bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lifespan neuroimaging of the 5xFAD mouse model of Alzheimer’s disease: Evolution of metabolic and vascular perturbations
Authors: Szu Jenny , Jullienne Amandine , Obenaus Andre , Territo Paul R , Consortium MODEL‐AD 
Published: December 2020

AbstractBackgroundThe Model Organism Development and Evaluation for Late‐Onset Alzheimer’s Disease (MODEL‐AD) consortium seeks to develop the next generation of Alzheimer’s disease models guided by human data. As new mice models become available, they are extensively phenotyped and compared to existing models, such as the 5xFAD. The 5xFAD models familial AD onset, which results in amyloid β (Aβ) deposition and cognitive decrements early in life; however, no studies have comprehensively phenotyped the vascular and metabolic aspects of this mouse over its lifespan (∼15mo). Here we report lifespan perturbations in male and female 5xFAD mice compared to healthy aging C57BL/6J (WT) mice using multi‐modal neuroimaging with assessment of vascular networks.MethodAge (4, 8, 12mo) and sex‐matched 5xFAD and healthy aging WT (C57BL/6J) mice underwent ex vivo MRI and in vivo PET evaluation for regional brain volumes (T2‐weighted imaging), Aβ load (susceptibility weighted imaging and 18F‐AV45 PET) and brain metabolism (18F‐FDG PET). After neuroimaging, selected mice underwent novel vessel painting (VP) to label whole brain vascular networks. Histology and immunohistochemical analyses verified neuroimaging findings.ResultWhole brain volumes were significantly decreased (∼6%) in 8mo female 5xFAD compared to WT, as were hippocampal volumes in both sexes. SWI and AV45‐PET were able to detect elevated Aβ plaques with age in 8‐12mo old 5xFAD mice when compared to WT. 18F‐FDG showed a reduction in glycolysis with age when compared to WT. Whole brain vascular networks in 8mo 5xFAD mice had vessel numbers and complexity compared to 4mo 5xFAD, with males having larger reductions than females. The middle cerebral artery vessel density in 5xFAD was also decreased. Immunohistochemistry confirmed Aβ deposition and microglia activation with genotype and age.ConclusionThis is the first report of vascular and metabolic disturbances during the lifespan in the 5xFAD model of AD. Our findings suggest that vascular and metabolic ageing are correlated to temporal cumulative Aβ deposition. Early decrements in vascularity in the 5xFAD may precede the development of pathology. Further, the 5XFAD mice exhibit age and region‐specific neuroimaging alterations coincident with metabolic disturbances.
Brain target occupancy of LY3372689, an inhibitor of the O‐GlcNAcase (OGA) enzyme: Translation from rat to human
Authors: Shcherbinin Sergey , Kielbasa William , Dubois Susan , Lowe Stephen L , Phipps Krista M , Tseng James , Kevin Donnelly B , Natanegara Fanni , Warner Susan , Dreyfus Nicolas , Lindsay‐Scott Peter , Hawk Mai Khanh , McDonald Nicholas , Zhang Xiaoyu , Gilmore Julie A , Biglan Kevin , Mergott Dustin J , Russell David , Gunn Roger N , Constantinescu Cristian , Nuthall Hugh Norman , Collins Emily C 
Published: December 2020

AbstractBackgroundLY3372689, an O‐GlcNAcase (OGA) enzyme inhibitor, is being developed as a potential treatment of tauopathies, including Alzheimer’s disease. OGA inhibition is proposed to delay the progression of tau‐related diseases by slowing the accumulation of hyper‐phosphorylated, insoluble tau filaments. Herein, we report on nonclinical and clinical studies that assessed the effect of LY3372689 on brain OGA enzyme occupancy (EO).MethodBrain OGA EO of LY3372689 was measured in the frontal cortex of rats using tracer LSN3291920, a non‐fluorinated analog of a positron emission tomography (PET) radioligand 18F‐ LY3316612. A single oral dose study in healthy volunteers (HV) utilizing18F‐LY3316612 is ongoing to assess brain OGA EO of LY3372689 (NCT03944031). The study consists of up to 5 Cohorts (N = 3 – 6 subjects per Cohort). Upon completion, each subject will have participated in one cohort and have received a baseline PET scan and up to two post‐dose PET scans. In the initial cohorts, the post‐dose PET scans were conducted at approximately 2 and 24 hours after LY3372689 administration. The study design is adaptive to allow adjustment of the LY3372689 dose, timing of PET scans and pharmacokinetic samples, and number of subjects, pending results of prior cohorts.ResultIn rat studies, LY3372689 demonstrated a dose‐dependent change in OGA EO following a single oral dose with a maximum EO of greater than 90%. In the human PET study, a total of 12 healthy volunteers across 3 dose cohorts (N = 4 HV per cohort) have been enrolled to date. A plasma concentration‐dependent increase in brain OGA EO was observed with EO exceeding 90% at 24 hours following the highest dose of LY3372689 administered.ConclusionNon‐clinical and clinical EO studies demonstrated that occupancy of the OGA enzyme effectively translated from rats to humans after single doses of LY3372689. The human PET data can be used to support LY3372869 dose selection for efficacy trials in tauopathies.
Late‐onset Alzheimer's disease‐associated gene, CPAMD8, increases B‐CTF and affects APP processing through regulation of the autophagy‐lysosome pathway
Authors: Qin Wei , Fernandez Victoria , Harari Oscar , Cruchaga Carlos , Benitez Bruno A. 
Published: December 2020

AbstractBackgroundC3‐ and PZP‐like alpha‐2‐macroglobulin domain containing 8 (CPAMD8) has been shown to be associated with familial late‐onset Alzheimer disease (LOAD) in recent studies. However, the role of CPAMD8 in AD‐related phenotypes is currently unknown.MethodsTo determine whether CPAMD8 affects known AD‐related phenotypes, we used RNA‐sequencing data from AD patients and healthy controls from WUTSL and publicly available from the Mount Sinai Brain Bank (195 individuals). Differential expression (DE) analysis was performed using DESeq2 software. We investigated the association of CPAMD8 transcript levels with AD case–control status and CDR scores. CPAMD protein levels were quantified from AD cases and controls from the ADRC‐WUSTL cohorts (N=105). Mouse neuroblastoma (N2A) cells stably expressing wild‐type human APP695 (N2A‐APP) were transiently transfected with wild‐type (NM_015692) human CPAMD8 (RC213448, Origene). CPAMD8 mRNA and protein levels were confirmed by pPCR and western blot. The levels of Aβ40 and Aβ42 were measured in cell culture media by sandwich ELISA (Invitrogen).ResultsCPAMD8 is differential expressed in cases and controls and is associated with CDR score (p = 8.45×10‐3). Co‐expression gene network analysis place CPAMD8 in the amyloid pathway (p = 8.5×10‐5). A significant reduction in CPAMD8 protein levels was found in postmortem brain tissue from AD patients compared to controls (p = 2.1×10‐3). N2A‐APP cells expressing CPAMD8 exhibited a dose‐dependent reduction in extracellular Aβ40, Aβ42, sAPPα and sAPPβ levels, a decrease in full‐length APP, and a significant increase in intracellular levels of α and β APP C‐terminal fragments (CTF). No significant differences were detected in α‐secretase or γ‐secretase protein levels. However, inhibition of γ‐secretase induced much higher levels of LC3‐II, SQSTM1/p62 and APP CTFs, and lower levels of Aβ40 and Aβ42 in N2A‐APP cells expressing CPAMD8. A direct interaction between CPAMD8 and APP was confirmed by co‐immunoprecipitation. N2A‐APP cells, but not HEK293 cells, expressing CPAMD8 displayed a significant increase in LC3‐II and SQSTM1/p62. Pharmacological modulation of autophagy demonstrated an increased autophagic flux in N2A‐APP cells expressing CPAMD8.ConclusionsOur data provides evidence that the AD‐associated gene, CPAMD8, alters APP processing through the regulation of the autophagy‐lysosome pathway.
Volumetry and cortical thickness of olfactory‐related structures in Alzheimer's disease: A systematic review and meta‐analysis
Authors: Jobin Benoît , Frasnelli Johannes , Boller Benjamin 
Published: December 2020

AbstractBackgroundA lesser known early symptom of Alzheimer’s disease is the olfactory decline. The ability to identify an odour may even be a predictor of conversion from mild cognitive impairment (MCI) to AD. This sensory decline could reflect AD‐related brain damage, including cerebral atrophy of structures related to the sense of smell.MethodThe aim of this systematic review is to summarize current knowledge about the volume and cortical thickness of olfactory brain structures in the course of AD. Articles were collected from the PubMed database using the keywords olfac*, smell, MRI, volume, VBM, thickness, Alzheimer, MCI, POC, olfactory bulb, hippocamp*, amygdala, entorhinal cortex, piriform cortex. Articles were included in the review according to the following criteria: (1) participants had a diagnosis of AD or Mild Cognitive Impairment (MCI); (2) the presence of a healthy control group of the same age range; (3) cortical volume or thickness was calculated from MRI scans; and (4) there was an assessment of olfactory capacities. A meta‐analysis is in preparation.ResultTwelve studies met the inclusion criteria. All of them report lower olfactory capacities in patients (AD or MCI). Eight studies report a reduced hippocampal volume and 9 studies relate olfactory capacities to hippocampal volume in these patients. Analogous results are found with the primary olfactory cortex. Amygdala and entorhinal cortex volumes are also affected, but their relationship to olfactory capacity is inconsistent. Only one study measured the volume of the olfactory bulb and reported no significant results. Links were also found between olfactory measurements and the volume of the pre‐central gyrus, ventricles and neocortex.ConclusionThe olfactory decline observed in the early stages of AD may reflect brain damage already present in these stages, mainly to the hippocampus and the primary olfactory cortex. These findings support the proposition that an olfactory decline could be an early marker of AD.
Patient‐tailored, connectivity‐based forecasts of spreading brain atrophy in frontotemporal dementia
Authors: Brown Jesse , Seeley William W. 
Published: December 2020

AbstractBackgroundNeurodegenerative diseases appear to progress by spreading via brain connections. Like Alzheimer’s disease, frontotemporal dementia (FTD) syndromes make compelling test cases for evaluating network‐based spreading models due to their focal and circumscribed atrophy patterns. In this talk, I will describe our recent work (Brown et al, 2019 Neuron) where we evaluated transneuronal degeneration by attempting to predict future atrophy in patients with behavioral variant frontotemporal dementia (bvFTD, n=42) and semantic variant primary progressive aphasia (svPPA, n=30). While evidence for this mode of progression has come from cross‐sectional studies, the critical test was whether network connectivity can predict longitudinal spread of atrophy in individual patients.MethodsWe used T1‐weighted MRI scans to identify each subject’s gray matter atrophy pattern. Using these maps, we identified each patient’s epicenter, the region whose healthy functional connectivity pattern most strongly resembled the patient’s atrophy. Next, we projected the patient’s epicenter and baseline atrophy map onto the healthy functional connectome. We used three measures to predict the amount future atrophy for 242 cortical and subcortical brain regions: 1) shortest path length to the epicenter (SPE); 2) nodal hazard, the amount of collective atrophy among a region’s first‐degree connected neighbors; and 3) regional baseline atrophy. A generalized additive model was used to generate predictions. Finally, we used a linear threshold model (LTM) to simulate disease spread from the identified epicenters.ResultbvFTD patients had epicenters in anterior cingulate and frontoinsula and svPPA patients in the anterior temporal lobe. The predictive model explained an average of 37% within‐scan variance in longitudinal atrophy. SPE, nodal hazard, and baseline atrophy were all significant predictors of change (all p < 2x10‐16). The regions most vulnerable to subsequent atrophy were functionally connected to the epicenter and had intermediate levels of baseline atrophy. LTM simulations revealed that epicenter‐neighboring nodes were network hubs and may drive amplification of disease spread.ConclusionA statistical model using connectivity‐based predictors could accurately predict the whole‐brain subsequent atrophy patterns in most FTD patients. This provides new human evidence that neurodegenerative disease spreads between functionally connected areas. The findings represent a next step toward clinical application of the network‐based neurodegeneration framework.
Achieving supportive dementia‐friendly transportation: Research to practice implications
Authors: Silverstein Nina M 
Published: December 2020

AbstractBackgroundResearch has documented the impact of Alzheimer’s disease on critical driving skills (Adler, Rottunda, & Dysken, 2005; Eby et al., 2012). Impairments in driving are likely to be similar reasons that hinder use of public transit or other modes of travel. Figure 1 illustrates examples where the warning signs of AD not only present challenges to driving but also may affect the use of transportation options. Figure 2 illustrates the continuum from driver to passenger. A framework for perceiving mobility as the outcome and driving as just one mode of travel can succeed in reducing the perception of loss to the individual if models of supportive transportation are more available in practice.MethodDrawing on the Dementia Friendly Calculator (Figure 3), and Silverstein and Turk (2015) interviews with transportation providers, supportive transportation is operationalized in terms of the level of assistance needed and whether transportation providers deliver that assistance. Understanding the 5As of availability, affordability, adaptability, accessibility, and acceptability led to strategies and tips for transportation providers, drivers, care partners, and the person with dementia.ResultsStrategies include pre‐trip checklists, passenger information; escorts to provide to the door, through the door, or stay at the destination assistance; training on communication and sensitivity in providing assistance in/out of vehicle.ConclusionExpanding the availability of supportive transportation options will enable persons with dementia to engage in their communities safely and longer throughout the disease process. References: Adler, G., Rottunda, S., & Dysken, M. (2005). The older driver with dementia: An updated literature review. Journal of Safety Research, 36(4), 399‐407. Eby, D., Silverstein, N., Molnar,L., LeBlanc,. D., Adler, G..(2012). Driving Behaviors in Early Stage Dementia: A Study Using In‐Vehicle Technology. Accident Analysis & Prevention. Kerschner, H.K., and Silverstein, N.M. (2018). Introduction to senior transportation. Routledge, New York. Silverstein, N.M., Dickerson, A., & Schold Davis, E. (2016). Community Mobility and Dementia: The Role for Health Care Professionals in Dementia Care: An Evidence‐Based Approach, Boltz, M., & Galvin, J., Editors. Springer Publications: 123‐148. Silverstein, N., & Turk, K. Students explore supportive transportation for older adults (2015). Gerontology & Geriatrics Education/Routledge Taylor & Francis.
Informal care time in dementia by cognitive, functional and behavioral disease severity from eight longitudinal cohorts across multiple countries
Authors: Handels Ron , Jönsson Linus , Green Colin , Winblad Bengt , Wimo Anders ,   Actifcare, ICTUS/DSA, IDA, LEARN, 4CD, MEDICIE, PLASA/DSA and RightTimePlaceCare Consortia Data Holder
Published: December 2020

AbstractBackgroundAbout half of the care for dementia is provided informally by family carers. Evidence on the hours of informal care by dementia symptoms of cognition, function and behavior is important to estimate the long‐term health‐economic effects beyond the common trial periods; especially as such evidence is not available from claims registries. We aim to estimate the informal care time provided by family carers to persons with dementia across states of cognition, function and behavior and demographic characteristics using merged data from multiple countries.MethodData was obtained from longitudinal cohorts Actifcare, ICTUS, IDA, LEARN, 4C, MEDICIE, PLASA and RightTimePlaceCare, including persons with Alzheimer’s and other type dementia recruited from a variety of clinical settings in countries BE, CH, DE, DK, EE, ES, FI, FR, GR, IE, IT, NL, NO, PT, SE and UK. Scores on cognition (MMSE), harmonized instrumental activities of daily living (IADLS, DAD) and neuropsychiatric symptoms (NPI) were categorized as mild, moderate or severe, resulting in 27 possible health states. Missing data were imputed using multiple imputation. Multivariate mixed regression models were fitted to the reported instrumental and personal informal care (obtained by the Resource Use in Dementia questionnaire) using the health states and demographic characteristics.ResultA total of 10,310 observations from 4866 persons were available with mean baseline person with dementia age of 79 (SD=7.4) and 64% female, and mean informal carer age of 63 (SD=13.8), 66% female and 63% living together with the person with dementia. The mean hours of informal care per week are provided in figure 1. Regression indicated a positive association with cognition, function, behavior, home living, female and cohabiting informal carer (for both instrumental and personal informal care), and age had varying effects.ConclusionInformal care is associated to dementia disease severity across cognitive, functional and behavioral domains independently. The results can serve as input for country‐specific models for epidemiological projections and health‐economic simulation for the evaluation of (new) interventions from a societal perspective. The harmonized longitudinal dataset has the potential to estimate within‐individual changes in informal care related to disease progression over time.
Genetic studies of Alzheimer's disease risk implicate clearance of lipid rich debris in myeloid cells
Authors: Novikova Gloriia , T.C.W. Julia , Marcora Edoardo , Kapoor Manav , Renton Alan E. , Efthymiou Anastasia M. , Abud Edsel M. , Bendl Jaroslav M. , Cheng Haoxiang M. , Fullard John F. , Roussos Panos , Poon Wayne W. , Hao Ke , Goate Alison M. 
Published: December 2020

AbstractBackgroundGenome‐wide association studies (GWAS) have identified more than forty loci associated with Alzheimer’s disease (AD), but the causal variants, regulatory elements and genes remain largely unknown, impeding a mechanistic understanding of AD pathogenesis. Earlier pathway analyses have implicated lipid metabolism, immune response and endocytosis.MethodWe used LDscore regression to determine the epigenomic annotations enriched for AD risk variants. We then integrated AD GWAS signals with epigenomic and transcriptomic datasets using novel analytical approaches to link myeloid enhancer activity to target gene expression regulation and AD risk modification.ResultWe show that AD risk variants are specifically enriched in active enhancers of monocytes, macrophages and microglia. Using summary‐data based Mendelian Randomization nominate candidate AD risk enhancers and identify their target causal genes (including AP4E1, AP4M1, APBB3, BIN1, CD2AP, MS4A4A, MS4A6A, PILRA, RABEP1, SPI1, SPPL2A, TP53INP1, ZKSCAN1, and ZYX) in sixteen loci. Fine‐mapping of these enhancers nominates candidate functional variants that likely modify disease susceptibility by regulating causal gene expression specifically in myeloid cells. In the APOE locus we used genome editing to generate isogenic human induced pluripotent stem cells (hiPSC) combined with transcriptomics to demonstrate dyshomeostasis of lipid metabolism in APOE44 glial cells from.ConclusionCombined, these results strongly implicate dysfunction of myeloid cell endo‐lysosomal pathways involved in clearance of lipid rich debris in the etiology of AD.
Gut microbiome perturbations influence brain amyloidosis only in the presence of microglia in APPPS1‐21 mice
Authors: Dodiya Hemraj B. , Lutz Holy , Weigle Ian , Roman‐Santiago Carlos , Patel Priyam , Olszewski Monica , Zhang Can , Zhang Xiaoqiong , Schipma Matthew John , Tanzi Rudolph E. , Gilbert Jack A. , Sisodia Sangram S. 
Published: December 2020

AbstractBackgroundIn prior efforts, we demonstrated reduced amyloidosis and altered microgliosis in long‐term antibiotics (abx)‐treated APPPS1‐21 male mice. Restoration of the gut microbiome into abx‐treated male mice by fecal microbiota transfer (FMT) established a causality between the gut microbiome and amyloidosis. We have used FMT studies using our current short‐term abx APPPS1‐21 mice to evaluate the microbiome‐microglia‐amyloidosis axis.MethodShort‐term, postnatal abx (4mg/ml Kanamycin, 0.35mg/ml Gentamicin, 8500U/ml Colistin, 2.15mg/ml Metronidazole, 0.45mg/ml Vancomycin: post‐natal day 14 to day 21) was performed. To establish causality, we performed FMT (200µl of 5mg/ml fecal slurry daily gavage) into abx‐treated APPPS1‐21 male mice. Pathogenicity of the gut microbiome in WT or Tg mice were confirmed using age‐matched FMT from WT and Tg controls into abx‐treated male mice. We performed total RNAseq transcriptome analysis to evaluate potential mechanism(s). The role of microglial cells were evaluated in PLX6522 (CSF‐1 receptor inhibitor)‐treated FMT‐transplanted abx‐treated APPPS1‐21 male mice. Nine weeks old GF APPPS1‐21 were used to characterize the amyloidosis and glial cells in both genders.ResultAn early life abx treatment resulted in gut microbiota changes in a sex‐dependent manner. Only male mice showed reduced amyloidosis and altered microglial phenotypes. Age matched Tg FMT or WT FMT resulted in higher amyloidosis in abx‐treated male mice. RNAseq analysis of total cortical RNA showed significantly different mRNA levels that occurred in a sex‐specific manner and changes in abx‐treated male mice were restored with FMT. GO term analysis showed gliogenesis and microglia development as significantly altered pathways in abx‐treated male group only. To confirm the exact role of the microglia in this model, we employed PLX6522 in FMT‐treated ABX‐male mice. Microglia depletion did not result in an FMT‐dependent increase in amyloidosis in abx‐treated male mice. Finally, germ‐free APPPS1‐21 mice showed reduced amyloidosis that occurs in a sex‐specific manner.ConclusionFrom GF APPPS1‐21 and FMT‐treated abx‐male APPPS1‐21 studies, we conclude that gut microbiome plays a critical role in modulating amyloidosis in APPPS1‐21 mice. Furthermore, microglia mediates the effects of early life gut microbiota perturbations, which results in altered amyloidosis in APPPS1‐21 male mice.