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Invasive tract-tracing studies in rodents implicate a direct connection between the subiculum and bed nucleus of the stria terminalis (BNST) as a key component of neural pathways mediating hippocampal regulation of the Hypothalamic-Pituitary-Adrenal (HPA) axis. A clear characterisation of the connections linking the subiculum and BNST in humans and non-human primates is lacking. To address this, we first delineated the projections from the subiculum to the BNST using anterograde tracers injected into macaque monkeys, revealing evidence for a monosynaptic subiculum-BNST projection involving the fornix. Second, we used in vivo diffusion MRI tractography in macaques and humans to demonstrate substantial subiculum complex connectivity to the BNST in both species. This connection was primarily carried by the fornix, with additional connectivity via the amygdala, consistent with rodent anatomy. Third, utilising the twin-based nature of our human sample, we found that microstructural properties of these tracts were moderately heritable (h2 â¼ 0.5). In a final analysis, we found no evidence of any significant association between subiculum complex-BNST tract microstructure and indices of perceived stress/dispositional negativity and alcohol use, derived from principal component analysis decomposition of self-report data. Our findings address a key translational gap in our knowledge of the neurocircuitry regulating stress.
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Núcleos Septales , Animales , Hipocampo/fisiología , Humanos , Sistema Hipotálamo-Hipofisario/metabolismo , Macaca , Sistema Hipófiso-Suprarrenal , Núcleos Septales/anatomía & histología , Núcleos Septales/diagnóstico por imagenRESUMEN
The hippocampus consists of anatomically and functionally distinct subfields that may be differentially involved in the pathophysiology of bipolar disorder (BD). Here we, the Enhancing NeuroImaging Genetics through Meta-Analysis Bipolar Disorder workinggroup, study hippocampal subfield volumetry in BD. T1-weighted magnetic resonance imaging scans from 4,698 individuals (BD = 1,472, healthy controls [HC] = 3,226) from 23 sites worldwide were processed with FreeSurfer. We used linear mixed-effects models and mega-analysis to investigate differences in hippocampal subfield volumes between BD and HC, followed by analyses of clinical characteristics and medication use. BD showed significantly smaller volumes of the whole hippocampus (Cohen's d = -0.20), cornu ammonis (CA)1 (d = -0.18), CA2/3 (d = -0.11), CA4 (d = -0.19), molecular layer (d = -0.21), granule cell layer of dentate gyrus (d = -0.21), hippocampal tail (d = -0.10), subiculum (d = -0.15), presubiculum (d = -0.18), and hippocampal amygdala transition area (d = -0.17) compared to HC. Lithium users did not show volume differences compared to HC, while non-users did. Antipsychotics or antiepileptic use was associated with smaller volumes. In this largest study of hippocampal subfields in BD to date, we show widespread reductions in nine of 12 subfields studied. The associations were modulated by medication use and specifically the lack of differences between lithium users and HC supports a possible protective role of lithium in BD.
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Trastorno Bipolar/diagnóstico por imagen , Trastorno Bipolar/patología , Hipocampo/diagnóstico por imagen , Hipocampo/patología , Imagen por Resonancia Magnética , Neuroimagen , Trastorno Bipolar/tratamiento farmacológico , Genética , Hipocampo/efectos de los fármacos , HumanosRESUMEN
Pre-clinical and human neuroimaging research implicates the extended-amygdala (ExtA) (including the bed nucleus of the stria terminalis [BST] and central nucleus of the amygdala [CeA]) in networks mediating negative emotional states associated with stress and substance-use behaviours. The extent to which individual ExtA structures form a functionally integrated unit is controversial. We utilised a large sample (n > 1,000 healthy young adult humans) to compare the intrinsic functional connectivity networks (ICNs) of the BST and CeA using task-free functional magnetic resonance imaging (fMRI) data from the Human Connectome Project. We assessed whether inter-individual differences within these ICNs were related to two principal components representing negative disposition and alcohol use. Building on recent primate evidence, we tested whether within BST-CeA intrinsic functional connectivity (iFC) was heritable and further examined co-heritability with our principal components. We demonstrate the BST and CeA to have discrete, but largely overlapping ICNs similar to previous findings. We found no evidence that within BST-CeA iFC was heritable; however, post hoc analyses found significant BST iFC heritability with the broader superficial and centromedial amygdala regions. There were no significant correlations or co-heritability associations with our principal components either across the ICNs or for specific BST-Amygdala iFC. Possible differences in phenotype associations across task-free, task-based, and clinical fMRI are discussed, along with suggestions for more causal investigative paradigms that make use of the now well-established ExtA ICNs.
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Núcleo Amigdalino Central/fisiología , Conectoma/métodos , Red Nerviosa/fisiología , Núcleos Septales/fisiología , Adulto , Núcleo Amigdalino Central/diagnóstico por imagen , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/fisiología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Herencia Multifactorial/fisiología , Red Nerviosa/diagnóstico por imagen , Linaje , Núcleos Septales/diagnóstico por imagen , Tálamo/diagnóstico por imagen , Tálamo/fisiologíaRESUMEN
A substantial proportion of schizophrenia liability can be explained by additive genetic factors. Risk profile scores (RPS) directly index risk using a summated total of common risk variants weighted by their effect. Previous studies suggest that schizophrenia RPS predict alterations to neural networks that support working memory and verbal fluency. In this study, we apply schizophrenia RPS to fMRI data to elucidate the effects of polygenic risk on functional brain networks during a probabilistic-learning neuroimaging paradigm. The neural networks recruited during this paradigm have previously been shown to be altered to unmedicated schizophrenia patients and relatives of schizophrenia patients, which may reflect genetic susceptibility. We created schizophrenia RPS using summary data from the Psychiatric Genetic Consortium (Schizophrenia Working Group) for 83 healthy individuals and explore associations between schizophrenia RPS and blood oxygen level dependency (BOLD) during periods of choice behavior (switch-stay) and reflection upon choice outcome (reward-punishment). We show that schizophrenia RPS is associated with alterations in the frontal pole (PWHOLE-BRAIN-CORRECTED = 0.048) and the ventral striatum (PROI-CORRECTED = 0.036), during choice behavior, but not choice outcome. We suggest that the common risk variants that increase susceptibility to schizophrenia can be associated with alterations in the neural circuitry that support the processing of changing reward contingencies. Hum Brain Mapp 37:491-500, 2016. © 2015 Wiley Periodicals, Inc.
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Encéfalo/fisiopatología , Predisposición Genética a la Enfermedad , Aprendizaje por Probabilidad , Esquizofrenia/genética , Esquizofrenia/fisiopatología , Psicología del Esquizofrénico , Adulto , Circulación Cerebrovascular/fisiología , Toma de Decisiones/fisiología , Femenino , Variación Genética , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Oxígeno/sangre , Recompensa , Percepción Visual/fisiología , Adulto JovenRESUMEN
Increased intra-subject variability (ISV) in reaction times (RTs) is a candidate endophenotype for several psychiatric and neurological conditions, including schizophrenia. ISV reflects the degree of variability in RTs and is thought to be an index of the stability of cognition. It is generally assumed to have the same underlying physiological basis across conditions, but recent evidence raises the possibility that the neural underpinnings of ISV vary with aetiology. Combining genetics with single-trial event-related potentials is an ideal method for investigating the neural basis of ISV in groups where ISV may vary for relatively homogenous reasons. Here we examine the association between P3b latency variability and a polymorphism on the ZNF804A gene associated with psychosis. Ninety-one healthy volunteers genotyped for rs1344706, a polymorphism on ZNF804A, had electroencephalographic data recorded while carrying out three n-back tasks. Data were analysed with a single-trial approach and latency variability of the P3b was compared between the AA homozygous risk group (N=30) and C allele carriers (N=61). P3b latencies were more variable for AA carriers than C carriers. Behavioural ISV, however, was not associated with genotype. The increase in neurophysiological variability, unaccompanied by increased behavioural variability, suggests that this risk gene is associated with an attenuated form of an endophenotype associated with the psychosis phenotype. The increase in both stimulus and response-locked variability also contrasts with previous work into attention-deficit hyperactivity disorder, where only response-locked P3b variability was elevated, suggesting that increased ISV may not signify the same underlying processes in all conditions with which it is associated.
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Corteza Cerebral/fisiología , Potenciales Relacionados con Evento P300 , Factores de Transcripción de Tipo Kruppel/genética , Desempeño Psicomotor/fisiología , Trastornos Psicóticos/genética , Tiempo de Reacción , Adulto , Alelos , Electroencefalografía , Femenino , Predisposición Genética a la Enfermedad , Humanos , Individualidad , Masculino , Fenotipo , Polimorfismo Genético , Factores de Riesgo , Adulto JovenRESUMEN
INTRODUCTION: Genome-wide association studies identify rs11136000 in the CLU gene, which codes for Apolipoprotein J/Clusterin, as a significant risk variant for Alzheimer's disease (AD). However, the mechanisms by which this variant confers susceptibility remain relatively unknown. METHODS: Eighty-five healthy Caucasian participants underwent functional magnetic resonance imaging during a working memory (WM) task and were genotyped for CLU rs11136000/APOE loci. RESULTS: Here we show that young individuals with the CLU rs11136000 risk variant (C) have higher activation levels in memory-related prefrontal and limbic areas during a WM task. We also found subtle reductions in gray matter in the right hippocampal formation in carriers of the risk variant. DISCUSSION: We suggest that this pattern of multimodal imaging results may reflect incipient structural differences and inefficient functional activation. This study supports accumulating evidence suggesting that genetic risk for AD affects the neural networks associated with memory in healthy individuals.
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Enfermedad de Alzheimer/genética , Clusterina/genética , Hipocampo/patología , Memoria a Corto Plazo , Red Nerviosa , Adulto , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Factores de Riesgo , Adulto JovenRESUMEN
Neuroimaging studies consistently show advanced brain age in schizophrenia, suggesting that brain structure is often 'older' than expected at a given chronological age. Whether advanced brain age is linked to genetic liability for schizophrenia remains unclear. In this pre-registered secondary data analysis, we utilised a recall-by-genotype approach applied to a population-based subsample from the Avon Longitudinal Study of Parents and Children to assess brain age differences between young adults aged 21-24 years with relatively high (n = 96) and low (n = 93) polygenic risk for schizophrenia (SCZ-PRS). A global index of brain age (or brain-predicted age) was estimated using a publicly available machine learning model previously trained on a combination of region-wise gray-matter measures, including cortical thickness, surface area and subcortical volumes derived from T1-weighted magnetic resonance imaging (MRI) scans. We found no difference in mean brain-PAD (the difference between brain-predicted age and chronological age) between the high- and low-SCZ-PRS groups, controlling for the effects of sex and age at time of scanning (b = -.21; 95% CI -2.00, 1.58; p = .82; Cohen's d = -.034; partial R2 = .00029). These findings do not support an association between SCZ-PRS and brain-PAD based on global age-related structural brain patterns, suggesting that brain age may not be a vulnerability marker of common genetic risk for SCZ. Future studies with larger samples and multimodal brain age measures could further investigate global or localised effects of SCZ-PRS.
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Esquizofrenia , Adulto Joven , Niño , Humanos , Adulto , Esquizofrenia/diagnóstico por imagen , Esquizofrenia/genética , Esquizofrenia/patología , Estudios Longitudinales , Imagen por Resonancia Magnética , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Genotipo , Predisposición Genética a la Enfermedad/genéticaRESUMEN
Introduction: The antigen-presenting cell function of insulin-reactive B cells promotes type 1 diabetes (T1D) in non-obese diabetic (NOD) mice by stimulating pathogenic T cells leading to destruction of insulin-producing ß-cells of pancreatic islets. Methods/Results: To target insulin-reactive B cells, AKS-107, a human IgG1 Fc molecule fused with human insulin A and B chains, was engineered to retain conformational insulin epitopes that bound mouse and human B cell receptors but prevented binding to the insulin metabolic receptor. AKS-107 Fc-mediated deletion of insulin-reactive B cells was demonstrated via ex vivo and in vivo experiments with insulin-reactive B cell receptor transgenic mouse strains, VH125Tg/NOD and Tg125(H+L)/NOD. As an additional immune tolerance feature, the Y16A mutation of the insulin B(9-23) dominant T cell epitope was engineered into AKS-107 to suppress activation of insulin-specific T cells. In mice and non-human primates, AKS-107 was well-tolerated, non-immunogenic, did not cause hypoglycemia even at high doses, and showed an expectedly protracted pharmacokinetic profile. AKS-107 reproducibly prevented spontaneous diabetes from developing in NOD and VH125Tg/NOD mice that persisted for months after cessation of treatment, demonstrating durable immune tolerance. Discussion: These preclinical outcomes position AKS-107 for clinical development in T1D prevention settings.
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Diabetes Mellitus Tipo 1 , Islotes Pancreáticos , Ratones , Animales , Humanos , Ratones Endogámicos NOD , Linfocitos B , Ratones Transgénicos , Receptores de Antígenos de Linfocitos B , InmunoterapiaRESUMEN
AKS-452, a subunit vaccine comprising an Fc fusion of the ancestral wild-type (WT) SARS-CoV-2 virus spike protein receptor binding domain (SP/RBD), was evaluated without adjuvant in a single cohort, non-randomized, open-labelled phase II study (NCT05124483) at a single site in The Netherlands for safety and immunogenicity. A single 90 µg subcutaneous booster dose of AKS-452 was administered to 71 adults previously primed with a registered mRNA- or adenovirus-based vaccine and evaluated for 273 days. All AEs were mild and no SAEs were attributable to AKS-452. While all subjects showed pre-existing SP/RBD binding and ACE2-inhibitory IgG titers, 60-68% responded to AKS-452 via ≥2-fold increase from days 28 to 90 and progressively decreased back to baseline by day 180 (days 28 and 90 mean fold-increases, 14.7 ± 6.3 and 8.0 ± 2.2). Similar response kinetics against RBD mutant proteins (including omicrons) were observed but with slightly reduced titers relative to WT. There was an expected strong inverse correlation between day-0 titers and the fold-increase in titers at day 28. AKS-452 enhanced neutralization potency against live virus, consistent with IgG titers. Nucleocapsid protein (Np) titers suggested infection occurred in 66% (46 of 70) of subjects, in which only 20 reported mild symptomatic COVID-19. These favorable safety and immunogenicity profiles support booster evaluation in a planned phase III universal booster study of this room-temperature stable vaccine that can be rapidly and inexpensively manufactured to serve vaccination at a global scale without the need of a complex distribution or cold chain.
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BACKGROUND: Genetic susceptibility to schizophrenia (SZ) has been suggested to influence the cortical systems supporting working memory (WM) and face processing. Genetic imaging studies link the SZ risk variant rs1344706 on the ZNF804A gene to psychosis via alterations in functional brain connectivity during WM, but no work has looked at the effects of ZNF804A on WM with face-processing components. METHODS: We therefore investigated healthy controls that were genotyped for rs1344706 with a face WM task during functional magnetic resonance imaging. We suggested that variation at the rs1344706 locus would be associated with similar alterations as patients previously tested using the same WM task for faces. RESULTS: The rs1344706 risk allele was indeed associated with altered activation in the right dorsolateral prefrontal (rDLPFC) cortex. We established that the rDLPFC was activated in a task-dependent manner, suggesting that the differences in activation between rs1344706 genotype groups reflected alterations in task processing. Furthermore, we demonstrated that the rDLPFC region showed significant volumetric overlap with the rDLPFC which had previously been reported to be altered during task processing for patients with SZ. CONCLUSIONS: The findings support an association between rs1344706 and alterations in DLPFC activity during WM for faces. We further suggest that WM for faces may be a useful intermediate phenotype in the investigation of genetic susceptibility to psychosis.
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Mapeo Encefálico , Cara , Factores de Transcripción de Tipo Kruppel/genética , Memoria a Corto Plazo/fisiología , Polimorfismo de Nucleótido Simple/genética , Corteza Prefrontal/fisiología , Adulto , Análisis de Varianza , Emociones/fisiología , Femenino , Lateralidad Funcional , Genotipo , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Oxígeno/sangre , Reconocimiento Visual de Modelos , Estimulación Luminosa , Corteza Prefrontal/irrigación sanguínea , Reconocimiento en Psicología/fisiología , Adulto JovenRESUMEN
Schizophrenia and bipolar disorder share a common structural brain alteration profile. However, there is considerable between- and within-diagnosis variability in these features, which may underestimate informative individual differences. Using a recently established morphometric risk score (MRS) approach, we aim to provide confirmation that individual MRS scores are higher in individuals with a psychosis diagnosis, helping to parse individual heterogeneity. Using the Human Connectome Project Early Psychosis (Nâ =â 124), we estimate MRS for psychosis and specifically for bipolar/schizophrenia using T1-weighted MRI data and prior meta-analysis effect sizes. We confirm associations in an independent replication sample (Nâ =â 69). We assess (1) the impact of diagnosis on these MRS, (2) compare effect sizes of MRS to all individual, cytoarchitecturally defined brain regions, and (3) perform negative control analyses to assess MRS specificity. The MRS specifically for SCZ was higher in the whole psychosis group (Cohen's dâ =â 0.56; Pâ =â 0.003) and outperformed any single region of interest in standardized mean difference (ZMRS>75 ROIS = 2.597; Pâ =â 0.009) and correlated with previously reported effect sizes (PSPIN/SHUFFLE < 0.005). MRS without Enhancing Neuroimaging Genomics through Meta-Analysis weights did not delineate groups with empirically null associations (tâ =â 2.29; Pâ =â 0.02). We replicate MRS specifically for SCZ associations in the independent sample. Akin to polygenic risk scoring and individual allele effect sizes, these observations suggest that assessing the combined impact of regional structural alterations may be more informative than any single cytoarchitecturally constrained cortical region, where well-powered, meta-analytical samples are informative in the delineation of diagnosis and within psychosis case differences, in smaller independent samples.
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Medial temporal lobe (MTL) atrophy is correlated with risk and severity of Alzheimer disease (AD) pathology and cognitive decline. Increasing evidence suggest that oestrogens affect the aging of MTL structures. Here we investigate the relationship between reproductive hormone exposure, polygenic scores for AD risk and oestradiol concentration, MTL anatomy and cognitive performance in postmenopausal women. To this end, we used data from 10,924 female participants in the UK Biobank from whom brain MRI and genetic data were available. We fitted linear regression models to test whether the volume of structures comprising the MTL were predicted by a) timing related to menopause, b) the use and timing of hormone replacement therapy (HRT) and c) polygenic scores for AD risk and oestradiol concentration. Results showed that longer use of HRT was associated with larger parahippocampal volumes (2.53 mm3/year, p = 0.042). A later age of natural menopause, and a longer reproductive span, was associated with larger hippocampal (6.08 and 5.72 mm3/year, p = 0.0006 and 0.0005), parahippocampal (4.17 mm3 and 4.19 mm3/year, p = 0.00006 and 0.00001), amygdala (2.10 and 2.22 mm3/year, p = 0.028 and 0.01) and perirhinal cortical (2.56 and 2.95 mm3/year, p = 0.028 and 0.008) volumes. Superior prospective memory performance was associated with later age at natural menopause, and a longer reproductive span (ß = 0.05 and 0.05 respectively, p = 0.019 and 0.019). Polygenic scores for AD risk and for oestradiol concentration were not associated with MTL volume and did not interact with menopause-related factors to affect MTL structure. Our results suggest that HRT use did not have any detrimental effects on cognition or brain structure, whilst greater exposure to reproductive hormones across time is associated both with slightly larger volumes of specific MTL structures and marginally superior memory performance, independent of genetic risk for AD and genetic predisposition for higher oestradiol levels. However, the clinical utility of maintenance of oestrogens post-menopause for brain health and protection against cognitive decline is curtailed by the small effect sizes observed.
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Enfermedad de Alzheimer , Posmenopausia , Humanos , Femenino , Duración de la Terapia , Lóbulo Temporal/patología , Enfermedad de Alzheimer/patología , Menopausia , Imagen por Resonancia Magnética , Estrógenos , EstradiolRESUMEN
Cerebral energy deficiency is increasingly recognised as an important feature of multiple sclerosis (MS). Until now, we have lacked non-invasive imaging methods to quantify energy utilisation and mitochondrial function in the human brain. Here, we used novel dual-calibrated functional magnetic resonance imaging (dc-fMRI) to map grey-matter (GM) deoxy-haemoglobin sensitive cerebral blood volume (CBVdHb), cerebral blood flow (CBF), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen consumption (CMRO2) in patients with MS (PwMS) and age/sex matched controls. By integrating a flow-diffusion model of oxygen transport, we evaluated the effective oxygen diffusivity of the capillary network (DC) and the partial pressure of oxygen at the mitochondria (PmO2). Significant between-group differences were observed as decreased CBF (p = 0.010), CMRO2 (p < 0.001) and DC (p = 0.002), and increased PmO2 (p = 0.043) in patients compared to controls. No significant differences were observed for CBVdHb (p = 0.389), OEF (p = 0.358), or GM volume (p = 0.302). Regional analysis showed widespread reductions in CMRO2 and DC for PwMS. Our findings may be indicative of reduced oxygen demand or utilisation in the MS brain and mitochondrial dysfunction. Our results suggest changes in brain physiology may precede MRI-detectable GM loss and may contribute to disease progression and neurodegeneration.
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Esclerosis Múltiple , Humanos , Esclerosis Múltiple/diagnóstico por imagen , Oxígeno , Imagen por Resonancia Magnética , Encéfalo/diagnóstico por imagenRESUMEN
BACKGROUND: Previous interim data from a phase I study of AKS-452, a subunit vaccine comprising an Fc fusion of the respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein receptor binding domain (SP/RBD) emulsified in the water-in-oil adjuvant, Montanide™ ISA 720, suggested a good safety and immunogenicity profile in healthy adults. This phase I study was completed and two dosing regimens were further evaluated in this phase II study. METHODS: This phase II randomized, open-labelled, parallel group study was conducted at a single site in The Netherlands with 52 healthy adults (18 - 72 years) receiving AKS-452 subcutaneously at one 90 µg dose (cohort 1, 26 subjects) or two 45 µg doses 28 days apart (cohort 2, 26 subjects). Serum samples were collected at the first dose (day 0) and at days 28, 56, 90, and 180. Safety and immunogenicity endpoints were assessed, along with induction of IgG isotypes, cross-reactive immunity against viral variants, and IFN-γ T cell responses. RESULTS: All AEs were mild/moderate (grades 1 or 2), and no SAEs were attributable to AKS-452. Seroconversion rates reached 100% in both cohorts, although cohort 2 showed greater geometric mean IgG titers that were stable through day 180 and associated with enhanced potencies of SP/RBD-ACE2 binding inhibition and live virus neutralization. AKS-452-induced IgG titers strongly bound mutant SP/RBD from several SARS-CoV-2 variants (including Omicrons) that were predominantly of the favorable IgG1/3 isotype and IFN-γ-producing T cell phenotype. CONCLUSION: These favorable safety and immunogenicity profiles of the candidate vaccine as demonstrated in this phase II study are consistent with those of the phase I study (ClinicalTrials.gov: NCT04681092) and suggest that a total of 90 µg received in 2 doses may offer a greater duration of cross-reactive neutralizing titers than when given in a single dose.
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COVID-19 , SARS-CoV-2 , Humanos , COVID-19/prevención & control , Glicoproteína de la Espiga del Coronavirus , Anticuerpos Antivirales , Vacunas contra la COVID-19/efectos adversos , Adyuvantes Inmunológicos/efectos adversos , Inmunoglobulina G , Inmunogenicidad Vacunal , Anticuerpos Neutralizantes , Método Doble CiegoRESUMEN
The parahippocampal cingulum bundle (PHCB) interconnects regions known to be vulnerable to early Alzheimer's disease (AD) pathology, including posteromedial cortex and medial temporal lobe. While AD-related pathology has been robustly associated with alterations in PHCB microstructure, specifically lower fractional anisotropy (FA) and higher mean diffusivity (MD), emerging evidence indicates that the reverse pattern is evident in younger adults at increased risk of AD. In one such study, Hodgetts et al. (2019) reported that healthy young adult carriers of the apolipoprotein-E (APOE) ε4 allele - the strongest common genetic risk factor for AD - showed higher FA and lower MD in the PHCB but not the inferior longitudinal fasciculus (ILF). These results are consistent with proposals claiming that heightened neural activity and intrinsic connectivity play a significant role in increasing posteromedial cortex vulnerability to amyloid-ß and tau spread beyond the medial temporal lobe. Given the implications for understanding AD risk, here we sought to replicate Hodgetts et al.'s finding in a larger sample (N = 128; 40 APOE ε4 carriers, 88 APOE ε4 non-carriers) of young adults (age range = 19-33). Extending this work, we also conducted an exploratory analysis using a more advanced measure of white matter microstructure: hindrance modulated orientational anisotropy (HMOA). Contrary to the original study, we did not observe higher FA or lower MD in the PHCB of APOE ε4 carriers relative to non-carriers. Bayes factors (BFs) further revealed moderate-to-strong evidence in support of these null findings. In addition, we observed no APOE ε4-related differences in PHCB HMOA. Our findings indicate that young adult APOE ε4 carriers and non-carriers do not differ in PHCB microstructure, casting some doubt on the notion that early-life variation in PHCB tract microstructure might enhance vulnerability to amyloid-ß accumulation and/or tau spread.
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Schizophrenia (SCZ) is associated with structural brain changes, with considerable variation in the extent to which these cortical regions are influenced. We present a novel metric that summarises individual structural variation across the brain, while considering prior effect sizes, established via meta-analysis. We determine individual participant deviation from a within-sample-norm across structural MRI regions of interest (ROIs). For each participant, we weight the normalised deviation of each ROI by the effect size (Cohen's d) of the difference between SCZ/control for the corresponding ROI from the SCZ Enhancing Neuroimaging Genomics through Meta-Analysis working group. We generate a morphometric risk score (MRS) representing the average of these weighted deviations. We investigate if SCZ-MRS is elevated in a SCZ case/control sample (NCASE = 50; NCONTROL = 125), a replication sample (NCASE = 23; NCONTROL = 20) and a sample of asymptomatic young adults with extreme SCZ polygenic risk (NHIGH-SCZ-PRS = 95; NLOW-SCZ-PRS = 94). SCZ cases had higher SCZ-MRS than healthy controls in both samples (Study 1: ß = 0.62, P < 0.001; Study 2: ß = 0.81, P = 0.018). The high liability SCZ-PRS group also had a higher SCZ-MRS (Study 3: ß = 0.29, P = 0.044). Furthermore, the SCZ-MRS was uniquely associated with SCZ status, but not attention-deficit hyperactivity disorder (ADHD), whereas an ADHD-MRS was linked to ADHD status, but not SCZ. This approach provides a promising solution when considering individual heterogeneity in SCZ-related brain alterations by identifying individual's patterns of structural brain-wide alterations.
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Imagen por Resonancia Magnética/métodos , Esquizofrenia/fisiopatología , Adulto , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Humanos , Imagen por Resonancia Magnética/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Neuroimagen/métodos , Neuroimagen/estadística & datos numéricos , Esquizofrenia/complicacionesRESUMEN
INTRODUCTION: Illuminating neurobiological mechanisms underlying the protective effect of recently discovered common genetic resilience variants for schizophrenia is crucial for more effective prevention efforts. Current models implicate adaptive neuroplastic changes in the visual system and their pro-cognitive effects as a schizophrenia resilience mechanism. We investigated whether common genetic resilience variants might affect brain structure in similar neural circuits. METHOD: Using structural magnetic resonance imaging, we measured the impact of an established schizophrenia polygenic resilience score (PRSResilience) on cortical volume, thickness, and surface area in 101 healthy subjects and in a replication sample of 33 224 healthy subjects (UK Biobank). FINDING: We observed a significant positive whole-brain correlation between PRSResilience and cortical volume in the right fusiform gyrus (FFG) (r = 0.35; P = .0004). Post-hoc analyses in this cluster revealed an impact of PRSResilience on cortical surface area. The replication sample showed a positive correlation between PRSResilience and global cortical volume and surface area in the left FFG. CONCLUSION: Our findings represent the first evidence of a neurobiological correlate of a genetic resilience factor for schizophrenia. They support the view that schizophrenia resilience emerges from strengthening neural circuits in the ventral visual pathway and an increased capacity for the disambiguation of social and nonsocial visual information. This may aid psychosocial functioning, ameliorate the detrimental effects of subtle perceptual and cognitive disturbances in at-risk individuals, and facilitate coping with the cognitive and psychosocial consequences of stressors. Our results thus provide a novel link between visual cognition, the vulnerability-stress concept, and schizophrenia resilience models.
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Esquizofrenia , Encéfalo/metabolismo , Humanos , Imagen por Resonancia Magnética , Herencia Multifactorial , Esquizofrenia/diagnóstico por imagen , Esquizofrenia/genética , Esquizofrenia/metabolismo , Vías Visuales/diagnóstico por imagen , Vías Visuales/patologíaRESUMEN
To address the coronavirus disease 2019 (COVID-19) pandemic caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a recombinant subunit vaccine, AKS-452, is being developed comprising an Fc fusion protein of the SARS-CoV-2 viral spike protein receptor binding domain (SP/RBD) antigen and human IgG1 Fc emulsified in the water-in-oil adjuvant, Montanide™ ISA 720. A single-center, open-label, phase I dose-finding and safety study was conducted with 60 healthy adults (18-65 years) receiving one or two doses 28 days apart of 22.5 µg, 45 µg, or 90 µg of AKS-452 (i.e., six cohorts, N = 10 subjects per cohort). Primary endpoints were safety and reactogenicity and secondary endpoints were immunogenicity assessments. No AEs ≥ 3, no SAEs attributable to AKS-452, and no SARS-CoV-2 viral infections occurred during the study. Seroconversion rates of anti-SARS-CoV-2 SP/RBD IgG titers in the 22.5, 45, and 90 µg cohorts at day 28 were 70%, 90%, and 100%, respectively, which all increased to 100% at day 56 (except 89% for the single-dose 22.5 µg cohort). All IgG titers were Th1-isotype skewed and efficiently bound mutant SP/RBD from several SARS-CoV-2 variants with strong neutralization potencies of live virus infection of cells (including alpha and delta variants). The favorable safety and immunogenicity profiles of this phase I study (ClinicalTrials.gov: NCT04681092) support phase II initiation of this room-temperature stable vaccine that can be rapidly and inexpensively manufactured to serve vaccination at a global scale without the need of a complex distribution or cold chain.
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Vacunas contra la COVID-19 , COVID-19 , Adolescente , Adulto , Anciano , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Vacunas contra la COVID-19/efectos adversos , Ensayos Clínicos Fase II como Asunto , Humanos , Inmunogenicidad Vacunal , Inmunoglobulina G , Persona de Mediana Edad , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Vacunas de Subunidad , Adulto JovenRESUMEN
Preclinical models of Alzheimer's disease (AD) suggest that volumetric reductions in medial temporal lobe (MTL) structures manifest before clinical onset. AD polygenic risk scores (PRSs) are further linked to reduced MTL volumes (the hippocampus/amygdala); however, the relationship between the PRS and specific subregions remains unclear. We determine the relationship between the AD-PRSs and MTL subregions in a large sample of young participants (N = 730, aged 22-35 years) using a multimodal (T1w/T2w) approach. We first demonstrate that the PRSs for the hippocampus/amygdala predict their respective volumes and specific hippocampal subregions (pFDR < 0.05). We further observe negative relationships between the AD-PRSs and whole hippocampal/amygdala volumes. Critically, we demonstrate novel associations between the AD-PRSs and specific hippocampal subfields such as CA1 (ß = -0.096, pFDR = 0.045) and the fissure (ß = -0.101, pFDR = 0.041). We provide evidence that the AD-PRS is linked to specific MTL subfields decades before AD onset. This may help inform preclinical models of AD risk, providing additional specificity for intervention and further insight into mechanisms by which common AD variants confer susceptibility.