Genetic analysis of the human microglial transcriptome across brain regions, aging and disease pathologies

Microglia have emerged as important players in brain aging and pathology. To understand how genetic risk for neurological and psychiatric disorders is related to microglial function, large transcriptome studies are essential. Here we describe the transcriptome analysis of 255 primary human microglial samples isolated at autopsy from multiple brain regions of 100 individuals. We performed systematic analyses to investigate various aspects of microglial heterogeneities, including brain region and aging. We mapped expression and splicing quantitative trait loci and showed that many neurological disease susceptibility loci are mediated through gene expression or splicing in microglia. Fine-mapping of these loci nominated candidate causal variants that are within microglia-specific enhancers, finding associations with microglial expression of USP6NL for Alzheimer's disease and P2RY12 for Parkinson's disease. We have built the most comprehensive catalog to date of genetic effects on the microglial transcriptome and propose candidate functional variants in neurological and psychiatric disorders

Lordose lombar: estudo dos valores angulares e da participação dos corpos vertebrais e discos intervertebrais Lumbar lordosis: a study of angle values and of vertebral bodies and intervertebral discs role

Foi estudado, em indivíduos normais, o valor angular da lordose lombar e a participação dos corpos vertebrais e discos intervertebrais na sua composição. Foram avaliadas as radiografias da coluna lombar de 350 indivíduos normais e assintomáticos com a idade variando de 18 a 50 anos (média 29,0 anos ± 8,24), sendo 143 homens e 207 mulheres. Foram medidas a curvatura lombossacra (L1S1) e a curvatura lombolombar (L1L5). As medidas das curvaturas lombares e dos seus componentes apresentaram grande variabilidade. Foram observados valores médios de -61° para a curvatura lombossacra e de -45° para a curvatura lombolombar. As medidas dos corpos vertebrais apresentaram valores cifóticos para L1, neutros para L2, e progressivamente lordóticos de L3 a L5. Os discos intervertebrais apresentaram angulação lordótica progressiva desde L1-L2. Os elementos caudais da curvatura, discos intervertebrais L4-L5 e L5-S1 e o corpo vertebral L5 corresponderam a quase 60% medida angular da curvatura lombossacra. Foi observada diferença significante entre os sexos masculino e feminino para as medidas das curvaturas lombares, e dos corpos vertebrais L2 e L4, tendo sido observados valores maiores no sexo feminino. Foram observadas diferenças relacionadas à idade na medida das curvaturas lombares e dos corpos vertebrais.<br>The angular value of lumbar lordosis and the role of vertebral bodies and intervertebral discs in its constitution were studied in normal individuals. X-Ray images of lumbar spine were studied in 350 normal and asymptomatic individuals, ages ranging from 18 to 50 years old (average 29.0 years old ± 8.24), being 143 males and 207 females. The lumbosacral (L1S1) and the lumbolumbar (L1L5) curves were measured. Measurements for lumbar curves and their components presented a large variation. Average values of -61º were seen for lumbosacral curve and of -45º for lumbolumbar curve. Vertebral bodies measurements presented kyphotic values for L1, neutral for L2, and progressively lordotic for L3 - L5. Intervertebral discs presented a progressive lordotic angulation from L1-L2. Caudal elements of curvature, intervertebral discs L4-L5 and L5-S1 and the vertebral body L5 accounted for nearly 60% of the angular measurement of lumbosacral curvature. A significant difference was seen between males and females for lumbar curvature measurements, and for vertebral bodies L2 and L4, with females presenting higher values. Age-related differences were found in lumbar curvature and vertebral bodies measurements

Genome-wide association study and functional validation implicates JADE1 in tauopathy.

Primary age-related tauopathy (PART) is a neurodegenerative pathology with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-β (Aβ) plaques. The pathogenesis of PART is not known, but evidence&nbsp;suggests an&nbsp;association with genes that promote tau pathology and others that protect from Aβ toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n = 647) using Braak neurofibrillary tangle stage as a quantitative trait. We found some significant associations with candidate loci associated with AD (SLC24A4, MS4A6A, HS3ST1) and progressive supranuclear palsy (MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brains with four microtubule-binding domain repeats (4R) isoforms and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation in post-mortem human PART brain tissue revealed a specific binding of JADE1 protein to four repeat tau lacking N-terminal inserts (0N4R). Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model, as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a modifier of neurofibrillary degeneration

Genome-wide association study and functional validation implicates JADE1 in tauopathy

AbstractPrimary age-related tauopathy (PART) is a neurodegenerative tauopathy with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-β (Aβ) deposition in plaques. The pathogenesis of PART is unknown, but evidence suggests it is associated with genes that promote tau pathology as well as others that protect from Aβ toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n=647) using Braak neurofibrillary tangle stage as a quantitative trait adjusting for sex, age, genotyping platform, and principal components. We found significant associations with some candidate loci associated with AD and progressive supranuclear palsy, a primary tauopathy (SLC24A4, MS4A6A, HS3ST1, MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brain from tauopathies containing isoforms with four microtubule-binding domain repeats (4R) and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation revealed a direct and specific binding of JADE1 protein to tau containing four (4R) and no N-terminal inserts (0N4R) in post-mortem human PART brain tissue. Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a mediator of neurofibrillary degeneration

Variations in management of A3 and A4 cervical spine fractures as designated by the AO Spine Subaxial Injury Classification System

© 2022 The authors.OBJECTIVE Optimal management of A3 and A4 cervical spine fractures, as defined by the AO Spine Subaxial Injury Classification System, remains controversial. The objectives of this study were to determine whether significant management variations exist with respect to 1) fracture location across the upper, middle, and lower subaxial cervical spine and 2) geographic region, experience, or specialty. METHODS A survey was internationally distributed to 272 AO Spine members across six geographic regions (North America, South America, Europe, Africa, Asia, and the Middle East). Participants’ management of A3 and A4 subaxial cervical fractures across cervical regions was assessed in four clinical scenarios. Key characteristics considered in the vignettes included degree of neurological deficit, pain severity, cervical spine stability, presence of comorbidities, and fitness for surgery. Respondents were also directly asked about their preferences for operative management and misalignment acceptance across the subaxial cervical spine. RESULTS In total, 155 (57.0%) participants completed the survey. Pooled analysis demonstrated that surgeons were more likely to offer operative intervention for both A3 (p &lt; 0.001) and A4 (p &lt; 0.001) fractures located at the cervicothoracic junction compared with fractures at the upper or middle subaxial cervical regions. There were no significant variations in management for junctional incomplete (p = 0.116) or complete (p = 0.342) burst fractures between geographic regions. Surgeons with more than 10 years of experience were more likely to operatively manage A3 (p &lt; 0.001) and A4 (p &lt; 0.001) fractures than their younger counterparts. Neurosurgeons were more likely to offer surgical stabilization of A3 (p &lt; 0.001) and A4 (p &lt; 0.001) fractures than their orthopedic colleagues. Clinicians from both specialties agreed regarding their preference for fixation of lower junctional A3 (p = 0.866) and A4 (p = 0.368) fractures. Overall, surgical fixation was recommended more often for A4 than A3 fractures in all four scenarios (p &lt; 0.001). CONCLUSIONS The subaxial cervical spine should not be considered a single unified entity. Both A3 and A4 fracture subtypes were more likely to be surgically managed at the cervicothoracic junction than the upper or middle subaxial cervical regions. The authors also determined that treatment strategies for A3 and A4 subaxial cervical spine fractures varied significantly, with the latter demonstrating a greater likelihood of operative management. These findings should be reflected in future subaxial cervical spine trauma algorithms.N