51886 research outputs found
Sort by
Polygenic scores for Alzheimer’s disease risk and resilience predict age at onset of amyloid‐β
No full textBackground:
Genome‐wide association studies (GWAS) have identified numerous genetic variants associated with Alzheimer’s disease (AD) risk, but genetic variation in the onset and progression of AD pathology is less understood. Accumulation of amyloid‐β (Aβ) in the brain is a key pathological hallmark of AD beginning 10 – 20 years prior to cognitive symptoms. We investigated the genetic basis of variation in age at onset (AAO) of brain Aβ by comparing the performance of polygenic scores (PGSs) based on AD risk and resilience with a Aβ‐AAO trait‐specific PGS.
Method:
1122 participants from the Alzheimer’s Dementia Onset and Progression in International Cohorts (ADOPIC) study underwent genome‐wide SNP genotyping and assessment of brain Aβ using positron emission tomography (PET) imaging at two or more timepoints. AAO was the age at which participants were estimated to have crossed the 20 centiloid (CL) threshold for high Aβ. We utilised AD risk and resilience GWAS summary statistics and conducted a GWAS for AAO using a cross‐validation approach (10 test‐validation folds). We used PRSice to identify optimal PGSs for Aβ‐AAO for risk (PGSRisk), resilience (PGSResilience) and Aβ‐AAO (PGSAAO).
Result:
PGSRisk and PGSResilience were both significantly associated with Aβ‐AAO, such that higher PGSRisk and lower PGSResilience were associated with an earlier Aβ‐AAO. PGSRisk showed the strongest association and explained more variance in Aβ‐AAO than did PGSAAO. When stratified by APOE ε4 carriage, the strongest genetic risk factor for AD, the association of PGSRisk with Aβ‐AAO was stronger among ε4 non‐carriers, whilst PGSResilience, was more strongly associated with Aβ‐AAO in ε4 carriers.
Conclusion:
PGS based on genetic risk and resilience for AD are both significant predictors of the age at which people are estimated to cross the threshold for high brain Aβ burden. Predicting the age at which a person will pass this threshold would enable treatment at an earlier stage, when it may more effectively delay or prevent symptom onset
Influence of tau on non‐traditional memory scores in early‐onset Alzheimer’s disease
No full textBackground:
A common neuropsychological test for assessing episodic memory is the Rey Auditory Verbal Learning Test (RAVLT), a sequence of 8 word‐list learning and recall tasks (five learning trials, immediate recall of an intrusion list, short‐delay and long‐delay recall). There is extensive research correlating patterns of RAVLT performance with clinical dementia syndromes, but little work relating these patterns to biomarkers in early‐onset dementia. Here, we analyze the relationship between patterns of tau deposition and RAVLT performance in early‐onset populations.
Method:
We transcribed RAVLT recordings from 249 subjects in the Longitudinal Early‐Onset Alzheimer’s Disease Study (LEADS). We calculated three composite scores from scores on the individual RAVLT tasks: learning ratio, raw learning score, and recency ratio. We then performed principle components analysis (PCA) on tau measurements in 108 regions of interest, identifying five components accounting for 90.9% of the variance. We entered RAVLT composite scores as dependent variables in a series of linear regression models. The PCA components, along with diagnostic syndrome and nuisance variables (age, sex, education), were entered as independent variables.
Result:
Principal component 1 loaded positively in all ROIs in both hemispheres, with weaker loadings in the motor strip, occipital region, and subcortical nuclei. Principal component 5 loaded positively on left > right temporal lobes and white matter. These two were significant predictors of both learning ratio and raw learning score, showing that an increase in tau affects the performance of these RAVLT metrics. Loadings for principal component 4 were more complex, but in general were positive in the right > left hemisphere, including parietal lobes and superior temporal gyri, with negative loadings elsewhere in the temporal lobes. This component was a significant predictor of recency ratio. In all cases, regression coefficients were negative, indicating that tau within ROIs with positive loadings was negatively correlated with the memory score in question.
Conclusion:
RAVLT measures are sensitive to the effects of tau deposition in early‐onset Alzheimer’s disease. Further work is needed to evaluate these scores as predictors of specific forms of pathology in early‐onset dementia
Elucidating the Role of the Essential Kinase TgGSK in the Human Parasite Toxoplasma Gondii
No full textIUIToxoplasma gondii is an intracellular parasite that infects nearly a third of the world’s human population. While infection is largely asymptomatic in an immunocompetent host, Toxoplasma infection in immunocompromised or immunosuppressed individuals can lead to toxoplasmosis, which can include brain lesions and lead to death. Similarly, toxoplasmosis can result in birth defects, brain swelling, and blindness of a developing fetus in the case of a congenital infection. With minimal treatments for toxoplasmosis available, it is crucial to study parasite-specific processes that could be potential drug targets for the treatment of toxoplasmosis. Toxoplasma gondii divides through a unique process known as endodyogeny, where two daughter parasites are formed within a mother. In this study, we investigated a novel protein called TgGSK that is crucial for proper parasite division. Experiments reveal that TgGSK changes its localization within the parasite dependent on the stage of division. Knockdown of TgGSK causes abnormal division phenotypes and causes Toxoplasma to be unable to complete its propagation cycle. We determined through microscopy and phosphoproteomics that TgGSK may play its role in parasite division through an interaction with the centrosome, an organelle which is a main feature of cell division in many organisms. Our findings suggest that TgGSK also regulates messenger RNA processing. Finally, our study suggests that TgGSK is regulated and stabilized through acetylation from the GCN5b lysine acetyltransferase complex. Taken together, we have performed an in-depth study of the functional role of the essential protein TgGSK in Toxoplasma gondii. This and future studies have potential to demonstrate that TgGSK is a parasite-specific drug target for the therapeutic treatment of toxoplasmosis
How do states regulate Certified Nurse Aides?
No full textCertified Nurse Aides (CNAs) are regulated by state-level agencies. All states require CNAs to complete state-approved training and pass a state exam in order to be registered with the state. The specific agency(ies) involved in CNA regulation varies by state. The Bowen Center completed a 50-state scan of state approaches to CNA regulation and findings are included in this report
Distinct mouse models correspond to distinct AD molecular subtypes
No full textBackground:
Alzheimer’s disease (AD) is a complex, multifactorial pathology with high heterogeneity in biological alterations. Our understanding of cellular and molecular mechanisms from disease risk variants to various phenotypes is still limited. Mouse models of AD serve as indispensable platforms for comprehensively characterizing AD pathology, disease progression, and biological mechanisms. However, selection of the right model in preclinical research and translation of findings to clinical populations are intricate processes that require identification of pathophysiological resemblance between model organisms and humans. Many existing clinical trials that showed promising efficacy in one particular mouse model later do not align with human trial results, assuming that study had consisted of a heterogeneous group of participants, and individual animal models may only recapitulate features of a subgroup of human cases. To improve interspecies translation, it is necessary to comprehensively compare molecular signatures in mouse models with subgroup of human AD cases with distinct molecular signatures.
Method:
We performed transcriptomic and proteomics analysis on whole brain samples from mouse models carrying LOAD risk variants. To assess the human disease relevance of LOAD risk variants in mice, we determined the extent to which changes due to genetic perturbations in mice matched those observed in human AD subtypes and disease stages of AD in the ROS/MAP, Mayo and Mount Sinai Brain Bank cohorts. Genesets within these disease subtypes are highly co‐expressed and represent specific molecular pathways.
Result:
We have identified that distinct mouse models match to distinct human AD subtypes in age‐dependent manner. Specifically, mouse models carrying human AD risk variants such as Abca7*A1527G showed strong correlation with inflammatory AD subtypes, while mouse models carrying risk variant such as Plcg2*M28L exhibited transcriptomics changes similar to non‐inflammatory AD subtypes.
Conclusion:
In this study, we highlighted that mouse model of AD may match to a particular subset of human AD subtypes but not all subtypes simultaneously, and that risk for these subtypes may be influenced by distinct AD genetic factors. Additional work toward validating and better understanding the role of each subtype key regulator in its matching mouse model will provide great value and have a great impact on future studies of AD
Enhanced microglial dynamics in the amyloid plaque microenvironment contributes to cognitive resilience in Alzheimer’s disease
No full textBackground:
Asymptomatic Alzheimer’s disease (AsymAD) refers to individuals with preserved cognition but identifiable Alzheimer’s disease (AD) brain pathology, including beta‐amyloid (Aβ) deposits, neuritic plaques and neurofibrillary tangles upon autopsy. Unlike AD cases, AsymAD exhibits low neuroinflammation and fewer soluble pathological tau species at synaptic levels. However, the link between these observations and the ability to counteract AD pathology is not fully understood. Evidence from AD mice models suggests that the plaque microenvironment significantly influences Aβ plaque‐associated tau pathogenesis. In this study, we investigated the postmortem brains of a cohort of AsymAD cases to gain insight into the mechanisms underlying resilience to AD pathology and cognitive decline.
Method:
We conducted a detailed histological and biochemical analysis using postmortem brain samples from age‐matched controls (N = 13), AD (N = 19), and AsymAD subjects (N = 17). In fixed brain tissue, we performed the GeoMx whole spatial transcriptome atlas to compare the gene expression within the Aβ‐plaque microenvironment in AsymAD versus AD cases. To further explore the mechanisms insights of our findings we used human microglial cells.
Result:
Our findings showed that AsymAD cases exhibit an enrichment of core plaques and decreased filamentous plaque accumulation with increased surrounding microglia. Less pathological tau aggregation in dystrophic neurites was found in AsymAD versus AD brains, and tau seeding activity was comparable to that in healthy brains. To further characterize the plaque niche, we used spatial transcriptomics, finding an increase in components of the actin‐based motility pathways within the microglia surrounding amyloid plaques in AsymAD brains. Ongoing mechanistic experiments in vitro aim to elucidate the role of this pathway in microglial response to Aβ.
Conclusion:
Our findings indicate that the amyloid‐plaque microenvironment in AsymAD brains is characterized by microglia with highly efficient actin‐based cell motility mechanisms and decreased tau seeding versus that observed in AD brains. These two mechanisms can potentially protect against the toxic cascade initiated by Aβ, preserving brain health, and slowing AD pathology progression
Overview of Alzheimer's Disease Neuroimaging Initiative and future clinical trials
No full textThe overall goal of the Alzheimer's Disease Neuroimaging Initiative (ADNI) is to optimize and validate biomarkers for clinical trials while sharing all data and biofluid samples with the global scientific community. ADNI has been instrumental in standardizing and validating amyloid beta (Aβ) and tau positron emission tomography (PET) imaging. ADNI data were used for the US Food and Drug Administration (FDA) approval of the Fujirebio and Roche Elecsys cerebrospinal fluid diagnostic tests. Additionally, ADNI provided data for the trials of the FDA-approved treatments aducanumab, lecanemab, and donanemab. More than 6000 scientific papers have been published using ADNI data, reflecting ADNI's promotion of open science and data sharing. Despite its enormous success, ADNI has some limitations, particularly in generalizing its data and findings to the entire US/Canadian population. This introduction provides a historical overview of ADNI and highlights its significant accomplishments and future vision to pioneer "the clinical trial of the future" focusing on demographic inclusivity. HIGHLIGHTS: The Alzheimer's Disease Neuroimaging Initiative (ADNI) introduced a novel model for public-private partnerships and data sharing. It successfully validated amyloid and Tau PET imaging, as well as CSF and plasma biomarkers, for diagnosing Alzheimer's disease. ADNI generated and disseminated vital data for designing AD clinical trials
Acute Communication Between Microglia and Nonparenchymal Immune Cells in the Anti-Aβ Antibody-Injected Cortex
No full textAnti-Aβ immunotherapy use to treat Alzheimer's disease is on the rise. While anti-Aβ antibodies provide hope in targeting Aβ plaques in the brain, there still remains a lack of understanding regarding the cellular responses to these antibodies in the brain. In this study, we sought to identify the acute effects of anti-Aβ antibodies on immune responses. To determine cellular changes due to anti-Aβ antibody exposure, we intracranially injected 14 mo APP male and female mice with anti-Aβ IgG1 (6E10) or control IgG1 into the cortex. After 24 h or 3 d, we harvested the cortex and performed a glial cell-enriched preparation for single-cell sequencing. Cell types, proportions, and cell-to-cell signaling were evaluated between the two injection conditions and two acute timepoints. We identified 23 unique cell clusters including microglia, astrocytes, endothelial cells, neurons, oligos/OPCs, immune cells, and unknown. The anti-Aβ antibody-injected cortices revealed more ligand-receptor (L-R) communications between cell types, as well as stronger communications at only 24 h. At 3 d, while there were more L-R communications for the anti-Aβ antibody condition, the strength of these connections was stronger in the control IgG condition. We also found evidence of an initial and strong communication emphasis in microglia-to-nonparenchymal immune cells at 24 h, specifically in the TGFβ signaling pathway. We identify several pathways that are specific to anti-Aβ antibody exposure at acute timepoints. These data lay the groundwork for understanding the brain's unique response to anti-Aβ antibodies
P-1502. Clindamycin and Group A Streptococcus: Is It Time To Say Goodbye?
No full textBackground:
Group A streptococci (GAS) can cause invasive disease leading to Toxic Shock Syndrome (TSS), a condition linked with high mortality. Initial antibiotic therapy for GAS-TSS includes beta-lactams and clindamycin. When clindamycin resistance is noted, linezolid may be used instead until clinical stability is achieved. We reviewed GAS susceptibility at IUH Ball Memorial Hospital to assess appropriateness of initial clindamycin use as adjunctive therapy for GAS-TSS.
Methods:
GAS positive cultures recovered from 1/1/23 – 12/31/23 at IU Health Ball Memorial Hospital, Muncie, IN were reviewed.
Results:
Out of 162 cultures positive for GAS, 29 (17.9%) had susceptibility results. All 29 GAS specimens were sensitive to penicillin and linezolid, but only 16/29 (55.2%) specimens were sensitive to clindamycin. Table 1. and Chart 1. show susceptibility results for penicillin, clindamycin, erythromycin, and linezolid. Table 2. shows number of specimens with inducible clindamycin resistance. Chart 2. shows various sources of culture specimens.
Conclusion:
GAS susceptibility testing was performed with invasive infections or when requested. Significant resistance was noted to clindamycin. Although our data is limited by a small sample size, it is in line with trends noted by US CDC’s Active Bacterial Core surveillance reports. This raises concern over initial use of clindamycin for TSS before susceptibilities are available. There are both advantages and disadvantages associated with use of clindamycin or linezolid. There is more data to support clindamycin use, however it is linked with increased risk of C. difficile infections. There is limited data for the use of linezolid for this indication, but it does maintain better susceptibility and negates the use of vancomycin at time of empiric therapy. Even though more data may be needed to definitively recommend linezolid over clindamycin or vice versa, clinical decisions will need to be made prior to susceptibility results. We recommend clinicians utilize their local antibiograms to guide decision making, while also accounting for patient factors. This also provides an opportunity for the development of clinical practice guidelines to better assist clinicians in the community
Whole genome sequence‐based association of cognitive decline and retinal thickness in the Japanese population
No full textBackground:
Dementia is age‐related with a significant genetic contribution, yet genome‐wide association studies have not fully accounted for heritability. This discrepancy may in part be due to reliance on SNPs and small indels. Whole‐genome sequencing (WGS) data in the Japanese population may reveal population‐specific susceptibility loci for dementia. Retinal imaging with optical coherence tomography (OCT) is noninvasive, reproducible, and can detect thinning associated with progressive neurodegeneration. Association of population‐specific genetic susceptibility loci with retinal thinning and cognitive decline may reveal novel aspects of dementia risk and pathophysiology.
Method:
Among participants with WGS data from the Tohoku Medical Megabank Organization (ToMMo) Ophthalmology Study ("ToMMo Eye Study"), individuals with adequate quality data on retinal nerve fiber layer and ganglion cell layer thickness from spectral‐domain optical coherence tomography (SD‐OCT) scans were selected. Since retinal thinning also occurs in glaucoma, we performed a GWAS using age, sex, and 10 principal components as covariates using SAGE1.2 to obtain a set of genes responsible for glaucoma and confirm that the genotyping was successful. We then attempted to identify susceptibility loci for cognitive decline by using (1) the Mini‐Mental State Examination, Japanese version (MMSE‐J), (2) the Montreal Cognitive Assessment, Japanese version (MoCA‐J), and (3) the Mini‐COG© (a simple screening for early detection of dementia, Japanese version) scores as associated factors, respectively. Furthermore, these validation results were also compared with those obtained from GWAS using imputation data performed on custom arrays (Japonica ArrayTM, v2 or NEO) for Japanese.
Result:
84 significant (p < 5.0E‐8) genome‐wide susceptibility loci (hg38) of RNFL were detected on 14K WGS‐based study (the top hit locus: Chr14, SIX6 gene, P=4.50E‐46). There were many genetic loci that have already been reported to be associated with glaucoma susceptibility, including the above locus. Among the results of GWAS for cognitive decline combining the three cognitive scores after normalization to z‐scores, several loci have shown significant susceptibility in both of RNFL and cognitive rating scale. Some loci suggested more than a high or moderate effect of altering protein efficacy.
Conclusion:
We present an initial WGS‐based genetic study of retinal thickness and cognitive decline in the Japanese population