| 61. |
- Thompson, Andrew G B, et al.
(författare)
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Evaluation of plasma tau and neurofilament light chain biomarkers in a 12-year clinical cohort of human prion diseases.
- 2021
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Ingår i: Molecular psychiatry. - : Springer Science and Business Media LLC. - 1476-5578 .- 1359-4184. ; 26, s. 5955-5966
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Tidskriftsartikel (refereegranskat)abstract
- Prion diseases are fatal neurodegenerative conditions with highly accurate CSF and imaging diagnostic tests, but major unmet needs for blood biomarkers. Using ultrasensitive immuno-assays, we measured tau and neurofilament light chain (NfL) protein concentrations in 709 plasma samples taken from 377 individuals with prion disease during a 12year prospective clinical study, alongside healthy and neurological control groups. This provides an unprecedented opportunity to evaluate their potential as biomarkers. Plasma tau and NfL were increased across all prion disease types. For distinguishing sCJD from control groups including clinically-relevant "CJD mimics", both show considerable diagnostic value. In sCJD, NfL was substantially elevated in every sample tested, including during early disease with minimal functional impairment and in all follow-up samples. Plasma tau was independently associated with rate of clinical progression in sCJD, while plasma NfL showed independent association with severity of functional impairment. In asymptomatic PRNP mutation carriers, plasma NfL was higher on average in samples taken within 2years of symptom onset than in samples taken earlier. We present biomarker trajectories for nine mutation carriers healthy at enrolment who developed symptoms during follow-up. NfL started to rise as early as 2years before onset in those with mutations typically associated with more slowly progressive clinical disease. This shows potential for plasma NfL as a "proximity marker", but further work is needed to establish predictive value on an individual basis, and how this varies across different PRNP mutations. We conclude that plasma tau and NfL have potential to fill key unmet needs for biomarkers in prion disease: as a secondary outcome for clinical trials (NfL and tau); for predicting onset in at-risk individuals (NfL); and as an accessible test for earlier identification of patients that may have CJD and require more definitive tests (NfL). Further studies should evaluate their performance directly in these specific roles.
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| 62. |
- van Dongen, J, et al.
(författare)
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DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan
- 2021
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Ingår i: Molecular psychiatry. - : Springer Science and Business Media LLC. - 1476-5578 .- 1359-4184. ; 26:6, s. 2148-2162
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Tidskriftsartikel (refereegranskat)abstract
- DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 × 10−7; Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3–82%) of the aggression–methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.
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| 63. |
- Wu, Hemmings, et al.
(författare)
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Deep brain stimulation for refractory obsessive-compulsive disorder (OCD) : emerging or established therapy?
- 2021
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Ingår i: Molecular Psychiatry. - : Springer Nature. - 1359-4184 .- 1476-5578. ; 26, s. 60-65
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Tidskriftsartikel (refereegranskat)abstract
- A consensus has yet to emerge whether deep brain stimulation (DBS) for treatment-refractory obsessive-compulsive disorder (OCD) can be considered an established therapy. In 2014, the World Society for Stereotactic and Functional Neurosurgery (WSSFN) published consensus guidelines stating that a therapy becomes established when "at least two blinded randomized controlled clinical trials from two different groups of researchers are published, both reporting an acceptable risk-benefit ratio, at least comparable with other existing therapies. The clinical trials should be on the same brain area for the same psychiatric indication." The authors have now compiled the available evidence to make a clear statement on whether DBS for OCD is established therapy. Two blinded randomized controlled trials have been published, one with level I evidence (Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score improved 37% during stimulation on), the other with level II evidence (25% improvement). A clinical cohort study (N = 70) showed 40% Y-BOCS score improvement during DBS, and a prospective international multi-center study 42% improvement (N = 30). The WSSFN states that electrical stimulation for otherwise treatment refractory OCD using a multipolar electrode implanted in the ventral anterior capsule region (including bed nucleus of stria terminalis and nucleus accumbens) remains investigational. It represents an emerging, but not yet established therapy. A multidisciplinary team involving psychiatrists and neurosurgeons is a prerequisite for such therapy, and the future of surgical treatment of psychiatric patients remains in the realm of the psychiatrist.
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| 64. |
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| 65. |
- Zetterberg, Henrik, 1973, et al.
(författare)
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Biomarkers for Alzheimer's disease-preparing for a new era of disease-modifying therapies.
- 2021
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Ingår i: Molecular psychiatry. - : Springer Science and Business Media LLC. - 1476-5578 .- 1359-4184. ; 26:1, s. 296-308
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Forskningsöversikt (refereegranskat)abstract
- Clinical trial results presented in 2019 suggest that antibody-based removal of cerebral amyloid β (Aβ) plaques may possibly clear tau tangles and modestly slow cognitive decline in symptomatic Alzheimer's disease (AD). Although regulatory approval of this approach is still pending, preparing the healthcare system for the advent of disease-modifying therapies against AD is imperative. In particular, it will be necessary to identify the most suitable biomarkers to facilitate appropriate treatment of AD. Here, we give an update on recent developments in fluid and imaging biomarkers for AD-related pathologies and discuss potential approaches that could be adopted to screen for and clarify the underlying pathology in people seeking medical advice because of cognitive symptoms. We succinctly review recent data regarding biomarkers for Aβ and tau pathology, neurodegeneration, synaptic dysfunction, and inflammation, highlight the need for further research into common copathologies, and suggest how different biomarkers could be used (most likely in combination) to facilitate the development and clinical implementation of novel drug candidates against AD.
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| 66. |
- Zhang, Ruyue, et al.
(författare)
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Familial co-aggregation of schizophrenia and eating disorders in Sweden and Denmark
- 2021
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Ingår i: Molecular Psychiatry. - : Nature Publishing Group. - 1359-4184 .- 1476-5578. ; 26:9, s. 5389-5397
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Tidskriftsartikel (refereegranskat)abstract
- Eating disorders and schizophrenia are both moderately to highly heritable and share significant genetic risk despite distinct diagnostic criteria. Large-scale family studies on the co-aggregation of these disorders are lacking. Thus, we aimed to estimate the co-occurrence and familial co-aggregation of these disorders within the entire Swedish and Danish population. The proband cohort consisted of individuals born in Sweden (1977-2003) and Denmark (1984-2006) and still residing in their respective country at age six (NSweden = 2,535,191, NDenmark = 1,382,367). Probands were linked to their biological parents, siblings, grandparents, uncles/aunts, and cousins. Diagnoses for anorexia nervosa (AN) and other eating disorders (OED: bulimia nervosa, binge-eating disorder, and eating disorder not otherwise specified) for probands and schizophrenia diagnoses for both probands and relatives were obtained. The likelihood of having schizophrenia in those with AN or OED and their relatives was compared with individuals without eating disorder diagnoses and their relatives. Probands with AN or OED were more likely to have schizophrenia than probands without these disorders. All relatives of probands with AN or OED (except parents and uncles/aunts of probands with AN) were at increased risk of schizophrenia. In general, the magnitude of odds ratios attenuated with decreasing genetic relatedness. These results suggest familial liability contributes to the association between eating disorders and schizophrenia. Clinicians should be mindful of this comorbid and co-aggregation pattern as it may influence case conceptualization and treatment decisions.
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| 67. |
- Zurcher, N. R., et al.
(författare)
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C-11 PBR28 MR-PET imaging reveals lower regional brain expression of translocator protein (TSPO) in young adult males with autism spectrum disorder
- 2021
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578.
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Tidskriftsartikel (refereegranskat)abstract
- Mechanisms of neuroimmune and mitochondrial dysfunction have been repeatedly implicated in autism spectrum disorder (ASD). To examine these mechanisms in ASD individuals, we measured the in vivo expression of the 18 kDa translocator protein (TSPO), an activated glial marker expressed on mitochondrial membranes. Participants underwent scanning on a simultaneous magnetic resonance-positron emission tomography (MR-PET) scanner with the second-generation TSPO radiotracer [C-11]PBR28. By comparing TSPO in 15 young adult males with ASD with 18 age- and sex-matched controls, we showed that individuals with ASD exhibited lower regional TSPO expression in several brain regions, including the bilateral insular cortex, bilateral precuneus/posterior cingulate cortex, and bilateral temporal, angular, and supramarginal gyri, which have previously been implicated in autism in functional MR imaging studies. No brain region exhibited higher regional TSPO expression in the ASD group compared with the control group. A subset of participants underwent a second MR-PET scan after a median interscan interval of 3.6 months, and we determined that TSPO expression over this period of time was stable and replicable. Furthermore, voxelwise analysis confirmed lower regional TSPO expression in ASD at this later time point. Lower TSPO expression in ASD could reflect abnormalities in neuroimmune processes or mitochondrial dysfunction.
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| 68. |
- Zwir, Igor, et al.
(författare)
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Three Genetic-Environmental Networks for Human Personality
- 2021
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 26, s. 3858-3875
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Tidskriftsartikel (refereegranskat)abstract
- Phylogenetic, developmental, and brain-imaging studies suggest that human personality is the integrated expression of three major systems of learning and memory that regulate (1) associative conditioning, (2) intentionality, and (3) self-awareness. We have uncovered largely disjoint sets of genes regulating these dissociable learning processes in different clusters of people with (1) unregulated temperament profiles (i.e., associatively conditioned habits and emotional reactivity), (2) organized character profiles (i.e., intentional self-control of emotional conflicts and goals), and (3) creative character profiles (i.e., self-aware appraisal of values and theories), respectively. However, little is known about how these temperament and character components of personality are jointly organized and develop in an integrated manner. In three large independent genome-wide association studies from Finland, Germany, and Korea, we used a data-driven machine learning method to uncover joint phenotypic networks of temperament and character and also the genetic networks with which they are associated. We found three clusters of similar numbers of people with distinct combinations of temperament and character profiles. Their associated genetic and environmental networks were largely disjoint, and differentially related to distinct forms of learning and memory. Of the 972 genes that mapped to the three phenotypic networks, 72% were unique to a single network. The findings in the Finnish discovery sample were blindly and independently replicated in samples of Germans and Koreans. We conclude that temperament and character are integrated within three disjoint networks that regulate healthy longevity and dissociable systems of learning and memory by nearly disjoint sets of genetic and environmental influences.
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