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BACKGROUND: Infections during pregnancy have been robustly associated with adverse mental and physical health outcomes in offspring, yet the underlying molecular pathways remain largely unknown. Here, we examined whether exposure to common infections in utero associates with DNA methylation (DNAm) patterns at birth and whether this in turn relates to offspring health outcomes in the general population. METHODS: Using data from 2,367 children from the Dutch population-based Generation R Study, we first performed an epigenome-wide association study to identify differentially methylated sites and regions at birth associated with prenatal infection exposure. We also examined the influence of infection timing by using self-reported cumulative infection scores for each trimester. Second, we sought to develop an aggregate methylation profile score (MPS) based on cord blood DNAm as an epigenetic proxy of prenatal infection exposure and tested whether this MPS prospectively associates with offspring health outcomes, including psychiatric symptoms, BMI, and asthma at ages 13-16 years. Third, we investigated whether prenatal infection exposure associates with offspring epigenetic age acceleration - a marker of biological aging. Across all analysis steps, we tested whether our findings replicate in 864 participants from an independent population-based cohort (ALSPAC, UK). RESULTS: We observed no differentially methylated sites or regions in cord blood in relation to prenatal infection exposure, after multiple testing correction. 33 DNAm sites showed suggestive associations (p < 5e10 - 5; of which one was also nominally associated in ALSPAC), indicating potential links to genes associated with immune, neurodevelopmental, and cardiovascular pathways. While the MPS of prenatal infections associated with maternal reports of infections in the internal hold out sample in the Generation R Study (R2incremental = 0.049), it did not replicate in ALSPAC (R2incremental = 0.001), and it did not prospectively associate with offspring health outcomes in either cohort. Moreover, we observed no association between prenatal exposure to infections and epigenetic age acceleration across cohorts and clocks. CONCLUSION: In contrast to prior studies, which reported DNAm differences in offspring exposed to severe infections in utero, we do not find evidence for associations between self-reported clinically evident common infections during pregnancy and DNAm or epigenetic aging in cord blood within the general pediatric population. Future studies are needed to establish whether associations exist but are too subtle to be statistically meaningful with present sample sizes, whether they replicate in a cohort with a more similar infection score as our discovery cohort, whether they occur in different tissues than cord blood, and whether other biological pathways may be more relevant for mediating the effect of prenatal common infection exposure on downstream offspring health outcomes.
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The human orphan G protein-coupled receptor GPR18, activated by Δ9-tetrahydrocannabinol (THC), constitutes a promising drug target in immunology and cancer. However, studies on GPR18 are hampered by the lack of suitable tool compounds. In the present study, potent and selective GPR18 agonists were developed showing low nanomolar potency at human and mouse GPR18, determined in ß-arrestin recruitment assays. Structure-activity relationships were analyzed, and selectivity versus cannabinoid (CB) and CB-like receptors was assessed. Compound 51 (PSB-KK1415, EC50 19.1 nM) was the most potent GPR18 agonist showing at least 25-fold selectivity versus CB receptors. The most selective GPR18 agonist 50 (PSB-KK1445, EC50 45.4 nM) displayed >200-fold selectivity versus both CB receptor subtypes, GPR55, and GPR183. The new GPR18 agonists showed minimal species differences, while THC acted as a weak partial agonist at the mouse receptor. The newly discovered compounds represent the most potent and selective GPR18 agonists reported to date.
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Receptores Acoplados a Proteínas G , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Humanos , Animais , Relação Estrutura-Atividade , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Células HEK293 , Receptores de Canabinoides/metabolismo , Dronabinol/farmacologia , Dronabinol/análogos & derivados , Dronabinol/químicaRESUMO
Introduction: Despite profitable group effects on functional outcomes after mechanical thrombectomy (MT) in large vessel occlusion (LVO), many patients with successful reperfusion show a non-favorable long-term outcome, highlighting the necessity to identify potential biomarkers predicting outcome variability. In this regard, the role of perfusion mismatch imaging for outcome variability in the early time window within 6 h after symptom onset is a matter of debate. We attempted to investigate under which conditions early perfusion mismatch imaging accounts for variability in functional outcomes after mechanical thrombectomy. Patients and methods: In a retrospective single-center study, we examined 190 consecutive patients with LVO who were admitted to the Medical Center Lübeck within 6 h after symptom onset, all of whom underwent MT. Perfusion mismatch was quantified by applying the Alberta Stroke Program Early CT score (ASPECTS) on CT-measured cerebral blood flow (CBF-ASPECTS) and subtracting it from an ASPECTS application on cerebral blood volume (CBV-ASPECTS), i.e., ASPECTS mismatch. Using multivariate ordinal regression models, associations between ASPECTS mismatch and modified Rankin Scale (mRS) after 90 days were assessed. Furthermore, the interaction between ASPECTS mismatch and the core lesion volume was calculated to evaluate conditional associations. Results: ASPECTS mismatch did not correlate with functional outcomes when corrected for multiple influencing covariables. However, interactions between ASPECTS mismatch and CBV-ASPECTS [OR: 1.12 (1.06-1.18), p-value < 0.001], as well as NCCT-ASPECTS [OR: 1.15 (1.06-1.25), p-value < 0.001], did show a significant association with functional outcomes. Model comparisons revealed that, profoundly, in patients with large core lesion volumes (CBV-ASPECTS < 6 or NCCT-ASPECTS < 6), perfusion mismatch showed a negative correlation with the mRS. Discussion and conclusion: Perfusion mismatch imaging within the first 6 h of symptom onset provides valuable insights into the outcome variability of LVO stroke patients receiving thrombectomy but only in patients with large ischemic core lesions.
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BACKGROUND: Maternal infection during pregnancy has been identified as a prenatal risk factor for the later development of psychopathology in exposed offspring. Neuroimaging data collected during childhood has suggested a link between prenatal exposure to maternal infection and child brain structure and function, potentially offering a neurobiological explanation for the emergence of psychopathology. Additionally, preclinical studies utilizing repeated measures of neuroimaging data suggest that effects of prenatal maternal infection on the offspring's brain may normalize over time (i.e., catch-up growth). However, it remains unclear whether exposure to prenatal maternal infection in humans is related to long-term differential neurodevelopmental trajectories. Hence, this study aimed to investigate the association between prenatal exposure to infections on child brain development over time using repeated measures MRI data. METHODS: We leveraged data from a population-based cohort, Generation R, in which we examined prospectively assessed self-reported infections at each trimester of pregnancy (N = 2,155). We further used three neuroimaging assessments (at mean ages 8, 10 and 14) to obtain cortical and subcortical measures of the offspring's brain morphology with MRI. Hereafter, we applied linear mixed-effects models, adjusting for several confounding factors, to estimate the association of prenatal maternal infection with child brain development over time. RESULTS: We found that prenatal exposure to infection in the third trimester was associated with a slower decrease in volumes of the pars orbitalis, rostral anterior cingulate and superior frontal gyrus, and a faster increase in the middle temporal gyrus. In the temporal pole we observed a divergent pattern, specifically showing an increase in volume in offspring exposed to more infections compared to a decrease in volume in offspring exposed to fewer infections. We further observed associations in other frontal and temporal lobe structures after exposure to infections in any trimester, though these did not survive multiple testing correction. CONCLUSIONS: Our results suggest that prenatal exposure to infections in the third trimester may be associated with slower age-related growth in the regions: pars orbitalis, rostral anterior cingulate and superior frontal gyrus, and faster age-related growth in the middle temporal gyrus across childhood, suggesting a potential sensitive period. Our results might be interpreted as an extension of longitudinal findings from preclinical studies, indicating that children exposed to prenatal infections could exhibit catch-up growth. However, given the lack of differences in brain volume between various infection groups at baseline, there may instead be either a longitudinal deviation or a subtle temporal deviation. Subsequent well-powered studies that extend into the period of full brain development (â¼25 years) are needed to confirm whether the observed phenomenon is indeed catch-up growth, a longitudinal deviation, or a subtle temporal deviation.
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Encéfalo , Imageamento por Ressonância Magnética , Complicações Infecciosas na Gravidez , Efeitos Tardios da Exposição Pré-Natal , Humanos , Gravidez , Feminino , Encéfalo/diagnóstico por imagem , Encéfalo/crescimento & desenvolvimento , Encéfalo/patologia , Criança , Masculino , Adolescente , Estudos Longitudinais , Neuroimagem , Desenvolvimento Infantil , AdultoRESUMO
Over 50% of children with a parent with severe mental illness will develop mental illness by early adulthood. However, intergenerational transmission of risk for mental illness in one's children is insufficiently considered in clinical practice, nor is it sufficiently utilised into diagnostics and care for children of ill parents. This leads to delays in diagnosing young offspring and missed opportunities for protective actions and resilience strengthening. Prior twin, family, and adoption studies suggest that the aetiology of mental illness is governed by a complex interplay of genetic and environmental factors, potentially mediated by changes in epigenetic programming and brain development. However, how these factors ultimately materialise into mental disorders remains unclear. Here, we present the FAMILY consortium, an interdisciplinary, multimodal (e.g., (epi)genetics, neuroimaging, environment, behaviour), multilevel (e.g., individual-level, family-level), and multisite study funded by a European Union Horizon-Staying-Healthy-2021 grant. FAMILY focuses on understanding and prediction of intergenerational transmission of mental illness, using genetically informed causal inference, multimodal normative prediction, and animal modelling. Moreover, FAMILY applies methods from social sciences to map social and ethical consequences of risk prediction to prepare clinical practice for future implementation. FAMILY aims to deliver: (i) new discoveries clarifying the aetiology of mental illness and the process of resilience, thereby providing new targets for prevention and intervention studies; (ii) a risk prediction model within a normative modelling framework to predict who is at risk for developing mental illness; and (iii) insight into social and ethical issues related to risk prediction to inform clinical guidelines.
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DNA methylation (DNAm) at specific sites can be used to calculate 'epigenetic clocks', which in adulthood are used as indicators of age(ing). However, little is known about how these clock sites 'behave' during development and what factors influence their variability in early life. This knowledge could be used to optimize healthy aging well before the onset of age-related conditions. Here, we leveraged results from two longitudinal population-based cohorts (N=5,019 samples from 2,348 individuals) to characterize trajectories of adult clock sites from birth to early adulthood. We find that clock sites (i) diverge widely in their developmental trajectories, often showing non-linear change over time; (ii) are substantially more likely than non-clock sites to vary between individuals already from birth, differences that are predictive of DNAm variation at later ages; and (iii) show enrichment for genetic and prenatal environmental exposures, supporting an early-origins perspective to epigenetic aging.
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Background: Combining magnetic particle imaging (MPI) and magnetic fluid hyperthermia (MFH) offers the ability to perform localized hyperthermia and magnetic particle imaging-assisted thermometry of hyperthermia treatment. This allows precise regional selective heating inside the body without invasive interventions. In current MPI-MFH platforms, separate systems are used, which require object transfer from one system to another. Here, we present the design, development and evaluation process for integrable MFH platforms, which extends a commercial MPI scanner with the functionality of MFH. Methods: The biggest issue of integrating magnetic fluid hyperthermia platforms into a magnetic particle imaging system is the magnetic coupling of the devices, which induces high voltage in the imaging system, and is harming its components. In this paper, we use a self-compensation approach derived from heuristic algorithms to protect the magnetic particle imaging scanner. The integrable platforms are evaluated regarding electrical and magnetic characteristics, cooling capability, field strength, the magnetic coupling to a replica of the magnetic particle imaging system's main solenoid and particle heating. Results: The MFH platforms generate suitable magnetic fields for the magnetic heating of particles and are compatible with a commercial magnetic particle imaging scanner. In combination with the imaging system, selective heating with a gradient field and steerable heating positioning using the MPI focus fields are possible. Conclusion: The proposed MFH platforms serve as a therapeutic tool to unlock the MFH functionality of a commercial magnetic particle imaging scanner, enabling its use in future preclinical trials of MPI-guided, spatially selective magnetic hyperthermia therapy.
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Hipertermia Induzida , Campos MagnéticosRESUMO
Physical activity is a protective factor against brain atrophy, while loss of brain volume could also be a determinant of physical activity. Therefore, we aimed to explore the bidirectional association of physical activity with brain structures in middle-aged and older adults from the UK Biobank. Overall, 3027 participants (62.45 ± 7.27 years old, 51.3% females) had data at two time points. Hippocampal volume was associated with total (ß=0.048, pFDR=0.016) and household (ß=0.075, pFDR<0.001) physical activity. Global fractional anisotropy (ß=0.042, pFDR=0.028) was also associated with household physical activity. In the opposite direction, walking was negatively associated with white matter volume (ß=-0.026, pFDR=0.008). All these associations were confirmed by the linear mixed models. Interestingly, sports at baseline were linked to hippocampal and frontal cortex volumes at follow-up but these associations disappeared after adjusting for multiple comparisons (pall>0.104). In conclusion, we found more consistent evidence that a healthier brain structure predicted higher physical activity levels than for the inverse, more established relationship.
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Biobanco do Reino Unido , Substância Branca , Feminino , Humanos , Pessoa de Meia-Idade , Idoso , Masculino , Bancos de Espécimes Biológicos , Encéfalo/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Exercício FísicoRESUMO
The growing size of make-on-demand chemical libraries is posing new challenges to cheminformatics. These ultra-large chemical libraries became too large for exhaustive enumeration. Using a combinatorial approach instead, the resource requirement scales approximately with the number of synthons instead of the number of molecules. This gives access to billions or trillions of compounds as so-called chemical spaces with moderate hardware and in a reasonable time frame. While extremely performant ligand-based 2D methods exist in this context, 3D methods still largely rely on exhaustive enumeration and therefore fail to apply. Here, we present SpaceGrow: a novel shape-based 3D approach for ligand-based virtual screening of billions of compounds within hours on a single CPU. Compared to a conventional superposition tool, SpaceGrow shows comparable pose reproduction capacity based on RMSD and superior ranking performance while being orders of magnitude faster. Result assessment of two differently sized subsets of the eXplore space reveals a higher probability of finding superior results in larger spaces highlighting the potential of searching in ultra-large spaces. Furthermore, the application of SpaceGrow in a drug discovery workflow was investigated in four examples involving G protein-coupled receptors (GPCRs) with the aim to identify compounds with similar binding capabilities and molecular novelty.
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Descoberta de Drogas , Bibliotecas de Moléculas Pequenas , Ligantes , Bibliotecas de Moléculas Pequenas/química , Descoberta de Drogas/métodosRESUMO
BACKGROUND: Cerebral damage after aneurysmal subarachnoid hemorrhage (SAH) results from various, sometimes unrelated causes. After the initial hemorrhage trauma with an increase in intracranial pressure, induced vasoconstriction, but also microcirculatory disturbances, inflammation and pathological electrophysiological processes (cortical spreading depolarization) can occur in the course of the disease, resulting in delayed cerebral ischemia (DCI). In the neuroradiological context, cerebral vasospasm (CVS) remains the focus of diagnostic imaging and endovascular therapy as a frequent component of the genesis of DCI. METHODS: The amount of blood leaked during aneurysm rupture (which can be detected by CT, for example) correlates with the occurrence and severity of CVS.âCT perfusion is then an important component in determining the indication for endovascular spasm therapies (EST). These include intra-arterial drug administration (also as long-term microcatheter treatment) and mechanical procedures (balloon angioplasty, vasodilatation using other instruments such as stent retrievers, stenting). CONCLUSION: This review summarizes the current findings on the diagnosis and treatment of CVS after aneurysmal SAH from a neuroradiological perspective, taking into account the complex and up-to-date international literature. KEY POINTS: · Vasospasm is a frequent component of the multifactorial genesis of delayed cerebral ischemia after SAH and remains the focus of diagnosis and treatment in the neuroradiological context.. · The initial extent of SAH on CT is associated with the occurrence and severity of vasospasm.. · CT perfusion is an important component in determining the indication for endovascular spasm therapy.. · Endovascular spasm therapies include local administration of medication (also as long-term therapies with microcatheters) and mechanical procedures (balloon angioplasty, dilatation using other devices such as stent retreivers, stenting).. CITATION FORMAT: · Neumann A, Schacht H, Schramm P. Neuroradiological diagnosis and therapy of cerebral vasospasm after subarachnoid hemorrhage. Fortschr Röntgenstr 2024; DOI: 10.1055/a-2266-3117.
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Laser cooling of a 5 cm long, 1 mm diameter ytterbium doped (6.56×1025 ions/m3) silica rod by 67 K from room temperature was achieved. For the pump source, a 100 W level ytterbium fiber amplifier was constructed along with a 1032 nm fiber Bragg grating seed laser. Experiments were done in vacuum and monitored with the non-contact differential luminescence thermometry method. Direct measurements of the absorption spectrum as a function of temperature were made, to avoid any possible ambiguities from site-selectivity and deviations from McCumber theory at low temperature. This allowed direct computation of the cooling efficiency versus temperature at the pump wavelength, permitting an estimated heat lift of 1.42 W/m as the sample cooled from ambient temperature to an absolute temperature of 229 K.
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Differential diagnosis between Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) using cerebrospinal fluid (CSF) biomarkers is challenging. A recent study suggested that the addition of Aß38 and Aß43 to a standard AD biomarker panel (Aß40, Aß42, t-tau, p-tau) to improve the differential diagnosis. We tested this hypothesis in an independent German cohort of CAA and AD patients and controls using the same analytical techniques. We found excellent discrimination between AD and controls and between CAA and controls, but not between AD and CAA. Adding Aß38 and Aß43 to the panel did not improve the discrimination between AD and CAA.
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Doença de Alzheimer , Angiopatia Amiloide Cerebral , Humanos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano , Angiopatia Amiloide Cerebral/diagnóstico , Biomarcadores/líquido cefalorraquidianoRESUMO
BACKGROUND: Lateral ventricular volume (LVV) enlargement has been repeatedly linked to schizophrenia; yet, what biological factors shape LVV during early development remain unclear. DNA methylation (DNAm), an essential process for neurodevelopment that is altered in schizophrenia, is a key molecular system of interest. METHODS: In this study, we conducted the first epigenome-wide association study of neonatal DNAm in cord blood with LVV in childhood (measured using T1-weighted brain scans at 10 years), based on data from a large population-based birth cohort, the Generation R Study (N = 840). Employing both probe-level and methylation profile score (MPS) approaches, we further examined whether epigenetic modifications identified at birth in cord blood are: (a) also observed cross-sectionally in childhood using peripheral blood DNAm at age of 10 years (Generation R, N = 370) and (b) prospectively associated with LVV measured in young adulthood in an all-male sample from the Avon Longitudinal Study of Parents and Children (ALSPAC, N = 114). RESULTS: At birth, DNAm levels at four CpGs (annotated to potassium channel tetramerization domain containing 3, KCTD3; SHH signaling and ciliogenesis regulator, SDCCAG8; glutaredoxin, GLRX) prospectively associated with childhood LVV after genome-wide correction; these genes have been implicated in brain development and psychiatric traits including schizophrenia. An MPS capturing a broader epigenetic profile of LVV - but not individual top hits - showed significant cross-sectional associations with LVV in childhood in Generation R and prospectively associated with LVV in early adulthood within ALSPAC. CONCLUSIONS: This study finds suggestive evidence that DNAm at birth prospectively associates with LVV at different life stages, albeit with small effect sizes. The prediction of MPS on LVV in a childhood sample and an independent male adult sample further underscores the stability and reproducibility of DNAm as a potential marker for LVV. Future studies with larger samples and comparable time points across development are needed to further elucidate how DNAm associates with this clinically relevant brain structure and risk for neuropsychiatric disorders, and what factors explain the identified DNAm profile of LVV at birth.
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Metilação de DNA , Estudo de Associação Genômica Ampla , Recém-Nascido , Criança , Adulto , Humanos , Masculino , Adulto Jovem , Estudos Longitudinais , Estudos Transversais , Reprodutibilidade dos Testes , Epigênese Genética , NeuroimagemRESUMO
BACKGROUND: A large body of work has reported a link between prenatal exposure to infection and increased psychiatric risk in offspring. However, studies to date have focused primarily on exposure to severe prenatal infections and/or individual psychiatric diagnoses in clinical samples, typically measured at single time points, and without accounting for important genetic and environmental confounders. In this study, we investigated whether exposure to common infections during pregnancy is prospectively associated with repeatedly assessed child psychiatric symptoms in a large population-based study. METHODS: Our study was embedded in a prospective pregnancy cohort (Generation R; n = 3,598 mother-child dyads). We constructed a comprehensive prenatal infection score comprising common infections for each trimester of pregnancy. Child total, internalizing, and externalizing problems were assessed repeatedly using the parent-rated Child Behavioral Checklist (average age: 1.5, 3, 6, 10, and 14 years). Linear mixed-effects models were run adjusting for a range of confounders, including child polygenic scores for psychopathology, maternal chronic illness, birth complications, and infections during childhood. We also investigated trimester-specific effects and child sex as a potential moderator. RESULTS: Prenatal exposure to infections was associated with higher child total, internalizing, and externalizing problems, showing temporally persistent effects, even after adjusting for important genetic and environmental confounders. We found no evidence that prenatal infections were associated with changes in child psychiatric symptoms over time. Moreover, in our trimester-specific analysis, we did not find evidence of significant timing effects of prenatal infection on child psychiatric symptoms. No interactions with child sex were identified. CONCLUSIONS: Our research adds to evidence that common prenatal infections may be a risk factor for psychiatric symptoms in children. We also extend previous findings by showing that these associations are present early on, and that rather than changing over time, they persist into adolescence. However, unmeasured confounding may still explain in part these associations. In the future, employing more advanced causal inference designs will be crucial to establishing the degree to which these effects are causal.
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Transtornos do Comportamento Infantil , Efeitos Tardios da Exposição Pré-Natal , Humanos , Feminino , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Gravidez , Criança , Pré-Escolar , Masculino , Estudos Longitudinais , Adolescente , Transtornos do Comportamento Infantil/epidemiologia , Transtornos do Comportamento Infantil/etiologia , Lactente , Complicações Infecciosas na Gravidez/epidemiologia , AdultoRESUMO
S-adenosylmethionine (SAM) represents a potent inhibitor of cancer cell proliferation, migration, and invasionin vitro.The underlying mechanisms remain elusive. Here, we examined, if treatment with SAM may cause alterations in the methylation of the histone marks H3K4me3 and H3K27me3, which are both known to play important roles in the initiation and progression of prostate cancer. We treated PC-3 cells with 200 µmol SAM, a concentration known to cause anticancerogenic effects, followed by ChIP-sequencing for H3K4me3 and H3K27me3. We detected 236 differentially methylated regions for H3K27me3 and 560 differentially methylated regions for H3K4me3. GO Term enrichment showed upregulation of anticancerogenic, as well as downregulation of cancerogenic related biological processes, molecular functions, and pathways. Furthermore, we compared specific methylation profiles of SAM treated samples to gene expression changes (RNA-Seq). 35 upregulated and 56 downregulated genes (total: 604 differentially expressed genes) could be related to hypomethylated and hypermethylated regions. 17 upregulated genes could be identified as tumor suppressor genes, 45 downregulated genes in contrast are considered as oncogenes. As a conclusion it can be stated that SAM treatment of prostate cancer cells resulted in alterations of H3K4me3 and H3K27me3 methylation profiles. Gene to peak annotation, alignment with results of a transcriptome study as well as GO-term analysis underpinned the biological relevance of methylation changes.
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Histonas , Neoplasias da Próstata , Masculino , Humanos , Metilação , Histonas/metabolismo , S-Adenosilmetionina/farmacologia , S-Adenosilmetionina/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Processamento de Proteína Pós-Traducional , Metilação de DNARESUMO
BACKGROUND: Use of iodine-containing contrast medium (CM) is obligatory for endovascular treatment (EVT) of cerebral aneurysms. After EVT, intracranial density increases (DIs) can be detected in cranial computed tomography (CT). Those DI can correspond to subarachnoid hemorrhage (SAH), infarction or reversible CM accumulation (RCMA). The latter can be mistaken for hemorrhage, especially if they are accompanied by neurological deficits. OBJECTIVE: To analyze postinterventional DI after EVT of unruptured cerebral aneurysms and associated clinical symptoms and to identify risk factors for the occurrence of RCMA. METHODS: For differentiation of DI, we compared CT scans following EVT and additionally 24 h ± 5 h later. Diagnosis of RCMA was based on marked regression of DI on follow-up scans. We analyzed continuous variables (age, duration of intervention and anesthesia, aneurysm diameter, amount of CM and renal function) and categorial variables (gender, aneurysm location, devices for EVT, antiplatelet therapy [APT] and associated neurological deficits) to identify risk factors for the occurrence of RCMA. RESULTS: We studied 58 patients (44 female, mean age 59.5 [range 39-81]) who underwent EVT for a total of 68 cerebral aneurysms in 62 therapy sessions over a 3-year period without periprocedural complications. Postinterventional DI occurred after 17 therapy sessions. All 17 DI turned out to be RCMA in the follow-up imaging. Two patients who had no DI on initial postinterventional CT showed new SAH on follow-up CT. Infarctions were not observed. Transient neurological deficits occurred in eight patients (12.9%) and were associated with RCMA (P = 0.010). Postinterventional RCMA was associated with the duration of EVT (P = 0.038) and with APT (acetylsalicylic acid [ASA] + clopidogrel: P =0.040; ASA alone: P =0.011). CONCLUSIONS: RCMA is common after EVT of unruptured cerebral aneurysms and often accompanied by transient neurological deficits. Long procedure duration and APT appear to predispose to the occurrence of RCMA.
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BACKGROUND: The indication for mechanical thrombectomy (MT) in stroke patients with large vessel occlusion has been constantly expanded over the past years. Despite remarkable treatment effects at the group level in clinical trials, many patients remain severely disabled even after successful recanalization. A better understanding of this outcome variability will help to improve clinical decision-making on MT in the acute stage. Here, we test whether current outcome models can be refined by integrating information on the preservation of the corticospinal tract as a functionally crucial white matter tract derived from acute perfusion imaging. METHODS: We retrospectively analyzed 162 patients with stroke and large vessel occlusion of the anterior circulation who were admitted to the University Medical Center Lübeck between 2014 and 2020 and underwent MT. The ischemic core was defined as fully automatized based on the acute computed tomography perfusion with cerebral blood volume data using outlier detection and clustering algorithms. Normative whole-brain structural connectivity data were used to infer whether the corticospinal tract was affected by the ischemic core or preserved. Ordinal logistic regression models were used to correlate this information with the modified Rankin Scale after 90 days. RESULTS: The preservation of the corticospinal tract was associated with a reduced risk of a worse functional outcome in large vessel occlusion-stroke patients undergoing MT, with an odds ratio of 0.28 (95% CI, 0.15-0.53). This association was still significant after adjusting for multiple confounding covariables, such as age, lesion load, initial symptom severity, sex, stroke side, and recanalization status. CONCLUSIONS: A preinterventional computed tomography perfusion-based surrogate of corticospinal tract preservation or disconnectivity is strongly associated with functional outcomes after MT. If validated in independent samples this concept could serve as a novel tool to improve current outcome models to better understand intersubject variability after MT in large vessel occlusion stroke.
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Isquemia Encefálica , Acidente Vascular Cerebral , Humanos , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/cirurgia , Estudos Retrospectivos , Tratos Piramidais/diagnóstico por imagem , Resultado do Tratamento , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/cirurgia , Trombectomia/métodos , Imagem de Perfusão/métodosRESUMO
BACKGROUND: Genome-wide association studies (GWAS) of Alzheimer's disease (AD) have identified several risk loci, but many remain unknown. Cerebrospinal fluid (CSF) biomarkers may aid in gene discovery and we previously demonstrated that six CSF biomarkers (ß-amyloid, total/phosphorylated tau, NfL, YKL-40, and neurogranin) cluster into five principal components (PC), each representing statistically independent biological processes. Here, we aimed to (1) identify common genetic variants associated with these CSF profiles, (2) assess the role of associated variants in AD pathophysiology, and (3) explore potential sex differences. METHODS: We performed GWAS for each of the five biomarker PCs in two multi-center studies (EMIF-AD and ADNI). In total, 973 participants (n = 205 controls, n = 546 mild cognitive impairment, n = 222 AD) were analyzed for 7,433,949 common SNPs and 19,511 protein-coding genes. Structural equation models tested whether biomarker PCs mediate genetic risk effects on AD, and stratified and interaction models probed for sex-specific effects. RESULTS: Five loci showed genome-wide significant association with CSF profiles, two were novel (rs145791381 [inflammation] and GRIN2D [synaptic functioning]) and three were previously described (APOE, TMEM106B, and CHI3L1). Follow-up analyses of the two novel signals in independent datasets only supported the GRIN2D locus, which contains several functionally interesting candidate genes. Mediation tests indicated that variants in APOE are associated with AD status via processes related to amyloid and tau pathology, while markers in TMEM106B and CHI3L1 are associated with AD only via neuronal injury/inflammation. Additionally, seven loci showed sex-specific associations with AD biomarkers. CONCLUSIONS: These results suggest that pathway and sex-specific analyses can improve our understanding of AD genetics and may contribute to precision medicine.
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Doença de Alzheimer , Humanos , Feminino , Masculino , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Estudo de Associação Genômica Ampla , Proteínas tau/genética , Biomarcadores , Inflamação , Apolipoproteínas E/genética , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Receptores de N-Metil-D-Aspartato/genéticaRESUMO
BACKGROUND: Evaluation of endovascular therapies for cerebral vasospasm (CVS) documented in the DeGIR registry from 2018-2021 to analyse the current clinical care situation in Germany. METHODS: Retrospective analysis of the clinical and procedural data on endovascular spasm therapies (EST) documented anonymously in the DeGIR registry. We analysed: pre-interventional findings of CTP and consciousness; radiation dose applied, interventional-technical parameters (local medication, devices, angiographic result), post-interventional symptoms, complications and mortality. RESULTS: 3584 patients received a total of 7628 EST (median age/patient: 53 [range: 13-100, IQR: 44-60], 68.2â% women) in 91 (2018), 92 (2019), 100 (2020) and 98 (2021) centres; 5388 (70.6â%) anterior circulation and 378 (5â%) posterior circulation (both involved in 1862 cases [24.4â%]). EST was performed once in 2125 cases (27.9â%), with a mean of 2.1 EST/patient. In 7476 times, purely medicated EST were carried out (nimodipine: 6835, papaverine: 401, nitroglycerin: 62, other drug not specified: 239; combinations: 90). Microcatheter infusions were documented in 1132 times (14.8â%). Balloon angioplasty (BA) (additional) was performed in 756 EST (9.9â%), other mechanical recanalisations in 154 cases (2â%) and stenting in 176 of the EST (2.3â%). The median dose area product during ET was 4069 cGycm² (drug: 4002/[+]BA: 8003 [pâ<â0.001]). At least 1 complication occurred in 95 of all procedures (1.2â%) (drug: 1.1â%/[+]BA: 4.2â% [pâ<â0.001]). Mortality associated with EST was 0.2â% (nâ=â18). After EST, overall improvement or elimination of CVS was found in 94.2â% of cases (drug: 93.8â%/[+]BA: 98.1â% [pâ<â0.001]). In a comparison of the locally applied drugs, papaverine eliminated CVS more frequently than nimodipine (pâ=â0.001). CONCLUSION: EST have a moderate radiation exposure and can be performed with few complications. Purely medicated EST are predominantly performed, especially with nimodipine. With (additional) BA, radiation exposure, complication rates and angiographic results are higher or better. When considering drug EST alone, there is evidence for an advantage of papaverine over nimodipine, but a different group size has to be taken into account. In the analysis of EST, the DeGIR registry data are suitable for answering more specific questions, especially due to the large number of cases; for this purpose, further subgroupings should be sought in the data documentation. KEY POINTS: · In Germany, there are currently no guidelines for the endovascular treatment of cerebral vasospasm following spontaneous subarachnoid hemorrhage.. · In addition to oral nimodipine administration endovascular therapy is used to treat cerebral vasospasm in most hospitals.. · This is the first systematic evaluation of nationwide registry data on endovascular treatment of cerebral vasopasm in Germany.. · This real-world data shows that endovascular treatment for cerebral vasospasm has a moderate radiation exposure and can be performed with few complications overall. With (additional) balloon angioplasty, radiation exposure, complication rates and angiographic therapy results are higher or better.. CITATION FORMAT: · Neumann A, Weber W, Küchler J etâal. Evaluation of DeGIR registry data on endovascular treatment of cerebral vasospasm in Germany 2018-2021: an overview of the current care situation. Fortschr Röntgenstr 2023; 195: 1018â-â1026.
Assuntos
Procedimentos Endovasculares , Hemorragia Subaracnóidea , Vasoespasmo Intracraniano , Humanos , Feminino , Masculino , Nimodipina/uso terapêutico , Papaverina/uso terapêutico , Vasodilatadores/uso terapêutico , Vasoespasmo Intracraniano/terapia , Vasoespasmo Intracraniano/tratamento farmacológico , Estudos Retrospectivos , Dados de Saúde Coletados Rotineiramente , Hemorragia Subaracnóidea/tratamento farmacológico , Procedimentos Endovasculares/métodos , Resultado do TratamentoRESUMO
From laser design to optical refrigeration, experimentally measured fluorescence spectra are often utilized to obtain input parameters for predictive models. However, in materials that exhibit site-selectivity, the fluorescence spectra depend on the excitation wavelength employed to take the measurement. This work explores different conclusions that predictive models reach after inputting such varied spectra. Here, temperature-dependent site-selective spectroscopy is carried out on an ultra-pure Yb, Al co-doped silica rod fabricated by the modified chemical vapor deposition technique. The results are discussed in the context of characterizing ytterbium doped silica for optical refrigeration. Measurements made between 80 K and 280 K at several different excitation wavelengths yield unique values and temperature dependencies of the mean fluorescence wavelength. For the excitation wavelengths studied here, the variation in emission lineshapes ultimately lead to calculated minimum achievable temperatures (MAT) ranging between 151 K and 169 K, with theoretical optimal pumping wavelengths between 1030 nm and 1037 nm. Direct evaluation of the temperature dependence of the fluorescence spectra band area associated with radiative transitions out of the thermally populated 2F5/2 sublevel may be a better approach to identifying the MAT of a glass where site-selective behavior precludes unique conclusions.