| 1. |
- Sønderby, Ida E., et al.
(författare)
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1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans
- 2021
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Ingår i: Translational Psychiatry. - : Nature Publishing Group. - 2158-3188. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.
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| 2. |
- van der Meer, Dennis, et al.
(författare)
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Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition
- 2020
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Ingår i: JAMA psychiatry. - : American Medical Association (AMA). - 2168-6238 .- 2168-622X. ; 77:4, s. 420-430
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Recurrent microdeletions and duplications in the genomic region 15q11.2 between breakpoints 1 (BP1) and 2 (BP2) are associated with neurodevelopmental disorders. These structural variants are present in 0.5% to 1.0% of the population, making 15q11.2 BP1-BP2 the site of the most prevalent known pathogenic copy number variation (CNV). It is unknown to what extent this CNV influences brain structure and affects cognitive abilities.Objective: To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance.Design, Setting, and Participants: In this genetic association study, T1-weighted brain magnetic resonance imaging were combined with genetic data from the ENIGMA-CNV consortium and the UK Biobank, with a replication cohort from Iceland. In total, 203 deletion carriers, 45 247 noncarriers, and 306 duplication carriers were included. Data were collected from August 2015 to April 2019, and data were analyzed from September 2018 to September 2019.Main Outcomes and Measures: The associations of the CNV with global and regional measures of surface area and cortical thickness as well as subcortical volumes were investigated, correcting for age, age2, sex, scanner, and intracranial volume. Additionally, measures of cognitive ability were analyzed in the full UK Biobank cohort.Results: Of 45 756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23 754 (51.9%) were female. Compared with noncarriers, deletion carriers had a lower surface area (Cohen d = -0.41; SE, 0.08; P = 4.9 × 10-8), thicker cortex (Cohen d = 0.36; SE, 0.07; P = 1.3 × 10-7), and a smaller nucleus accumbens (Cohen d = -0.27; SE, 0.07; P = 7.3 × 10-5). There was also a significant negative dose response on cortical thickness (β = -0.24; SE, 0.05; P = 6.8 × 10-7). Regional cortical analyses showed a localization of the effects to the frontal, cingulate, and parietal lobes. Further, cognitive ability was lower for deletion carriers compared with noncarriers on 5 of 7 tasks.Conclusions and Relevance: These findings, from the largest CNV neuroimaging study to date, provide evidence that 15q11.2 BP1-BP2 structural variation is associated with brain morphology and cognition, with deletion carriers being particularly affected. The pattern of results fits with known molecular functions of genes in the 15q11.2 BP1-BP2 region and suggests involvement of these genes in neuronal plasticity. These neurobiological effects likely contribute to the association of this CNV with neurodevelopmental disorders.
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| 3. |
- Sonderby, Ida E., et al.
(författare)
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Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia
- 2020
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Ingår i: Molecular Psychiatry. - : Nature Publishing Group. - 1359-4184 .- 1476-5578. ; 25:3, s. 584-602
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Tidskriftsartikel (refereegranskat)abstract
- Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = −0.71 to −1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = −0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10−6, 1.7 × 10−9, 3.5 × 10−12 and 1.0 × 10−4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes.
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| 4. |
- Kaufmann, Tobias, et al.
(författare)
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Common brain disorders are associated with heritable patterns of apparent aging of the brain
- 2019
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Ingår i: Nature Neuroscience. - : Nature Publishing Group. - 1097-6256 .- 1546-1726. ; 22:10, s. 1617-
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Tidskriftsartikel (refereegranskat)abstract
- Common risk factors for psychiatric and other brain disorders are likely to converge on biological pathways influencing the development and maintenance of brain structure and function across life. Using structural MRI data from 45,615 individuals aged 3-96 years, we demonstrate distinct patterns of apparent brain aging in several brain disorders and reveal genetic pleiotropy between apparent brain aging in healthy individuals and common brain disorders.
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| 5. |
- Myrum, Craig, et al.
(författare)
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Common variants in the ARC gene are not associated withcognitive abilities
- 2015
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Ingår i: Brain and Behavior. - : Wiley. - 2162-3279. ; 5:10
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The Activity-Regulated Cytoskeleton-associated (ARC) gene encodes a protein that is critical for the consolidation of synaptic plasticity and long-term memory formation. Given ARC's key role in synaptic plasticity, we hypothesized that genetic variations in ARC may contribute to interindividual variability in human cognitive abilities or to attention-deficit hyperactivity disorder (ADHD) susceptibility, where cognitive impairment often accompanies the disorder. Methods: We tested whether ARC variants are associated with six measures of cognitive functioning in 670 healthy subjects in the Norwegian Cognitive NeuroGenetics (NCNG) by extracting data from its Genome-Wide Association Study (GWAS). In addition, the Swedish Betula sample of 1800 healthy subjects who underwent similar cognitive testing was also tested for association with 19 tag SNPs. Results: No ARC variants show association at the study-wide level, but several markers show a trend toward association with human cognitive functions. We also tested for association between ARCSNPs and ADHD in a Norwegian sample of cases and controls, but found no significant associations. Conclusion: This study suggests that common genetic variants located in ARC do not account for variance in human cognitive abilities, though small effects cannot be ruled out.
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| 6. |
- Wehling, Eike, et al.
(författare)
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Does it matter how we pose the question "How is your sense of smell?"
- 2014
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Ingår i: Chemosensory Perception. - : Springer Science and Business Media LLC. - 1936-5802 .- 1936-5810. ; 7:3-4, s. 103-107
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Tidskriftsartikel (refereegranskat)abstract
- There is a rather large, and unfortunate, discrepancy in the outcome between self-reported and standardized assessment of olfactory function. Questions for self-evaluation are commonly used that provide no information of with what to compare (comparison target) one's olfactory function. We therefore investigated whether responses differed between an unspecific question and two questions providing comparison targets. Ninety-six healthy community-dwelling individuals (62.5 % women) aged 49-80 years evaluated their odor identification ability, followed by standardized assessment of odor identification ability. Results revealed that response patterns varied significantly depending on comparison target. While 81 % reported normal function when no further comparison target was presented, 69 % reported normal function when referring to age-related olfactory changes in identification ability. In turn, sensitivity of the accuracy of self-reported reduced odor identification ability (with standardized assessment as reference) increased from 11 to 37 %, whereas specificity decreased from 86 to 71 % when providing a comparison target. Accuracy of self-reported olfactory function can be increased by including a comparison target. However, standardized assessment is to be preferred over self-reported assessment, irrespective of how the question is formulated.
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| 7. |
- Wehling, Eike, et al.
(författare)
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Even cognitively well-functioning adults are unaware of their olfactory dysfunction : Implications for ENT clinicians and researchers
- 2015
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Ingår i: Rhinology. - Utrecht, Netherlands : International Rhinologic Society. - 0300-0729 .- 1996-8604. ; 53:1, s. 89-94
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Tidskriftsartikel (refereegranskat)abstract
- Background: Past findings of an impact of cognitive impairment on awareness of olfactory dysfunction, and high prevalence of age-associated cognitive impairment motivated the present study of whether middle-aged and elderly adults are unaware of an olfactory dysfunction despite being carefully screened for cognitive impairment. Methodology: The sample included 203 Norwegian participants, aged 46-79 years, 134 women and 69 men, who underwent comprehensive neuropsychological assessment for screening of cognitive impairment. Subjective assessment of olfactory function ("How would you estimate your sense of smell?") was compared with outcome on objective assessment of olfactory function with the Scandinavian Odor Identification Test, which in the present study was shown to be valid for use on Norwegian populations. Results: We found that 79% of this cognitively healthy sample with objectively assessed olfactory dysfunction reported normal olfactory function (57% of functionally anosmics reported normal function). In contrast, only 9% with objectively assessed normal olfactory function reported olfactory dysfunction. Conclusion: A large proportion of cognitively well-functioning middle-aged and elderly adults with an olfactory dysfunction are unaware of their dysfunction.The ENT physician who suspects that the sense of smell may be compromised should, in addition to an anamnesis, assess the patient's olfactory function objectively.
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| 8. |
- Wehling, Eike I., et al.
(författare)
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Longitudinal Changes in Familiarity, Free and Cued Odor Identification, and Edibility Judgments for Odors in Aging Individuals
- 2016
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Ingår i: Chemical Senses. - : Oxford University Press (OUP). - 0379-864X .- 1464-3553. ; 41:2, s. 155-161
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Tidskriftsartikel (refereegranskat)abstract
- This longitudinal study investigated changes in olfaction as assessed by a set of tasks requiring different aspects of semantic information in normal aging individuals. Using 16 odorous items from a standardized olfactory test, the Scandinavian Odor Identification Test, 107 middle aged and older adults were assessed up to three times over a period of 6.5 years, requesting them to rate familiarity and edibility for each odorous item before identifying it with or without presenting verbal cues. Using linear mixed models, the longitudinal analyses revealed significant correlations between all olfactory measures. Furthermore, we found an almost parallel age-related decline in all olfactory tasks, although free identification performance indicated a trend toward faster decline with age. Women showed less decline compared with men, in particular for edibility judgments. The results corroborate earlier cross-sectional findings showing significant correlations between the olfactory tasks. In the present study of healthy middle-aged and older adults, we found a parallel longitudinal decline across different tests of olfaction.
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| 9. |
- Wehling, Eike I., et al.
(författare)
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Longitudinal Changes in Odor Identification Performance and Neuropsychological Measures in Aging Individuals
- 2016
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Ingår i: Neuropsychology. - : American Psychological Association (APA). - 0894-4105 .- 1931-1559. ; 30:1, s. 87-97
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To examine changes in odor identification performance and cognitive measures in healthy aging individuals. While cross-sectional studies reveal associations between odor identification and measures of episodic memory, processing speed, and executive function, longitudinal studies so far have been ambiguous with regard to demonstrating that odor identification may be predictive of decline in cognitive function.Method: One hundred and 7 healthy aging individuals (average age 60.2 years, 71% women) were assessed with an odor identification test and nonolfactory cognitive measures of verbal episodic memory, mental processing speed, executive function, and language 3 times, covering a period of 6.5 years.Results: The cross-sectional results revealed odor identification performance to be associated with age, measures of verbal episodic memory, and processing speed. Using linear mixed models, the longitudinal analyses revealed age-associated decline in all measures. Controlling for retest effects, the analyses demonstrated that gender was a significant predictor for episodic memory and mental processing speed. Odor identification performance was further shown to be a significant predictor for episodic verbal memory.Conclusion: This study shows age-related decline in odor identification as well as nonolfactory cognitive measures. The finding showing that odor identification is a significant predictor for verbal episodic memory is of great clinical interest as odor identification has been suggested as a sensitive measure of incipient pathologic cognitive decline.
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| 10. |
- Wehling, Eike, et al.
(författare)
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Unawareness of olfactory dysfunction and its association with cognitive functioning in middle aged and old adults
- 2011
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Ingår i: Archives of clinical neuropsychology. - : Oxford University Press. - 0887-6177 .- 1873-5843. ; 26:3, s. 260-269
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Tidskriftsartikel (refereegranskat)abstract
- The objective of this study was (a) to investigate the accordance of self-reported and objectively assessed olfactory functioning and (b) to compare performance on cognitive tests of individuals unaware of their olfactory dysfunction with individuals aware of their olfactory status. Two hundred forty participants, constituting two age groups, were evaluated with the Scandinavian Odor Identification Test, a question of self-evaluated olfactory function, tests of cognitive function, and a memory questionnaire. The proportion of individuals being unaware of an olfactory dysfunction was high in both middle aged (86%) and old (78%) participants. Performance on neuropsychological tests showed that persons unaware of their olfactory dysfunction performed poorer on tests of verbal learning and memory and attention/processing speed compared to individuals aware of a normal olfactory status as well as individuals aware of their olfactory dysfunction. The clinical relevance of unawareness of olfactory dysfunction, as suggested earlier, needs further investigation and stresses the need of an extensive multi-modal and longitudinal assessment of unawareness of sensory and cognitive function to learn more about the facets of the concept of unawareness.
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