| 11. |
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| 12. |
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| 13. |
- Chiotis, Konstantinos, et al.
(författare)
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[F-18]THK5317 imaging as a tool for predicting prospective cognitive decline in Alzheimer's disease
- 2021
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Ingår i: Molecular Psychiatry. - : Springer Nature. - 1359-4184 .- 1476-5578. ; 26:10, s. 5875-5887
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Tidskriftsartikel (refereegranskat)abstract
- Cross-sectional studies have indicated potential for positron emission tomography (PET) in imaging tau pathology in Alzheimer's disease (AD); however, its prognostic utility remains unproven. In a longitudinal, multi-modal, prognostic study of cognitive decline, 20 patients with a clinical biomarker-based diagnosis in the AD spectrum (mild cognitive impairment or dementia and a positive amyloid-beta PET scan) were recruited from the Cognitive Clinic at Karolinska University Hospital. The participants underwent baseline neuropsychological assessment, PET imaging with [F-18]THK5317, [C-11]PIB and [F-18]FDG, magnetic resonance imaging, and in a subgroup cerebrospinal fluid (CSF) sampling, with clinical follow-up after a median 48 months (interquartile range = 32:56). In total, 11 patients declined cognitively over time, while 9 remained cognitively stable. The accuracy of baseline [F-18]THK5317 binding in temporal areas was excellent at predicting future cognitive decline (area under the receiver operating curve 0.84-1.00) and the biomarker levels were strongly associated with the rate of cognitive decline (beta estimate -33.67 to -31.02,p < 0.05). The predictive accuracy of the other baseline biomarkers was poor (area under the receiver operating curve 0.58-0.77) and their levels were not associated with the rate of cognitive decline (beta estimate -4.64 to 15.78,p > 0.05). Baseline [F-18]THK5317 binding and CSF tau levels were more strongly associated with the MMSE score at follow-up than at baseline (p < 0.05). These findings support a temporal dissociation between tau deposition and cognitive impairment, and suggest that [F-18]THK5317 predicts future cognitive decline better than other biomarkers. The use of imaging markers for tau pathology could prove useful for clinical prognostic assessment and screening before inclusion in relevant clinical trials.
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| 14. |
- Clements, C. C., et al.
(författare)
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Genome-wide association study of patients with a severe major depressive episode treated with electroconvulsive therapy
- 2021
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 26:10
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Tidskriftsartikel (refereegranskat)abstract
- Although large genome-wide association studies (GWAS) of major depressive disorder (MDD) have identified many significant loci, the SNP-based heritability remains notably low, which might be due to etiological heterogeneity in existing samples. Here, we test the utility of targeting the severe end of the MDD spectrum through genome-wide SNP genotyping of 2725 cases who received electroconvulsive therapy (ECT) for a major depressive episode (MDE) and 4035 controls. A subset of cases (n = 1796) met a narrow case definition (MDE occurring in the context of MDD). Standard GWAS quality control procedures and imputation were conducted. SNP heritability and genetic correlations with other traits were estimated using linkage disequilibrium score regression. Results were compared with MDD cases of mild-moderate severity receiving internet-based cognitive behavioral therapy (iCBT) and summary results from the Psychiatric Genomics Consortium (PGC). The SNP-based heritability was estimated at 29-34% (SE: 6%) for the narrow case definition, considerably higher than the 6.5-8.0% estimate in the most recent PGC MDD study. Our severe MDE cases had smaller genetic correlations with neurodevelopmental disorders and neuroticism than PGC MDD cases but higher genetic risk scores for bipolar disorder than iCBT MDD cases. One genome-wide significant locus was identified (rs114583506, P = 5e-8) in an intron of HLA-B in the major histocompatibility locus on chr6. These results indicate that individuals receiving ECT for an MDE have higher burden of common variant risk loci than individuals with mild-moderate MDD. Furthermore, severe MDE shows stronger relations with other severe adult-onset psychiatric disorders but weaker relations with personality and stress-related traits than mild-moderate MDD. These findings suggest a different genetic architecture at the severest end of the spectrum, and support further study of the severest MDD cases as an extreme phenotype approach to understand the etiology of MDD.
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| 15. |
- Córdova-Palomera, Aldo, et al.
(författare)
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Genetic control of variability in subcortical and intracranial volumes
- 2021
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Ingår i: Molecular Psychiatry. - : Nature Publishing Group. - 1359-4184 .- 1476-5578. ; 26:8, s. 3876-3883
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Tidskriftsartikel (refereegranskat)abstract
- Sensitivity to external demands is essential for adaptation to dynamic environments, but comes at the cost of increased risk of adverse outcomes when facing poor environmental conditions. Here, we apply a novel methodology to perform genome-wide association analysis of mean and variance in ten key brain features (accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus, intracranial volume, cortical surface area, and cortical thickness), integrating genetic and neuroanatomical data from a large lifespan sample (n = 25,575 individuals; 8-89 years, mean age 51.9 years). We identify genetic loci associated with phenotypic variability in thalamus volume and cortical thickness. The variance-controlling loci involved genes with a documented role in brain and mental health and were not associated with the mean anatomical volumes. This proof-of-principle of the hypothesis of a genetic regulation of brain volume variability contributes to establishing the genetic basis of phenotypic variance (i.e., heritability), allows identifying different degrees of brain robustness across individuals, and opens new research avenues in the search for mechanisms controlling brain and mental health.
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| 16. |
- de las Fuentes, Lisa, et al.
(författare)
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Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci
- 2021
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Ingår i: Molecular Psychiatry. - : Springer Nature. - 1359-4184 .- 1476-5578. ; 26:6, s. 2111-2125
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Tidskriftsartikel (refereegranskat)abstract
- Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, “Some College” (yes/no) and “Graduated College” (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10-8). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
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| 17. |
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| 18. |
- Dickstein, D. L., et al.
(författare)
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Brain and blood biomarkers of tauopathy and neuronal injury in humans and rats with neurobehavioral syndromes following blast exposure
- 2021
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 26, s. 5940-5954
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Tidskriftsartikel (refereegranskat)abstract
- Traumatic brain injury (TBI) is a risk factor for the later development of neurodegenerative diseases that may have various underlying pathologies. Chronic traumatic encephalopathy (CTE) in particular is associated with repetitive mild TBI (mTBI) and is characterized pathologically by aggregation of hyperphosphorylated tau into neurofibrillary tangles (NFTs). CTE may be suspected when behavior, cognition, and/or memory deteriorate following repetitive mTBI. Exposure to blast overpressure from improvised explosive devices (IEDs) has been implicated as a potential antecedent for CTE amongst Iraq and Afghanistan Warfighters. In this study, we identified biomarker signatures in rats exposed to repetitive low-level blast that develop chronic anxiety-related traits and in human veterans exposed to IED blasts in theater with behavioral, cognitive, and/or memory complaints. Rats exposed to repetitive low-level blasts accumulated abnormal hyperphosphorylated tau in neuronal perikarya and perivascular astroglial processes. Using positron emission tomography (PET) and the [F-18]AV1451 (flortaucipir) tau ligand, we found that five of 10 veterans exhibited excessive retention of [F-18]AV1451 at the white/gray matter junction in frontal, parietal, and temporal brain regions, a typical localization of CTE tauopathy. We also observed elevated levels of neurofilament light (NfL) chain protein in the plasma of veterans displaying excess [F-18]AV1451 retention. These findings suggest an association linking blast injury, tauopathy, and neuronal injury. Further study is required to determine whether clinical, neuroimaging, and/or fluid biomarker signatures can improve the diagnosis of long-term neuropsychiatric sequelae of mTBI.
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| 19. |
- Forstner, A. J., et al.
(författare)
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Genome-wide association study of panic disorder reveals genetic overlap with neuroticism and depression
- 2021
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 26, s. 4179-4190
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Tidskriftsartikel (refereegranskat)abstract
- Panic disorder (PD) has a lifetime prevalence of 2–4% and heritability estimates of 40%. The contributory genetic variants remain largely unknown, with few and inconsistent loci having been reported. The present report describes the largest genome-wide association study (GWAS) of PD to date comprising genome-wide genotype data of 2248 clinically well-characterized PD patients and 7992 ethnically matched controls. The samples originated from four European countries (Denmark, Estonia, Germany, and Sweden). Standard GWAS quality control procedures were conducted on each individual dataset, and imputation was performed using the 1000 Genomes Project reference panel. A meta-analysis was then performed using the Ricopili pipeline. No genome-wide significant locus was identified. Leave-one-out analyses generated highly significant polygenic risk scores (PRS) (explained variance of up to 2.6%). Linkage disequilibrium (LD) score regression analysis of the GWAS data showed that the estimated heritability for PD was 28.0–34.2%. After correction for multiple testing, a significant genetic correlation was found between PD and major depressive disorder, depressive symptoms, and neuroticism. A total of 255 single-nucleotide polymorphisms (SNPs) with p < 1 × 10−4 were followed up in an independent sample of 2408 PD patients and 228,470 controls from Denmark, Iceland and the Netherlands. In the combined analysis, SNP rs144783209 showed the strongest association with PD (pcomb = 3.10 × 10−7). Sign tests revealed a significant enrichment of SNPs with a discovery p-value of <0.0001 in the combined follow up cohort (p = 0.048). The present integrative analysis represents a major step towards the elucidation of the genetic susceptibility to PD. © 2019, The Author(s), under exclusive licence to Springer Nature Limited.
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| 20. |
- Garcia-Gonzalez, D, et al.
(författare)
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Neurogenesis of medium spiny neurons in the nucleus accumbens continues into adulthood and is enhanced by pathological pain
- 2021
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Ingår i: Molecular psychiatry. - : Springer Science and Business Media LLC. - 1476-5578 .- 1359-4184. ; 26:9, s. 4616-4632
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Tidskriftsartikel (refereegranskat)abstract
- In mammals, most adult neural stem cells (NSCs) are located in the ventricular–subventricular zone (V-SVZ) along the wall of the lateral ventricles and they are the source of olfactory bulb interneurons. Adult NSCs exhibit an apico-basal polarity; they harbor a short apical process and a long basal process, reminiscent of radial glia morphology. In the adult mouse brain, we detected extremely long radial glia-like fibers that originate from the anterior–ventral V-SVZ and that are directed to the ventral striatum. Interestingly, a fraction of adult V-SVZ-derived neuroblasts dispersed in close association with the radial glia-like fibers in the nucleus accumbens (NAc). Using several in vivo mouse models, we show that newborn neurons integrate into preexisting circuits in the NAc where they mature as medium spiny neurons (MSNs), i.e., a type of projection neurons formerly believed to be generated only during embryonic development. Moreover, we found that the number of newborn neurons in the NAc is dynamically regulated by persistent pain, suggesting that adult neurogenesis of MSNs is an experience-modulated process.
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