reduced number of activated egr‐1+ DGCs were observed. On the other hand, chemoactivation led to a complete reversal of the morphological alterations and partial reversal of the alterations in the connectivity of these cells.ConclusionsDGCs are disconnected from distal brain regions and local sources of excitatory innervation in a mouse model of FTD. These cells exhibit remarkable similarities with those of FTD patients. Significantly, the functional defects observed in TauVLW newborn DGCs are reversed by chemoactivation.
Attitudes towards genetic susceptibility testing for Alzheimer’s disease dementia in cognitively normal adults: A survey study
Authors: Masselink Larissa A , Visser Leonie NC , Cleutjens Solange , van der Lee Sven J , van der Schaar Jetske , Scheltens Philip , van Der Flier Wiesje , Zwan Marissa D 
Published: December 2020

AbstractBackgroundInterest in Apolipoprotein E (ApoE) genetic testing for Alzheimer’s disease dementia (AD) is increasing. Even though ApoE‐status is more often being disclosed to cognitively normal adults in clinical trials and services like 23andMe are growing, disclosure in the context of individualized risk profiling is not yet common practice. Our objective was to examine attitudes towards genetic susceptibility testing for AD in a sample of Dutch cognitively normal adults.MethodAn online survey was completed by 428 cognitively normal respondents (response rate 29%) between the age of 50 and 75 years from the Dutch Brain Research Registry (Hersenonderzoek.nl). The survey assessed interest in participating in research studies about genetic testing and disclosure, perceptions of its reasons and possible impact and degree of control respondents want in deciding to test their genetic risk (Control Preferences Scale). Furthermore, we randomly presented three fictional scenarios to assess interest in genetic risk disclosure for different risks of AD (10, 30 and 50%).ResultThe majority of respondents was interested in genetic risk disclosure (80%) and preferred to decide themselves whether to receive their genetic risk (73%) rather than leaving this decision to a health care professional. The most commonly endorsed reason for testing was contributing to scientific research (94%). When presented with specific scenarios, most respondents were still interested in their genetic risk, regardless of the presented risk (73‐79%). The three most important consequences indicated were: 1) sharing their genetic risk with their close environment (77‐89%), 2) participating in a medication trial (79‐87%) and 3) making long‐term arrangements, e.g. for retirement and health care (69‐82%). More than half of the respondents (50‐67%) would probably adjust their lifestyle, e.g. exercise more or eat healthier.ConclusionOur findings indicate that the majority of respondents wants to be informed about their genetic risk for AD and wants to make this decision themselves. The main reason for interest in testing is contributing to scientific research. Future studies should examine the best way to disclose genetic risk for AD by informing participants carefully and closely looking at the possible impact, especially in the context of future individualized risk profiling.
Recruitment and retention strategies to improve inclusion of family caregivers of African American older adults with dementia in advance care planning research
Authors: Grieff Abigail M , Moss Karen , Hurst Laurel Myers , Wills Celia 
Published: December 2020

AbstractBackgroundRecruitment and retention approaches for including family caregivers of lower socioeconomic status African American older adults living with dementia for advance care planning research are currently inadequate. Such underrepresented populations often face multiple and suboptimally‐addressed obstacles to research participation. Subsequently, they are less likely than Caucasians to participate in research. Adequate recruitment and retention is essential for the conduct of high quality research to improve communication about advance directives and to achieve improved interventions to better meet the needs of underserved populations. The purpose of this study is to use a participatory design process to assess and develop enhanced approaches to optimize research recruitment and retention strategies for caregivers of lower socioeconomic status African American older adults living with dementia for advance care planning research.MethodThis qualitative descriptive study uses audio‐recorded telephone interviews conducted with up to 20 current and 20 former caregivers of lower socioeconomic status African American older adults living with dementia who previously participated in at least one research study. Interviews will be conducted with participants that will broadly explore barriers and facilitators to research participation. Audio recordings will be transcribed verbatim. Content analysis will be conducted using qualitative descriptive methods to describe themes that emerge from these data. Transcribed qualitative data will be coded using Dedoose software for qualitative analysis. SPSS software will be used for demographic data analysis.ResultWe anticipate that study findings will fill essential gaps in existing knowledge about recruitment and retention for advance care planning research participation for caregivers of lower socioeconomic status African American older adults living with dementia. This knowledge will inform changes to improve advance care planning research participation towards receipt of preference‐consistent healthcare and increasing advance directive completion rates. Study results will be provided to participants at study completion.ConclusionStudy results will yield insights to increase advance care planning research participation in this population and will be scalable to support recruitment and retention of other underrepresented vulnerable populations for other research studies. This will lead to the use of more culturally‐tailored approaches to research recruitment and retention to increase research participation by people from diverse backgrounds.
Developing therapeutic protein disaggregases for neurodegenerative disease
Authors: Lin Jiabei , Shorter James 
Published: December 2020

AbstractBackgroundThe accumulation of abnormal protein aggregates in human brain is connected with neurodegenerative diseases. The mammalian protein‐disaggregase system comprised of Hsp110, Hsp70, and Hsp40 can protect cells from proteinopathies. However, this disaggregase system has limitations and its activity declines with age. As a therapeutic strategy for neurodegenerative disease we propose to introduce an exogenous, synthetic disaggregase machinery, based on Hsp104 that converts amyloid to soluble, functional protein. Hsp104 is a hexameric AAA+ ATPase that is critical for stress tolerance in yeast by facilitating the resolubilization of stress‐damaged, aggregated proteins. The homologues of Hsp104 are highly conserved in bacteria, fungi, and plants, but absent from metazoa. The disaggregase activity of Hsp104 can be enhanced by the presence Hsp70 and Hsp40. Hsp104 can dissolve α‐synuclein, β‐amyloid, and TDP‐43 aggregates, but impractically high Hsp104 concentrations are needed.MethodNimble yeast models are used to perform an initial evaluation to enhance experimental efficiency. Promising variants will be purified for further characterization and will be advanced to neuronal and glial cell models.ResultWe have engineered and evolved potentiated Hsp104 variants with minimized “off‐target” effect that eradicate α‐synuclein, β‐amyloid, or TDP‐43 misfolding and toxicity. We have discovered Hsp104 variant that reverse TDP‐43 toxicity specifically with no "off‐target" effect. We have exploited new cryo‐EM structures of Hsp104 to engineer key interfaces to yield several novel Hsp104 variants with tunable activity, which can reverse protein aggregation in the presence or absence of human Hsp70 and Hsp40.ConclusionThese novel Hsp104 variants effectively rescue the aggregation and toxicity of diverse human neurodegenerative disease proteins and could have therapeutic utility.
Gene‐neuroimaging brain model decodes neuropathological mechanisms in Alzheimer’s disease
Authors: Adewale Quadri , Medina Yasser Iturria 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is characterized by aberrations of several biological processes/factors (e.g., genes, misfolded proteins, atrophy). Investigating the interplay between these factors at multiple scales can advance our understanding of AD and facilitate the development of cost‐effective treatments while unifying biomarkers for early AD diagnosis and prevention. We propose a mathematical framework that models how gene expression (GE) modulates the interaction between six macroscopic imaging modalities in AD progression. The identified genes and pathways provide novel insight into AD pathology.Method1) We pre‐processed 6 longitudinal neuroimaging data (beta‐amyloid and tau proteins, cerebral blood flow, glucose metabolism, R‐fMRI, and grey matter volume) of 157 healthy and 317 diseased subjects from ADNI. 2) Using GE data of 6 neurotypical brains from Allen Human Brain Atlas, we derived brain‐wide GE of 990 genes with leading roles in central biological functions. 3) We built a mathematical model that incorporates: (i) disease‐related longitudinal changes in neuroimaging data, (ii) GE‐modulated interactions between the different neuroimaging modalities, (iii) propagation of alterations resulting from (ii) across brain networks. 4) By evaluating the latent relationship between GE modulating effects and cognitive measures (MMSE, ADAS, executive function, memory score) of 127 subjects (converters) who advanced to subsequent stages in the AD continuum, causal genes and altered pathways in AD progression were identified.ResultThe model explains 64% of the common variance between GE‐dependent brain alterations and cognitive scores of the converters. We identified 89 disease‐driving genes, including some notable previously identified AD genetic determinants: APPB2, TOP2A, CLU, BACE1 and CD44. The biological factors causally modulated by each gene, and factor alterations resulting from the modulation were also reported; e.g., our model reveals that APPB2 gene modulates beta‐amyloid to cause longitudinal alteration of beta‐amyloid, while CLU could interact with vascular flow to alter tau protein (Fig. 1). We also identified 54 likely altered pathways in AD evolution.ConclusionWe developed a mathematical model to investigate the influence of gene expression on multifactorial alterations of biological processes in AD progression. Our results are strongly consistent with previously reported studies and provided further insight into the molecular mechanism underlying AD progression.
Novel MRI techniques identifying vascular leak and paravascular flow reduction in early Alzheimer disease
Authors: Joseph Charles R 
Published: December 2020

AbstractBackgroundWith beta amyloid and tau antibody treatment trial failures, avenues directed to other facets of the disease pathophysiology are being explored to treat in the preclinical or early clinical state. Clear evidence of blood brain barrier (BBB) breakdown occurring early in the AD process has recently been established. Likewise, the glymphatic system regulating water and solute inflow and outflow in parallel with the vascular system is affected causing delayed clearance of fluid waste. It’s dysfunction as a component of AD along with BBB leak are reasonable candidates to explore for future treatments.MethodWe will review the known physiology and anatomy of the BBB system, its relationship to the glymphatic system and the microglial surveillance system. Ideally, human medication trials require a non or minimally invasive method of quantifying both improvements in BBB integrity and glymphatic fluid clearance correlated with clinical outcomes.ResultDysfunction of this tripart system occurring in Alzheimer disease (AD) will be reviewed along with existing MRI tools for identifying altered flow dynamics useful for monitoring improved functionality with future treatments.ConclusionHigh resolution dynamic contrast enhanced MRI imaging demonstrating BBB leak and the recently reported non‐invasive 3D PASL MRI pilot study demonstrating significant delay in glymphatic clearance in AD subjects appear to be the best candidates.
Novel MRI techniques identifying vascular leak and paravascular flow reduction in early Alzheimer disease
Authors: Joseph Charles R 
Published: December 2020

AbstractBackgroundWith beta amyloid and tau antibody treatment trial failures, avenues directed to other aspects of the disease pathophysiology are being explored to treat in the preclinical or early clinical state. Clear evidence of blood brain barrier (BBB) breakdown occurring early in the AD process has recently been established. Likewise, the glymphatic system regulating water and solute inflow and outflow in parallel with the vascular system is affected causing delayed clearance of fluid waste. Its dysfunction as a component of AD along with BBB leak are reasonable candidates to explore for future treatments.MethodWe will review the known physiology and anatomy of the BBB system, its relationship to the glymphatic system and the microglial surveillance system. Ideally, human medication trials require a non or minimally invasive method of quantifying both improvements in BBB integrity and glymphatic fluid clearance correlated with clinical outcomes.ResultDysfunction of this tripart system occurring in Alzheimer disease (AD) will be reviewed along with existing MRI tools for identifying altered flow dynamics useful for monitoring improved functionality with future treatments.ConclusionHigh resolution dynamic contrast enhanced MRI imaging demonstrating BBB leak and the recently reported non‐invasive 3D PASL MRI pilot study demonstrating significant delay in glymphatic clearance in AD subjects appear to be the best candidates.
The Changing Talk: Online training (CHATO) — Developing and testing an implementation strategy for a national randomized control trial
Authors: Coleman Carissa K , Williams Kristine N , Hein Maria , Perkhounkova Yelena , Beachy Tim , Berkley Amy , Shaw Clarissa 
Published: December 2020

AbstractBackgroundThe Changing Talk (CHAT) training effectively reduces elderspeak and subsequent behavioral challenges in residents with dementia in nursing homes. The Changing Talk: Online (CHATO) training was developed to increase staff access to education using a new online format. In order to test the online training using a national nursing home (NH) sample, an implementation strategy and process evaluation were necessary to capture organizational factors, ensure consistent application across NHs, and test the most effective and efficient implementation strategies.MethodsA planning grant was used to design an implementation strategy using an advisory board. The board consisted of NH Administrators, Directors of Nursing, Nurse Training Specialists, and a marketing consultant. Multiple products were designed including a website, implementation toolkit, training manual, posters, implementation checklist, surveys, and leadership interviews. A pilot test was then conducted to confirm the strategy in 8 nursing homes with a 90‐day implementation timeline. At the initial meeting, an implementation lead was identified. During planning phase, strategies were tailored to the organizational culture and current practices. During the training phase, weekly participation and completion rates were shared. After the training closed, surveys and interviews were conducted.ResultsAn initial feasibility NH (NH0) and seven NHs (NH1‐7) were tested. The mean total implementation time was 70.3 days (SD = 9.3) with a mean planning phase of 20.1 days (SD = 6.7) and a mean training phase of 50 days (SD = 7.6). The implementation strategies varied across NHs (Table 1). The best outcomes were associated with champions, four mediums for weekly reminders, and a group reward. Leadership evaluation was positive (Tables 2 and 3). Differences between leadership perspectives will be used to make improvements prior to the national trial.ConclusionsNH homes utilized the website and implementation toolkit to create a method of implementation tailored for their NH. Process evaluation methods were able to capture strategies used, compatibility, and NH goals for using CHATO. Evaluation of CHATO from both administration and direct care leadership provided multiple perspectives. The implementation strategy will be used to scale up the intervention and test the impact of implementation on CHATO’s primary outcomes.
Correspondence between blood‐based amyloid‐β by immuno‐precipitation mass spectrometry and PIB‐PET imaging in a population cohort
Authors: Snitz Beth E , Chang Chung‐Chou H , Zeng Xumei , Yates Nathan , Kamboh M Ilyas , Klunk William E , Lopresti Brian J , Becker Carl , Ganguli Mary 
Published: December 2020

AbstractBackgroundRecently developed immuno‐precipitation mass spectrometry (IP‐MS) assays to measure blood‐based amyloid‐β with high accuracy holds exciting potential. Adoption of amyloid‐β measurement will be especially valuable in large population studies where not previously feasible. We evaluated the correspondence between a new IP‐MS assay developed on a commercially available platform with brain amyloid PET imaging as the gold standard.MethodN=99 older participants without dementia, active in the population‐based Monongahela‐Youghiogheny Healthy Aging Team (MYHAT) study, underwent blood draws at the time of brain amyloid imaging with PiB‐PET (50‐70 minutes post‐injection, SUVR with cerebellar reference). Adapting methods of Nakamura et al. (2018), immunoprecipitation from plasma was followed by time‐of‐flight MS, using a benchtop mass spectrometer, to measure relative amounts of endogenous peptides Aβ1‐40, Aβ1‐42, APP669‐711, and a stable‐isotope‐labeled internal standard. A composite plasma biomarker was calculated as the mean of the normalized ratios APP669711/Aβ142 and Aβ140/Aβ142.Resultn= 24 (24%) of participants were PiB‐positive by a global cutoff, 7 (7%) were CDR 0.5, and 13 (13%) were APOE*4 carriers. Higher global PiB SUVR was associated with older age, higher CDR (0.5 vs. 0) and APOE*4 genotype (p’s < .05), while higher plasma composite biomarker was similarly associated with CDR and APOE*4 but not age. ROC analysis yielded an AUC of 0.78 (SE 0.05) for the composite plasma biomarker predicting PiB‐PET status, with an optimized cut‐point corresponding to sensitivity of 0.75 and specificity of 0.69. Including age and APOE*4 into the model yielded an overall AUC of 0.89, and plasma biomarker sensitivity of 0.91 and specificity of 0.77.ConclusionThis IP‐MS assay was successfully implemented using a commercially‐available, benchtop MALDI‐TOF instrument that is easy to operate and already used in clinic settings. Concurrent prediction of amyloid status from plasma amyloid alone was significant, with moderately high accuracy. Combining plasma amyloid with age and APOE genotype improved prediction to high accuracy. Planned follow‐up of the sample with repeat PiB scans will yield yet further information about prospective prediction of brain amyloid status. This non‐invasive approach using a peripheral biomarker could be highly useful and feasible to apply in large population studies of AD risk.