RESUMEN
Consumer wearables and health monitors, internet-based health and cognitive assessments, and at-home biosample (e.g., saliva and capillary blood) collection kits are increasingly used by public health researchers for large population-based studies without requiring intensive in-person visits. Alongside reduced participant time burden, remote and virtual data collection allows the participation of individuals who live long distances from hospital or university research centers, or who lack access to transportation. Unfortunately, studies that include magnetic resonance neuroimaging are challenging to perform remotely given the infrastructure requirements of MRI scanners, and, as a result, they often omit socially, economically, and educationally disadvantaged individuals. Lower field strength systems (< 100 mT) offer the potential to perform neuroimaging at a participant's home, enabling more accessible and equitable research. Here we report the first use of a low-field MRI "scan van" with an online assessment of paired-associate learning (PAL) to examine associations between brain morphometry and verbal memory performance. In a sample of 67 individuals, 18-93 years of age, imaged at or near their home, we show expected white and gray matter volume trends with age and find significant (p < 0.05 FWE) associations between PAL performance and hippocampus, amygdala, caudate, and thalamic volumes. High-quality data were acquired in 93% of individuals, and at-home scanning was preferred by all individuals with prior MRI at a hospital or research setting. Results demonstrate the feasibility of remote neuroimaging and cognitive data collection, with important implications for engaging traditionally under-represented communities in neuroimaging research.
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Encéfalo , Envejecimiento Saludable , Humanos , Adulto , Encéfalo/patología , Cognición , Imagen por Resonancia Magnética/métodos , Neuroimagen/métodosRESUMEN
Transient ACE (angiotensin-converting enzyme) inhibition in spontaneously hypertensive rats is known to protect against future injury-induced cardiac inflammation, fibrosis, and dysfunction; however, the mechanisms of protection have not been delineated. Here, we used single-cell RNA sequencing to test the hypothesis that transient ACE inhibitor treatment would induce a persistent shift in cardiac fibroblast subpopulations. Adult male spontaneously hypertensive rats (11 weeks old, hypertensive with cardiac hypertrophy) were treated for 2 weeks with an ACE inhibitor, enalapril (30 mg/kg per day, PO), or water (untreated spontaneously hypertensive rats) followed by a 2-week washout period (n=7/group). Cardiac fibroblasts were isolated from the left ventricle and subjected to single-cell RNA sequencing. Nine clusters of fibroblasts were identified, with 98% of cells in clusters 0 to 6. The transient treatment produced significant changes both within and across clusters. Cluster 1 depicted a highly fibrogenic gene profile, with cluster 6 serving as a gateway to cluster 1. Transient ACE inhibition depleted the gateway and expanded cluster 0, which was the least fibrogenic profile. Moreover, within cluster 1 fibroblasts, ACE inhibition reduced expression of individual fibrosis genes (eg, COL1A1, COL3A1, and FN1; all P<1×10-35). Clusters 2 to 5 reflected proliferative, moderately fibrogenic, translationally active, and less inflammatory subsets of fibroblasts, all of which exhibited attenuated fibrogenic gene expression after transient ACE inhibition. In conclusion, transient ACE inhibition shifts cardiac fibroblast subpopulations and degree of activation resulting in an overall reduced fibrogenic phenotype.
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Enalapril/farmacología , Fibroblastos/efectos de los fármacos , Corazón/efectos de los fármacos , Hipertensión/fisiopatología , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Células Cultivadas , Análisis por Conglomerados , Colágeno Tipo I/genética , Cadena alfa 1 del Colágeno Tipo I , Colágeno Tipo III/genética , Fibroblastos/metabolismo , Fibronectinas/genética , Fibrosis , Perfilación de la Expresión Génica/métodos , Regulación de la Expresión Génica/efectos de los fármacos , Corazón/fisiopatología , Masculino , Miocardio/metabolismo , Miocardio/patología , Ratas Endogámicas SHRRESUMEN
Canine idiopathic pulmonary fibrosis (CIPF) is a chronic fibrotic lung disease that is observed at a higher frequency in the West Highland White Terrier dog breed (WHWT) and may have molecular pathological overlap with human lung fibrotic disease. We conducted a genome-wide association study (GWAS) in the WHWT using whole genome sequencing (WGS) to discover genetic variants associated with CIPF. Saliva-derived DNA samples were sequenced using the Riptide DNA library prep kit. After quality controls, 28 affected, 44 unaffected, and 1,843,695 informative single nucleotide polymorphisms (SNPs) were included in the GWAS. Data were analyzed both at the single SNP and gene levels using the GEMMA and GATES methods, respectively. We detected significant signals at the gene level in both the cleavage and polyadenylation specific factor 7 (CPSF7) and succinate dehydrogenase complex assembly factor 2 (SDHAF2) genes (adjusted p = 0.016 and 0.024, respectively), two overlapping genes located on chromosome 18. The top SNP for both genes was rs22669389; however, it did not reach genome-wide significance in the GWAS (adjusted p = 0.078). Our studies provide, for the first time, candidate loci for CIPF in the WHWT. CPSF7 was recently associated with lung adenocarcinoma, further highlighting the potential relevance of our results because IPF and lung cancer share several pathological mechanisms.
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Enfermedades de los Perros/genética , Estudios de Asociación Genética , Fibrosis Pulmonar Idiopática/genética , Proteínas con Motivos de Reconocimiento de ARN/genética , Animales , Enfermedades de los Perros/patología , Perros , Predisposición Genética a la Enfermedad , Humanos , Fibrosis Pulmonar Idiopática/patología , Fibrosis Pulmonar Idiopática/veterinaria , Proteínas Mitocondriales/genética , Poliadenilación/genética , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
OBJECTIVE: We describe herein a bioinformatics approach that leverages gene expression data from brain homogenates to derive cell-type specific differential expression results. RESULTS: We found that differentially expressed (DE) cell-specific genes were mostly identified as neuronal, microglial, or endothelial in origin. However, a large proportion (75.7%) was not attributable to specific cells due to the heterogeneity in expression among brain cell types. Neuronal DE genes were consistently downregulated and associated with synaptic and neuronal processes as described previously in the field thereby validating this approach. We detected several DE genes related to angiogenesis (endothelial cells) and proteoglycans (oligodendrocytes). CONCLUSIONS: We present a cost- and time-effective method exploiting brain homogenate DE data to obtain insights about cell-specific expression. Using this approach we identify novel findings in AD in endothelial cells and oligodendrocytes that were previously not reported. METHODS: We derived an enrichment score for each gene using a publicly available RNA profiling database generated from seven different cell types isolated from mouse cerebral cortex. We then classified the differential expression results from 3 publicly accessible Late-Onset Alzheimer's disease (AD) studies including seven different brain regions.
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Enfermedad de Alzheimer/metabolismo , Encéfalo/metabolismo , Biología Computacional/métodos , Perfilación de la Expresión Génica/métodos , Expresión Génica , Enfermedad de Alzheimer/genética , Células Endoteliales/metabolismo , Humanos , Microglía/metabolismo , Neuronas/metabolismo , Sinapsis/metabolismoRESUMEN
Multiple system atrophy (MSA) is a rare adult-onset neurodegenerative disease of unknown cause, with no effective therapeutic options, and no cure. Limited work to date has attempted to characterize the transcriptional changes associated with the disease, which presents as either predominating parkinsonian (MSA-P) or cerebellar (MSC-C) symptoms. We report here the results of RNA expression profiling of cerebellar white matter (CWM) tissue from two independent cohorts of MSA patients (n = 66) and healthy controls (HC; n = 66). RNA samples from bulk brain tissue and from oligodendrocytes obtained by laser capture microdissection (LCM) were sequenced. Differentially expressed genes (DEGs) were obtained and were examined before and after stratifying by MSA clinical sub-type.We detected the highest number of DEGs in the MSA-C group (n = 747) while only one gene was noted in MSA-P, highlighting the larger dysregulation of the transcriptome in the MSA-C CWM. Results from both bulk tissue and LCM analysis showed a downregulation of oligodendrocyte genes and an enrichment for myelination processes with a key role noted for the QKI gene. Additionally, we observed a significant upregulation of neuron-specific gene expression in MSA-C and enrichment for synaptic processes. A third cluster of genes was associated with the upregulation of astrocyte and endothelial genes, two cell types with a key role in inflammation processes. Finally, network analysis in MSA-C showed enrichment for ß-amyloid related functional classes, including the known Alzheimer's disease (AD) genes, APP and PSEN1.This is the largest RNA profiling study ever conducted on post-mortem brain tissue from MSA patients. We were able to define specific gene expression signatures for MSA-C highlighting the different stages of the complex neurodegenerative cascade of the disease that included alterations in several cell-specific transcriptional programs. Finally, several results suggest a common transcriptional dysregulation between MSA and AD-related genes despite the clinical and neuropathological distinctions between the two diseases.
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Enfermedades Cerebelosas/genética , Atrofia de Múltiples Sistemas/genética , Trastornos Parkinsonianos/genética , Transcriptoma , Anciano , Anciano de 80 o más Años , Enfermedades Cerebelosas/patología , Biología Computacional , Femenino , Perfilación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Atrofia de Múltiples Sistemas/patología , Oligodendroglía/metabolismo , Trastornos Parkinsonianos/patología , ARN/genética , Sustancia Blanca/metabolismoRESUMEN
We explored RNA expression changes in the middle temporal gyrus (MTG) of Alzheimer's Disease patients (AD) by RNA sequencing the whole transcriptome of 8 AD and 8 Non-Demented (ND) controls. We used three additional expression datasets from related brain regions to validate the findings. The results highlighted the upregulation of AEBP1 and downregulation of NRN1 in AD, as well as their association with Braak staging and neurofibrillary tangles density. Furthermore, more than 400 protein-coding RNAs enriched for "Clathrin-mediated endocytosis" were validated in independent datasets from the same brain region. Finally, using in silico prediction analysis we found a signature of 52 non-protein coding RNAs that perturb key pathways involved in GABAergic transmission and peptide chain elongation. The association of AEBP1 in our data confirmed other published work examining gene expression in the hippocampus of AD patients. NRN1 is involved in neurite outgrowth, and in previous studies it has been shown to reverse synaptic defects and cognitive function impairment in Tg2576 mice. Finally, our results on non-protein coding RNAs suggest a role of these transcripts in altering synaptic and amyloid-ß associated pathways.
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Enfermedad de Alzheimer/metabolismo , Carboxipeptidasas/genética , Neuropéptidos/genética , Proteínas Represoras/genética , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/genética , Encéfalo/metabolismo , Carboxipeptidasas/metabolismo , Disfunción Cognitiva/metabolismo , Femenino , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/metabolismo , Expresión Génica/genética , Hipocampo/metabolismo , Humanos , Masculino , Ovillos Neurofibrilares/genética , Ovillos Neurofibrilares/metabolismo , Neuropéptidos/metabolismo , ARN/metabolismo , Proteínas Represoras/metabolismo , Lóbulo Temporal/metabolismo , Proteínas tau/metabolismoRESUMEN
In humans, a first-degree family history of dementia (FH) is a well-documented risk factor for Alzheimer's disease (AD); however, the influence of FH on cognition across the lifespan is poorly understood. To address this issue, we developed an internet-based paired-associates learning (PAL) task and tested 59,571 participants between the ages of 18-85. FH was associated with lower PAL performance in both sexes under 65 years old. Modifiers of this effect of FH on PAL performance included age, sex, education, and diabetes. The Apolipoprotein E ε4 allele was also associated with lower PAL scores in FH positive individuals. Here we show, FH is associated with reduced PAL performance four decades before the typical onset of AD; additionally, several heritable and non-heritable modifiers of this effect were identified.
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Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/fisiopatología , Cognición , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Apolipoproteína E4/genética , Escolaridad , Femenino , Humanos , Aprendizaje , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Introduction: SuperAgers are adults age 80+ with episodic memory performance that is at least as good as that of average middle-aged adults. Understanding the biological determinants of SuperAging may have relevance to preventing age-related cognitive decline and dementia. This study aimed to identify associations between genetic variations and the SuperAging phenotype using Whole Exome Sequencing (WES). Methods: Sequence Kernel Association Combined (SKAT-C) test was conducted at the gene level including both rare and common variants in 56 SuperAgers and 22 cognitively-average controls from the Alzheimer's disease Neuroimaging Initiative (ADNI). Results: The SuperAging phenotype was associated with variants in the Mitogen-Activated Protein Kinase Kinase 3 (MAP2K3) gene. Three single nucleotide polymorphisms (SNPs) contributed to the significance (rs2363221 [intron 1], rs2230435 [exon 5], rs736103 [intron 7]). Conclusions: MAP2K3 resides in a biological pathway linked to memory. It is in a signaling cascade associated with beta-amyloid mediated apoptosis and has enriched expression in microglia. This preliminary work suggests MAP2K3 may represent a novel therapeutic target for age-related memory decline and perhaps Alzheimer's disease (AD).