Publications by authors named "Henrik Larsson"

469 Publications

Interictal pontine metabolism in migraine without aura patients: A 3 Tesla proton magnetic resonance spectroscopy study.

Neuroimage Clin 2021 Sep 20;32:102824. Epub 2021 Sep 20.

Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, Glostrup, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark. Electronic address:

In the pons, glutamatergic mechanisms are involved in regulating inhibitory descending pain modulation, serotoninergic neurotransmission as well as modulating the sensory transmission of the trigeminovascular system. Migraine involves altered pontine activation and structural changes, while biochemical, genetic and clinical evidence suggests that altered interictal pontine glutamate levels may be an important pathophysiological feature of migraine abetting to attack initiation. Migraine without aura patients were scanned outside attacks using a proton magnetic resonance spectroscopy protocol optimized for the pons at 3 Tesla. The measurements were performed on two separate days to increase accuracy and compared to similar repeated measurements in healthy controls. We found that interictal glutamate (i.e. Glx) levels in the pons of migraine patients (n = 33) were not different from healthy controls (n = 16) (p = 0.098), while total creatine levels were markedly increased in patients (9%, p = 0.009). There was no correlation of glutamate or total creatine levels to migraine frequency, days since the last attack, usual pain intensity of attacks or disease duration. In conclusion, migraine is not associated with altered interictal pontine glutamate levels. However, the novel finding of increased total creatine levels suggests that disequilibrium in the pontine energy metabolism could be an important feature of migraine pathophysiology.
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http://dx.doi.org/10.1016/j.nicl.2021.102824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8498457PMC
September 2021

Attention-deficit/hyperactivity disorder and Alzheimer's disease and any dementia: A multi-generation cohort study in Sweden.

Alzheimers Dement 2021 Sep 9. Epub 2021 Sep 9.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Introduction: We examined the extent to which attention-deficit/hyperactivity disorder (ADHD), a neurodevelopmental disorder, is linked with Alzheimer's disease (AD) and any dementia, neurodegenerative diseases, across generations.

Methods: A nationwide cohort born between 1980 and 2001 (index persons) were linked to their biological relatives (parents, grandparents, uncles/aunts) using Swedish national registers. We used Cox models to examine the cross-generation associations.

Results: Among relatives of 2,132,929 index persons, 3042 parents, 171,732 grandparents, and 1369 uncles/aunts had a diagnosis of AD. Parents of individuals with ADHD had an increased risk of AD (hazard ratio 1.55, 95% confidence interval 1.26-1.89). The associations attenuated but remained elevated in grandparents and uncles/aunts. The association for early-onset AD was stronger than late-onset AD. Similar results were observed for any dementia.

Discussion: ADHD is associated with AD and any dementia across generations. The associations attenuated with decreasing genetic relatedness, suggesting shared familial risk between ADHD and AD.
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http://dx.doi.org/10.1002/alz.12462DOI Listing
September 2021

Human Cerebral Perfusion, Oxygen Consumption, and Lactate Production in Response to Hypoxic Exposure.

Cereb Cortex 2021 Aug 27. Epub 2021 Aug 27.

Functional Imaging Unit, Department of Clinical Physiology, Nuclear Medicine, and PET, Copenhagen University Hospital Rigshospitalet, Glostrup 2600, Denmark.

Exposure to moderate hypoxia in humans leads to cerebral lactate production, which occurs even when the cerebral metabolic rate of oxygen (CMRO2) is unaffected. We searched for the mechanism of this lactate production by testing the hypothesis of upregulation of cerebral glycolysis mediated by hypoxic sensing. Describing the pathways counteracting brain hypoxia could help us understand brain diseases associated with hypoxia. A total of 65 subjects participated in this study: 30 subjects were exposed to poikilocapnic hypoxia, 14 were exposed to isocapnic hypoxia, and 21 were exposed to carbon monoxide (CO). Using this setup, we examined whether lactate production reacts to an overall reduction in arterial oxygen concentration or solely to reduced arterial oxygen partial pressure. We measured cerebral blood flow (CBF), CMRO2, and lactate concentrations by magnetic resonance imaging and spectroscopy. CBF increased (P < 10-4), whereas the CMRO2 remained unaffected (P > 0.076) in all groups, as expected. Lactate increased in groups inhaling hypoxic air (poikilocapnic hypoxia: $0.0136\ \frac{\mathrm{mmol}/\mathrm{L}}{\Delta{\mathrm{S}}_{\mathrm{a}}{\mathrm{O}}_2}$, P < 10-6; isocapnic hypoxia: $0.0142\ \frac{\mathrm{mmol}/\mathrm{L}}{\Delta{\mathrm{S}}_{\mathrm{a}}{\mathrm{O}}_2}$, P = 0.003) but was unaffected by CO (P = 0.36). Lactate production was not associated with reduced CMRO2. These results point toward a mechanism of lactate production by upregulation of glycolysis mediated by sensing a reduced arterial oxygen pressure. The released lactate may act as a signaling molecule engaged in vasodilation.
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http://dx.doi.org/10.1093/cercor/bhab294DOI Listing
August 2021

Association of Tourette Syndrome and Chronic Tic Disorder With Cervical Spine Disorders and Related Neurological Complications.

JAMA Neurol 2021 Oct;78(10):1205-1211

Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, & Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden.

Importance: Severe forms of Tourette syndrome or chronic tic disorder (TS/CTD) may involve repeated head jerking. Isolated case reports have described a spectrum of severe neck disorders in individuals with TS/CTD. However, the nature and prevalence of cervical spine disorders in TS/CTD are unknown.

Objective: To establish if TS/CTD are associated with an increased risk of cervical spine disorders and related neurological complications compared with individuals from the general population.

Design, Setting, And Participants: All individuals born from 1973 to 2013 and living in Sweden between 1997 and 2013 were identified. Individuals with a record of TS/CTD diagnosed in specialist settings were matched on age, sex, and county of birth with 10 unexposed individuals randomly selected from the general population. Cox proportional hazards regression models were used to estimate the risk of vascular and nonvascular cervical spine disorders among exposed individuals, compared with unexposed individuals. Models were adjusted for other known causes of cervical spine injury. Data were analyzed from March 19 to May 16, 2021.

Exposures: International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnoses of TS/CTD in the Swedish National Patient Register.

Main Outcomes And Measures: Records of cervical vascular disorders (ie, aneurysm, cerebral infarction, transitory cerebral ischemia) and cervical nonvascular disorders (ie, spondylosis, cervical disc disorders, fractures of the cervical spine, cervicalgia) and cervical surgeries. Covariates included rheumatic disorders, traffic injuries, fall- or sport-related injuries, and attention-deficit/hyperactivity disorder comorbidity.

Results: A total of 6791 individuals with TS/CTD were identified (5238 [77.1%] were male; median [interquartile] age at first diagnosis, 15.6 [11.4-23.7] years) and matched to 67 910 unexposed individuals. Exposed individuals had a 39% increased risk of any cervical spine disorder (adjusted hazard ratio, 1.39; 95% CI, 1.22-1.59). Adjusted hazard ratios for cervical vascular and nonvascular disorders were 1.57 (95% CI, 1.16-2.13) and 1.38 (95% CI, 1.19-1.60), respectively. Risks were similar among men and women.

Conclusions And Relevance: Individuals with severe TS/CTD are at increased risk of cervical spine disorders. These outcomes are relatively rare but may lead to persistent disability in some individuals and thus require close monitoring to facilitate early interventions.
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http://dx.doi.org/10.1001/jamaneurol.2021.2798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8383162PMC
October 2021

Investigation of cortical thickness and volume during spontaneous attacks of migraine without aura: a 3-Tesla MRI study.

J Headache Pain 2021 Aug 21;22(1):98. Epub 2021 Aug 21.

Danish Headache Center, Department of Neurology, Faculty of Health and Medical Sciences, Rigshospitalet Glostrup, University of Copenhagen, Valdemar Hansens Vej 5, 2600, Glostrup, Denmark.

Background: Structural imaging has revealed changes in cortical thickness in migraine patients compared to healthy controls is reported, but presence of dynamic cortical and subcortical changes during migraine attack versus inter-ictal phase is unknown. The aim of the present study was to investigate possible changes in cortical thickness during spontaneous migraine attacks. We hypothesized that pain-related cortical area would be affected during the attack compared to an inter-ictal phase.

Methods: Twenty-five patients with migraine without aura underwent three-dimensional T1-weighted imaging on a 3-Tesla MRI scanner during spontaneous and untreated migraine attacks. Subsequently, 20 patients were scanned in the inter-ictal phase, while 5 patients did not show up for the inter-ictal scan. Four patients were excluded from the analysis because of bilateral migraine pain and another one patient was excluded due to technical error in the imaging. Longitudinal image processing was done using FreeSurfer. Repeated measures ANOVA was used for statistical analysis and to control for multiple comparison the level of significance was set at p = 0.025.

Results: In a total of 15 patients, we found reduced cortical thickness of the precentral (p = 0.023), pericalcarine (p = 0.024), and temporal pole (p = 0.017) cortices during the attack compared to the inter-ictal phase. Cortical volume was reduced in prefrontal (p = 0.018) and pericalcarine (p = 0.017) cortices. Hippocampus volume was increased during attack (p = 0.007). We found no correlations between the pain side or any other clinical parameters and the reduced cortical size.

Conclusion: Spontaneous migraine attacks are accompanied by transient reduced cortical thickness and volume in pain-related areas. The findings constitute a fingerprint of acute pain in migraine patients, which can be used as a possible biomarker to predict antimigraine treatment effect in future studies.

Trial Registration: The study was registered at ClinicalTrials.gov ( NCT02202486 ).
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http://dx.doi.org/10.1186/s10194-021-01312-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380396PMC
August 2021

Low autonomic arousal as a risk factor for reoffending: A population-based study.

PLoS One 2021 20;16(8):e0256250. Epub 2021 Aug 20.

School of Psychology, Law and Social Work, Örebro University, Örebro, Sweden.

Background: Low resting heart rate (RHR) and low systolic blood pressure (SBP) are associated with criminal behavior. However, knowledge is lacking about their predictive value for reoffending.

Aim: We aimed to examine associations of RHR and SBP with reoffending in a large population-based sample.

Methods: We conducted a cohort study of all convicted male conscripts born in Sweden 1958-1990 (N = 407,533). We obtained data by linking Swedish population-based registers. Predictor variables were RHR and SBP, measured at conscription which was mandatory until 2010 for men at age 18. The outcome variable was reoffending, defined as criminal convictions (any crime, violent crime and non-violent crime), obtained from the National Crime Register. We used survival analyses to test for associations of RHR and SBP with reoffending, adjusting for pertinent covariates such as socioeconomic status, height, weight and physical energy capacity.

Results: In fully adjusted Cox regression models, men with lower RHR (≤60 bpm) had higher risk of reoffending (any crime: HR = 1.17, 95% CI: 1.14, 1.19, violent crime: HR = 1.23, 95% CI: 1.17, 1.29, non-violent crime: HR = 1.16, 95% CI: 1.14, 1.19), compared to men with higher RHR (≥ 82 bpm). Men with lower SBP (≤80 mmHg) had higher risk of reoffending (any crime: HR = 1.19, 95% CI: 1.17, 1.21, violent crime: HR = 1.16, 95% CI: 1.12, 1.20, non-violent crime: HR = 1.20, 95% CI: 1.18, 1.22), compared to men with higher SBP (≥138 mmHg).

Conclusions: Low autonomic arousal is associated with increased risk of reoffending. RHR and SBP should be investigated further as potential predictors for reoffending as they each may have predictive value in risk assessment protocols.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0256250PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8378731PMC
August 2021

Familial and genetic associations between autism spectrum disorder and other neurodevelopmental and psychiatric disorders.

J Child Psychol Psychiatry 2021 Aug 20. Epub 2021 Aug 20.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Background: Familial and genetic associations between autism spectrum disorder (ASD) and other neurodevelopmental and psychiatric disorders have been reported, sometimes with conflicting results. We estimated familial and genetic associations between ASD and nine disorder groups, and explored differences in these associations for ASD in the context of intellectual disability, epilepsy, chromosomal abnormalities, and congenital malformations.

Methods: Individuals born between 1985 and 2009 living in Sweden on their seventh birthday were linked to their biological parents in order to identify different types of relatives. We retrieved information on all the disorders considered from the National Patient Register. Logistic regression was used to estimate the familial association between ASD and other neurodevelopmental and psychiatric disorders in the different groups of relatives. Structural equation modeling was used to estimate phenotypic (r ) and genetic associations (r ), as well as the contribution of genetic influences to r .

Results: The study included 2,398,608 individuals. Among relatives of individuals diagnosed with ASD, there was an increased risk of the disorders considered, compared to relatives of individuals who were not diagnosed with ASD. Stronger associations were detected for ASD without any additional diagnosis of intellectual disability, epilepsy, chromosomal abnormalities, and congenital malformations. The strongest genetic correlation was estimated between ASD and other neurodevelopmental disorders (r  = 0.73; 95% CI = 0.66-0.79). Moderate genetic correlations were estimated for anxiety disorders (r  = 0.47; 95% CI = 0.33-0.61), depression (r  = 0.52; 95% CI = 0.37-0.66), and intentional self-harm (r  = 0.54; 95% CI = 0.36-0.71).

Conclusions: ASD shows familial and genetic association not only with other neurodevelopmental disorders, but also with other psychiatric disorders, such as anxiety, depression, and intentional self-harm. Family history of ASD comorbid with intellectual disability, epilepsy, congenital malformations, or chromosomal abnormalities is less related to other psychiatric disorders, potentially suggesting a different etiology for this subgroup of patients.
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http://dx.doi.org/10.1111/jcpp.13508DOI Listing
August 2021

The Combined Effects of Young Relative Age and Attention-Deficit/Hyperactivity Disorder on Negative Long-Term Outcomes.

J Am Acad Child Adolesc Psychiatry 2021 Aug 10. Epub 2021 Aug 10.

Karolinska Institutet, Stockholm, Sweden.

Objective: Young relative age (ie, being among the youngest in a school class) and attention-deficit/hyperactivity disorder (ADHD) are both potential risk factors for adverse long-term outcomes. Young relative age also increases the risk of ADHD diagnosis. Using data from Swedish national registers, we investigate the independent and joint long-term effects of young relative age and ADHD on educational achievement, substance use disorder (SUD), criminality, and depression.

Method: We identified a national cohort of individuals with young relative age (born November-December) and a comparison group with old relative age (born January-February). Of the total sample of 297,840 individuals, 6,528 individuals had a diagnosis of ADHD in childhood. The 4 outcomes were measured at ages 15 to 23 years. We examined main, additive, and interactive effects of young relative age and ADHD on long-term outcomes.

Results: In the individuals without ADHD, young relative age was associated with increased risk of depression (odds ratio [OR] = 1.14 [95% CI =1.09-1.20]), SUD (OR = 1.14 [1.09-1.20]), and low educational achievement (OR = 1.17 [1.14-1.20]), but not criminality (OR = 1.00 [0.98-1.03]). In the individuals with ADHD, young relative age was associated with increased risk of SUD (OR = 1.23 [1.01-1.50]) and low educational achievement (OR = 1.12 [1.00-0.26]; CI included 1), but not depression or criminality (OR = 0.88 [0.73-1.07] and OR = 0.89 [0.79-1.01], respectively). An interaction emerged between young relative age and ADHD for depression (OR = 0.78 [0.64-0.95]).

Conclusion: We observed relative age effects that add to the evidence supporting a more flexible approach to school starting age and that emphasize the importance of careful age-match comparisons during assessment of childhood ADHD symptoms.
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http://dx.doi.org/10.1016/j.jaac.2021.07.002DOI Listing
August 2021

Acute effects of dapagliflozin on renal oxygenation and perfusion in type 1 diabetes with albuminuria: A randomised, double-blind, placebo-controlled crossover trial.

EClinicalMedicine 2021 Jul 28;37:100895. Epub 2021 Jun 28.

Steno Diabetes Center Copenhagen, Denmark.

Background: Inhibitors of the sodium-glucose cotransporter 2 (SGLT2) slow the progression of diabetic kidney disease, possibly by reducing the proximal tubule transport workload with subsequent improvement of renal oxygenation. We aimed to test this hypothesis in individuals with type 1 diabetes and albuminuria.

Methods: A randomised, double-blind, placebo-controlled, crossover trial with a single 50 mg dose of the SGLT2 inhibitor dapagliflozin and placebo in random order, separated by a two-week washout period. Magnetic resonance imaging (MRI) was used to assess renal R* (a low value corresponds to a high tissue oxygenation), renal perfusion (arterial spin labelling) and renal artery flow (phase contrast imaging) at baseline, three- and six hours from tablet ingestion. Exploratory outcomes, including baroreflex sensitivity, peripheral blood oxygen saturation, peripheral blood mononuclear cell mitochondrial oxygen consumption rate, and biomarkers of inflammation were evaluated at baseline and 12 h from medication. The study is registered in the EU Clinical Trials Register (EudraCT 2019-004,557-92), on ClinicalTrials.gov (NCT04193566), and is completed.

Findings: Between February 3, 2020 and October 23, 2020, 31 individuals were screened, and 19 eligible individuals were randomised. Three dropped out before receiving any of the interventions and one dropped out after receiving only placebo. We included 15 individuals (33% female) in the per-protocol analysis with a mean age of 58 (SD 14) years, median urinary albumin creatinine ratio of 46 [IQR 21-58] mg/g and an eGFR of 73 (32) ml/min/1·73m. The mean changes in renal cortical R* from baseline to six hours were for dapagliflozin -1·1 (SD 0·7) s and for placebo +1·3 (0·7) s, resulting in a difference between interventions of -2·3 s [95% CI -4·0 to -0·6];  = 0·012. No between-intervention differences were found in any other MRI outcomes, physiological parameters or exploratory outcomes. There were no adverse events.

Interpretation: A single dose of 50 mg dapagliflozin acutely improved renal cortical R* without changing renal perfusion or blood flow. This suggests improved renal cortical oxygenation due to a reduced tubular transport workload in the proximal tubules. Such improved oxygenation may in part explain the long-term beneficial renal effects seen with SGLT2 inhibitors, but it remains to be determined whether the observed effects can be achieved with lower doses, with chronic treatment and if they occur in type 2 diabetes as well.
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http://dx.doi.org/10.1016/j.eclinm.2021.100895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8343250PMC
July 2021

Familial co-aggregation of attention-deficit/hyperactivity disorder and autoimmune diseases: a cohort study based on Swedish population-wide registers.

Int J Epidemiol 2021 Aug 11. Epub 2021 Aug 11.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Background: Attention-deficit/hyperactivity disorder (ADHD) has been associated with several autoimmune diseases (AD), both within individuals and across relatives, implying common underlying genetic or environmental factors in line with studies indicating that immunological mechanisms are key to brain development. To further elucidate the relationship between ADHD and autoimmunity we performed a population-wide familial co-aggregation study.

Methods: We linked Swedish national registries, defined a birth cohort with their biological relatives and identified individuals diagnosed with ADHD and/or 13 ADs. The cohort included 5 178 225 individuals born between 1960 and 2010, of whom 118 927 (2.30%) had been diagnosed with ADHD. We then investigated the associations between ADHD and ADs within individuals and across relatives, with logistic regression and structural equation modelling.

Results: Within individuals, ADHD was associated with a diagnosis of any of the 13 investigated ADs (adjusted odds ratio (OR) =1.34, 95% confidence interval (CI) = 1.30-1.38) as well as several specific ADs. Familial co-aggregation was observed. For example, ADHD was associated with any of the 13 ADs in mothers (OR = 1.29, 95% CI = 1.26-1.32), fathers (OR = 1.14, 95% CI = 1.11-1.18), full siblings (OR = 1.19, 95% CI = 1.15-1.22), aunts (OR = 1.12, 95% CI = 1.10-1.15), uncles (OR = 1.07, 95% CI = 1.05-1.10) and cousins (OR = 1.04, 95% CI = 1.03-1.06). Still, the absolute risks of AD among those with ADHD were low. The genetic correlation between ADHD and a diagnosis of any of the investigated ADs was 0.13 (95% CI = 0.09-0.17) and the environmental correlation was 0.02 (95% CI = -0.03-0.06).

Conclusions: We found that ADHD and ADs co-aggregate among biological relatives, indicating that the relationship between ADHD and autoimmune diseases may in part be explained by shared genetic risk factors. The patterns of familial co-aggregation of ADHD and ADs do not readily support a role of maternal immune activation in the aetiology of ADHD. The findings have implications for aetiological models of ADHD. However, screening for autoimmunity among individuals with ADHD is not warranted.
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http://dx.doi.org/10.1093/ije/dyab151DOI Listing
August 2021

Perceived child impairment and the 'autism epidemic'.

J Child Psychol Psychiatry 2021 Aug 7. Epub 2021 Aug 7.

Gillberg Neuropsychiatry Centre, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.

Background: The prevalence of diagnosed Autism Spectrum Disorder (ASD) has increased substantially across the world. Much - or even most - prevalence increase seems to reflect changes in diagnostic practice and ascertainment. A key part of ASD assessment is to document that the relevant symptoms are associated with clinical impairment. The aim of the present study is to capitalize on a nationwide longitudinal study spanning 15 consecutive birth year cohorts in order to investigate whether there has been a secular change in how parents perceive the impairment and suffering conferred by autism symptomatology in their children.

Methods: Data came from the Child and Adolescent Twin Study in Sweden (27,240 individuals), where parents had reported on their child's ASD symptoms and impairment. Impairment due to ASD symptoms was regressed on an ASD symptom score across time. This was done for five 3-year birth cohorts (1995-1997, 1998-2000, 2001-2003, 2004-2006, and 2007-2009).

Results: Reported impairment increased with consecutively later birth cohorts. This was evident across all levels of autism symptomatology. At clinically relevant levels of symptomatology, parents of those born 2007-2009 reported a 23% higher degree of impairment as compared with parents of those born in 1995-1997. The relative difference, however, was even greater at levels that previously would have been considered below the diagnostic threshold.

Discussion: The results presented here contribute to the notion of a growing diffuseness in the conceptualization of the ASD diagnosis by adding the element of secular changes in the parental perception of the consequences of ASD symptom expression.
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http://dx.doi.org/10.1111/jcpp.13497DOI Listing
August 2021

Genetic association study of childhood aggression across raters, instruments, and age.

Transl Psychiatry 2021 07 30;11(1):413. Epub 2021 Jul 30.

Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGG) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGG. The gene-based analysis returned three significant genes: ST3GAL3 (P = 1.6E-06), PCDH7 (P = 2.0E-06), and IPO13 (P = 2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (r) among rater-specific assessment of AGG ranged from r = 0.46 between self- and teacher-assessment to r = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range [Formula: see text]: 0.19-1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (r = ~-0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range [Formula: see text]: 0.46-0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.
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http://dx.doi.org/10.1038/s41398-021-01480-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324785PMC
July 2021

Mortality among family members of patients with amyotrophic lateral sclerosis - a Swedish register-based study.

Amyotroph Lateral Scler Frontotemporal Degener 2021 Jul 23:1-10. Epub 2021 Jul 23.

Unit of Integrative Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

: To test two hypotheses: (1) partners of ALS patients have higher mortality due to outcomes related to psychological distress, and (2) parents and siblings of ALS patients have higher mortality due to diseases that co-occur with ALS. We performed a nationwide, register-based cohort study in Sweden. We included ALS-free partners, biological parents and full siblings ( = 11,704) of ALS patients, as well as ALS-free partners, biological parents and full siblings ( = 14,460,150) of ALS-free individuals, and followed them during 1961-2013. Hazard ratios (HRs) and 95% confidence intervals (CIs) of overall and cause-specific mortality were derived from Cox regression. Partners of ALS patients, compared to partners of ALS-free individuals, displayed higher mortality due to external causes (HR 2.14; 95% CI 1.35-3.41), including suicide (HR 2.44; 95% CI 1.09-5.44) and accidents (HR 2.09; 95% CI 1.12-3.90), after diagnosis of the ALS patients. Parents of ALS patients had a slightly higher overall mortality (HR 1.03; 95% CI 1.00-1.07), compared with parents of ALS-free individuals. This was driven by mortality due to dementias and cardiovascular, respiratory, and skin diseases. Parents of ALS patients had, however, lower mortality than parents of ALS-free individuals due to neoplasms. Siblings of ALS patients had higher mortality due to dementias, and digestive and skin diseases. Increased mortality due to suicide and accidents among partners of ALS patients is likely attributable to severe psychological distress following the ALS diagnosis. Increased mortality due to dementias among parents and full siblings of ALS patients suggests shared mechanisms between neurodegenerative diseases.
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http://dx.doi.org/10.1080/21678421.2021.1953075DOI Listing
July 2021

Genetic Influence on Nociceptive Processing in the Human Brain-A Twin Study.

Cereb Cortex 2021 Jul 21. Epub 2021 Jul 21.

Department of Clinical Neuroscience, Karolinska Institutet, SE-171 77, Stockholm, Sweden.

Nociceptive processing in the human brain is complex and involves several brain structures and varies across individuals. Determining the structures that contribute to interindividual differences in nociceptive processing is likely to improve our understanding of why some individuals feel more pain than others. Here, we found specific parts of the cerebral response to nociception that are under genetic influence by employing a classic twin-design. We found genetic influences on nociceptive processing in the midcingulate cortex and bilateral posterior insula. In addition to brain activations, we found genetic contributions to large-scale functional connectivity (FC) during nociceptive processing. We conclude that additive genetics influence specific brain regions involved in nociceptive processing. The genetic influence on FC during nociceptive processing is not limited to core nociceptive brain regions, such as the dorsal posterior insula and somatosensory areas, but also involves cognitive and affective brain circuitry. These findings improve our understanding of human pain perception and increases chances to find new treatments for clinical pain.
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http://dx.doi.org/10.1093/cercor/bhab206DOI Listing
July 2021

Do psychiatric diseases follow annual cyclic seasonality?

PLoS Biol 2021 07 19;19(7):e3001347. Epub 2021 Jul 19.

Committee on Genetics, Genomics and Systems Biology, The University of Chicago, Chicago, Illinois, United States of America.

Seasonal affective disorder (SAD) famously follows annual cycles, with incidence elevation in the fall and spring. Should some version of cyclic annual pattern be expected from other psychiatric disorders? Would annual cycles be similar for distinct psychiatric conditions? This study probes these questions using 2 very large datasets describing the health histories of 150 million unique U.S. citizens and the entire Swedish population. We performed 2 types of analysis, using "uncorrected" and "corrected" observations. The former analysis focused on counts of daily patient visits associated with each disease. The latter analysis instead looked at the proportion of disease-specific visits within the total volume of visits for a time interval. In the uncorrected analysis, we found that psychiatric disorders' annual patterns were remarkably similar across the studied diseases in both countries, with the magnitude of annual variation significantly higher in Sweden than in the United States for psychiatric, but not infectious diseases. In the corrected analysis, only 1 group of patients-11 to 20 years old-reproduced all regularities we observed for psychiatric disorders in the uncorrected analysis; the annual healthcare-seeking visit patterns associated with other age-groups changed drastically. Analogous analyses over infectious diseases were less divergent over these 2 types of computation. Comparing these 2 sets of results in the context of published psychiatric disorder seasonality studies, we tend to believe that our uncorrected results are more likely to capture the real trends, while the corrected results perhaps reflect mostly artifacts determined by dominantly fluctuating, health-seeking visits across a given year. However, the divergent results are ultimately inconclusive; thus, we present both sets of results unredacted, and, in the spirit of full disclosure, leave the verdict to the reader.
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http://dx.doi.org/10.1371/journal.pbio.3001347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345894PMC
July 2021

Disparities in Screening and Treatment of Cardiovascular Diseases in Patients With Mental Disorders Across the World: Systematic Review and Meta-Analysis of 47 Observational Studies.

Am J Psychiatry 2021 09 14;178(9):793-803. Epub 2021 Jul 14.

Neurosciences Department (Solmi, Miola), Padua Neuroscience Center (Solmi), Department of General Psychology (Poddighe), and Department of Philosophy, Sociology, Education, and Applied Psychology (Delogu), University of Padua, Italy; Early Psychosis: Interventions and Clinical Detection (EPIC) Lab, Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Solmi, Fusar-Poli); Psychiatry Department, University of Ottawa, Ottawa (Fiedorowicz); Department of Clinical Medicine, Faculty of Health Sciences, UiT-Arctic University of Norway, Tromsø (Høye); Division of Mental Health and Substance Abuse, University Hospital of North Norway, Tromsø (Høye); Center for Clinical Documentation and Evaluation (SKDE), Tromsø (Høye, Heiberg); Physiotherapy Department, South London and Maudsley NHS Foundation Trust, and Department of Psychological Medicine, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Stubbs); Cambridge Centre for Sport and Exercise Science, Anglia Ruskin University, Cambridge, U.K. (Smith); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, and School of Medical Sciences, Örebro University, Örebro, Sweden (Larsson); Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark, and Department of Clinical Sciences, Lund University, Lund, Sweden (Attar); Department of Psychiatry, Aalborg University Hospital, and Department of Clinical Medicine, Aalborg University, Aalborg, Denmark (Nielsen); Centre for Innovation in Mental Health-Developmental Lab, School of Psychology, University of Southampton, and NHS Trust, Southampton, U.K. (Cortese); Hassenfeld Children's Hospital at NYU Langone, New York University Child Study Center, New York (Cortese); Division of Psychiatry and Applied Psychology, School of Medicine, University of Nottingham, Nottingham, U.K. (Cortese); Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea (Shin); National Institute for Health Research, Maudsley Biomedical Research Centre, and OASIS Service, South London and Maudsley NHS Foundation Trust, London (Fusar-Poli); Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy (Fusar-Poli); Division of Psychology and Mental Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, U.K. (Firth); NICM Health Research Institute, Western Sydney University, Westmead, Australia (Firth); Department of Psychiatry, University of British Columbia, Vancouver (Yatham); Department of Psychiatry, University of Toronto, and Centre for Addiction and Mental Health, Toronto (Castle, Seeman); IMPACT (Innovation in Mental and Physical Health and Clinical Treatment) Strategic Research Centre, School of Medicine, Barwon Health, Deakin University, Geelong, Australia (Carvalho); Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, Charité University Medicine Berlin, Berlin (Correll); Department of Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, N.Y. (Correll); and Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, N.Y. (Correll).

Objective: This study used meta-analysis to assess disparities in cardiovascular disease (CVD) screening and treatment in people with mental disorders, a group that has elevated CVD incidence and mortality.

Methods: The authors searched PubMed and PsycInfo through July 31, 2020, and conducted a random-effect meta-analysis of observational studies comparing CVD screening and treatment in people with and without mental disorders. The primary outcome was odds ratios for CVD screening and treatment. Sensitivity analyses on screening and treatment separately and on specific procedures, subgroup analyses by country, and by controlling for confounding by indication, as well as meta-regressions, were also run, and publication bias and quality were assessed.

Results: Forty-seven studies (N=24,400,452 patients, of whom 1,283,602 had mental disorders) from North America (k=26), Europe (k=16), Asia (k=4), and Australia (k=1) were meta-analyzed. Lower rates of screening or treatment in patients with mental disorders emerged for any CVD (k=47, odds ratio=0.773, 95% CI=0.742, 0.804), coronary artery disease (k=34, odds ratio=0.734, 95% CI=0.690, 0.781), cerebrovascular disease (k=8, odds ratio=0.810, 95% CI=0.779, 0.842), and other mixed CVDs (k=11, odds ratio=0.839, 95% CI=0.761, 0.924). Significant disparities emerged for any screening, any intervention, catheterization or revascularization in coronary artery disease, intravenous thrombolysis for stroke, and treatment with any and with specific medications for CVD across all mental disorders (except for CVD medications in mood disorders). Disparities were largest for schizophrenia, and they differed across countries. Median study quality was high (Newcastle-Ottawa Scale score, 8); higher-quality studies found larger disparities, and publication bias did not affect results.

Conclusions: People with mental disorders, and those with schizophrenia in particular, receive less screening and lower-quality treatment for CVD. It is of paramount importance to address underprescribing of CVD medications and underutilization of diagnostic and therapeutic procedures across all mental disorders.
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http://dx.doi.org/10.1176/appi.ajp.2021.21010031DOI Listing
September 2021

Mapping phenotypic and aetiological associations between ADHD and physical conditions in adulthood in Sweden: a genetically informed register study.

Lancet Psychiatry 2021 09 6;8(9):774-783. Epub 2021 Jul 6.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; School of Medical Sciences, Örebro University, Örebro, Sweden.

Background: Emerging evidence suggests increased risk of several physical health conditions in people with ADHD. Only a few physical conditions have been thoroughly studied in relation to ADHD, and there is little knowledge on associations in older adults in particular. We aimed to investigate the phenotypic and aetiological associations between ADHD and a wide range of physical health conditions across adulthood.

Methods: We did a register study in Sweden and identified full-sibling and maternal half-sibling pairs born between Jan 1, 1932, and Dec 31, 1995, through the Population and Multi-Generation Registers. We excluded individuals who died or emigrated before Jan 1, 2005, and included full-siblings who were not twins and did not have half-siblings. ICD diagnoses were obtained from the National Patient Register. We extracted ICD diagnoses for physical conditions, when participants were aged 18 years or older, from inpatient (recorded 1973-2013) and outpatient (recorded 2001-13) services. Diagnoses were regarded as lifetime presence or absence. Logistic regression models were used to estimate the associations between ADHD (exposure) and 35 physical conditions (outcomes) in individuals and across sibling pairs. Quantitative genetic modelling was used to estimate the extent to which genetic and environmental factors accounted for the associations with ADHD.

Findings: 4 789 799 individuals were identified (2 449 146 [51%] men and 2 340 653 [49%] women), who formed 4 288 451 unique sibling pairs (3 819 207 full-sibling pairs and 469 244 maternal half-sibling pairs) and 1 841 303 family clusters (siblings, parents, cousins, spouses). The mean age at end of follow-up was 47 years (range 18-81; mean birth year 1966); ethnicity data were not available. Adults with ADHD had increased risk for most physical conditions (34 [97%] of 35) compared with adults without ADHD; the strongest associations were with nervous system disorders (eg, sleep disorders, epilepsy, dementia; odds ratios [ORs] 1·50-4·62) and respiratory diseases (eg, asthma, chronic obstructive pulmonary disease; ORs 2·42-3·24). Sex-stratified analyses showed similar patterns of results in men and women. Stronger cross-disorder associations were found between full-siblings than between half-siblings for nervous system, respiratory, musculoskeletal, and metabolic diseases (p<0·007). Quantitative genetic modelling showed that these associations were largely explained by shared genetic factors (60-69% of correlations), except for associations with nervous system disorders, which were mainly explained by non-shared environmental factors.

Interpretation: This mapping of aetiological sources of cross-disorder overlap can guide future research aiming to identify specific mechanisms contributing to risk of physical conditions in people with ADHD, which could ultimately inform preventive and lifestyle intervention efforts. Our findings highlight the importance of assessing the presence of physical conditions in patients with ADHD.

Funding: Swedish Research Council; Swedish Brain Foundation; Swedish Research Council for Health, Working Life, and Welfare; Stockholm County Council; StratNeuro; EU Horizon 2020 research and innovation programme; National Institute of Mental Health.
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http://dx.doi.org/10.1016/S2215-0366(21)00171-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376653PMC
September 2021

Etiological links between autism and difficulties in initiating and maintaining sleep: a familial co-aggregation and twin study.

J Child Psychol Psychiatry 2021 Jul 1. Epub 2021 Jul 1.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Background: Difficulties initiating and maintaining sleep (DIMS) are frequent features of autism, yet little is known about why these conditions co-occur. One possibility is that they share etiological factors, yet this hypothesis remains to be tested using quantitative genetic designs. We thus investigated etiological links between autism and DIMS using familial co-aggregation and twin methods.

Methods: Twins, siblings, half-siblings, and cousins of 50,097 individuals with autism were identified from Swedish population registries. Their risk of DIMS, defined through diagnoses of insomnia and/or melatonin prescriptions, was then estimated. Twin analyses conducted on 15,279 child and adolescent twin pairs investigated etiological links between DIMS and ASD.

Results: 22.8% of autistic individuals had DIMS. Monozygotic co-twins of individuals with autism were most at risk of DIMS compared to the reference group (OR = 6.6 [2.5-17.4]), followed by dizygotic co-twins (OR = 2.6 [1.5-4.5]) and full siblings (OR = 2.5 [2.4-2.6]). Half-siblings and cousins of individuals with autism were least likely to have DIMS relative to the reference group (OR range = 1.3-1.5). Twin analyses estimated a correlation of 0.57 (0.53-0.61) between autism and DIMS, with a genetic correlation of 0.62 (0.60-0.68). These overlapping genetic factors explained 94% of the covariance between these conditions. Autistic traits also showed genetic overlap with DIMS.

Conclusions: Our results suggest that shared genetic mechanisms underlie autism and DIMS, which may lead them to co-occur. Untangling the etiological overlap between these conditions has potential to assist in understanding the etiology of each condition, as well as their associated outcomes.
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http://dx.doi.org/10.1111/jcpp.13473DOI Listing
July 2021

Association of selective serotonin re-uptake inhibitor (SSRI) treatment with acute substance misuse outcomes.

Addiction 2021 Jun 29. Epub 2021 Jun 29.

Institute of Criminology and Legal Policy, University of Helsinki, Helsinki, Finland.

Background And Aims: Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed medications for patients with anxiety/depression. These patients often have problems with substance use, but it remains unclear whether the risk of substance misuse is influenced by SSRI treatment. We aimed to determine whether SSRI treatment is associated with a decreased risk of acute substance misuse-related outcomes.

Design: Cohort study following individuals through Swedish nation-wide registers between July 2005 and December 2013 and comparing the risk of substance misuse outcomes during periods on- versus off-treatment within the same individual.

Setting: Swedish general population.

Participants: Individuals with a newly dispensed prescription of SSRIs between July 2006 and December 2013 and an ICD-10 diagnosis of anxiety/depressive disorder before the first treatment initiation. The cohort included 146 114 individuals (60.7% women).

Measurements: Substance misuse outcomes included ICD-10 diagnoses of acute intoxications (F10.0-F19.0), accidental poisonings by alcohol or drugs (X41-X42, X45-X46) and substance-related criminal offenses.

Findings: The absolute rate of substance misuse increased sharply before the onset of SSRI treatment and decreased after treatment initiation. Stratified Cox regression models showed an elevated risk [hazard ratio (HR) = 1.70, 95% confidence interval (CI) = 1.62-1.78] of substance misuse outcomes during a 1-month period preceding treatment initiation, compared with the reference period of more than 1 month before treatment start. The on-treatment estimates (1-30 days, HR = 1.29, 95% CI = 1.23-1.37; 31-120 days, HR = 1.30, 95% CI = 1.24-1.35; and > 120 days, HR = 1.24, 95% CI = 1.18-1.30 after treatment initiation] were consistently lower than the 1-month pre-treatment estimate, but still elevated compared with the reference period.

Conclusions: For people with anxiety/depression, the risk of substance misuse appears to be particularly elevated immediately before initiating selective serotonin reuptake inhibitor (SSRI) treatment, which may reflect the emergence or worsening of substance use problems concurrently with anxiety/depression. SSRI treatment appears to be associated with a lower risk of substance misuse compared with the 1-month period preceding treatment initiation, but causality remains uncertain.
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http://dx.doi.org/10.1111/add.15625DOI Listing
June 2021

Neurodevelopmental disorders, glycaemic control and diabetic complications in type 1 diabetes: a nationwide cohort study.

J Clin Endocrinol Metab 2021 Jun 25. Epub 2021 Jun 25.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden.

Context: Neurodevelopmental disorders are more prevalent in childhood-onset type 1 diabetes than in the general population, and the symptoms may limit the individual's ability of diabetes management. It remains unknown whether comorbid neurodevelopmental disorders are associated with long-term glycaemic control and risk of diabetic complications.

Methods: This population-based cohort study used longitudinally collected data from Swedish registers. We identified 11,326 individuals born 1973-2013, diagnosed with type 1 diabetes 1990-2013 (median onset age: 9.6 years). Out of them, 764 had a comorbid neurodevelopmental disorder, including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, and intellectual disability. We used multinomial logistic regression to calculate odds ratios (ORs) of having poor glycaemic control (assessed by mean of glycated haemoglobin [HbA1c]) and Cox regression to estimate hazard ratios (HRs) of nephropathy and retinopathy.

Results: The median of follow-up was 7.5 (IQR 3.9, 11.2) years. Having any neurodevelopmental disorder (ORadjusted 1.51 [95%CI 1.13, 2.03]), or ADHD (ORadjusted 2.31 [95%CI 1.54, 3.45]) was associated with poor glycaemic control (mean HbA1c >8.5%). Increased risk of diabetic complications was observed in patients with comorbid neurodevelopmental disorders (HRadjusted 1.72 [95%CI 1.21, 2.44] for nephropathy, HRadjusted 1.18 [95%CI 1.00, 1.40] for retinopathy) and patients with ADHD (HRadjusted 1.90 [95%CI 1.20, 3.00] for nephropathy, HRadjusted 1.33 [95%CI 1.07, 1.66] for retinopathy). Patients with intellectual disability have a particularly higher risk of nephropathy (HRadjusted 2.64 [95%CI 1.30, 5.37]).

Conclusions: Comorbid neurodevelopmental disorders, primarily ADHD and intellectual disability, were associated with poor glycaemic control and a higher risk of diabetic complications in childhood-onset type 1 diabetes.
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http://dx.doi.org/10.1210/clinem/dgab467DOI Listing
June 2021

Diet, Physical Activity, and Disinhibition in Middle-Aged and Older Adults: A UK Biobank Study.

Nutrients 2021 May 11;13(5). Epub 2021 May 11.

Interdisciplinary Center Psychopathology and Emotion Regulation, University Medical Center Groningen, 9700 RB Groningen, The Netherlands.

Disinhibition is a prominent feature of multiple psychiatric disorders, and has been associated with poor long-term somatic outcomes. Modifiable lifestyle factors including diet and moderate-to-vigorous physical activity (MVPA) may be associated with disinhibition, but their contributions have not previously been quantified among middle-aged/older adults. Here, among N = 157,354 UK Biobank participants aged 40-69, we extracted a single disinhibition principal component and four dietary components (prudent diet, elimination of wheat/dairy/eggs, meat consumption, full-cream dairy consumption). In addition, latent profile analysis assigned participants to one of five empirical dietary groups: prudent-moderate, unhealthy, restricted, meat-avoiding, low-fat dairy. Disinhibition was regressed on the four dietary components, the dietary grouping variable, and self-reported MVPA. In men and women, disinhibition was negatively associated with prudent diet, and positively associated with wheat/dairy/eggs elimination. In men, disinhibition was also associated with consumption of meat and full-cream dairy products. Comparing groups, disinhibition was lower in the prudent-moderate diet (reference) group compared to all other groups. Absolute βs ranged from 0.02-0.13, indicating very weak effects. Disinhibition was not associated with MVPA. In conclusion, disinhibition is associated with multiple features of diet among middle-aged/older adults. Our findings foster specific hypotheses (e.g., early malnutrition, elevated immune-response) to be tested in alternative study designs.
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http://dx.doi.org/10.3390/nu13051607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151887PMC
May 2021

Longitudinal Associations Between Symptoms of ADHD and BMI From Late Childhood to Early Adulthood.

Pediatrics 2021 Jun;147(6)

Department of Psychiatry, Interdisciplinary Center Psychopathology and Emotion Regulation, University Medical Center Groningen, University of Groningen, Groningen, Netherlands;

Background And Objectives: Attention-deficit/hyperactivity disorder (ADHD) and obesity are 2 frequent conditions that co-occur, which has implications for the management of both conditions. We hypothesized that ADHD symptoms predict BMI and vice versa from late childhood (10-12 years) up to early adulthood (20-22 years).

Methods: Participants were adolescents in the Netherlands ( = 2773, 52.5% male, mean age = 11 years at baseline, 5 waves up to mean age 22) from the Tracking Adolescents' Individual Lives Survey cohort. We examined bidirectional relationship between ADHD symptoms (hyperactivity/impulsivity and inattention) and BMI using the random intercept cross-lagged panel model. Time-varying covariates were pubertal status, stimulant use, depressive symptoms, and family functioning, and socioeconomic status was a time-invariant covariate.

Results: We found a time-invariant association of BMI with hyperactivity and impulsivity, but not with inattention, which was slightly stronger in female adolescents (female: = 0.102; male: = 0.086, < .05). No longitudinal direct effects were found between ADHD symptoms and BMI during this period.

Conclusions: Over the course of adolescence, the link between ADHD and BMI is stable and is predominantly with hyperactive and impulsive symptoms rather than inattention. There was no direct effect of ADHD symptoms on BMI increase nor of BMI on enhanced ADHD symptoms during this developmental period. The findings point to a shared genetic or familial background and/or potential causal effects established already earlier in childhood, thus suggesting that intervention and prevention programs targeting overweight and obesity in children with ADHD should be implemented in early childhood.
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http://dx.doi.org/10.1542/peds.2020-036657DOI Listing
June 2021

Association of family history of schizophrenia and clinical outcomes in individuals with eating disorders.

Psychol Med 2021 Apr 30:1-8. Epub 2021 Apr 30.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Background: Familial co-aggregation studies of eating disorders (EDs) and schizophrenia reveal shared genetic and environment factors, yet their etiological and clinical relationship remains unclear. We evaluate the influence of schizophrenia family history on clinical outcomes of EDs.

Methods: We conducted a cohort evaluation of the association between family history of schizophrenia and ED clinical features, psychiatric comorbidities, and somatic and mental health burden in individuals born in Sweden 1977-2003 with anorexia nervosa (AN) or other EDs (OED: bulimia nervosa, binge-eating disorder, and ED not otherwise specified).

Results: Of 12 424 individuals with AN and 20 716 individuals with OED, 599 (4.8%) and 1118 (5.4%), respectively, had a family history of schizophrenia (in up to third-degree relatives). Among individuals with AN, schizophrenia in first-degree relatives was significantly associated with increased comorbid attention-deficit/hyperactivity disorder (ADHD) [HR(95% CI) 2.26 (1.27-3.99)], substance abuse disorder (SUD) [HR (95% CI) 1.93 (1.25-2.98)], and anxiety disorders [HR (95% CI) 1.47 (1.08-2.01)], but higher lowest illness-associated body mass index (BMI) [1.14 kg/m2, 95% CI (0.19-2.10)]. Schizophrenia in any relative (up to third-degree) in AN was significantly associated with higher somatic and mental health burden, but lower ED psychopathology scores [-0.29, 95% CI (-0.54 to -0.04)]. Schizophrenia in first-degree relatives in individuals with OED was significantly associated with increased comorbid ADHD, obsessive-compulsive disorder, SUD, anxiety disorders, somatic and mental health burden, and suicide attempts.

Conclusions: We observed different patterns of ED-related outcomes, psychiatric comorbidity, and illness burden in individuals with EDs with and without family histories of schizophrenia and provide new insights into the diverse manifestations of EDs.
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http://dx.doi.org/10.1017/S0033291721001574DOI Listing
April 2021

Exercise-induced fluid shifts are distinct to exercise mode and intensity: a comparison of blood flow-restricted and free-flow resistance exercise.

J Appl Physiol (1985) 2021 06 29;130(6):1822-1835. Epub 2021 Apr 29.

Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

MRI can provide fundamental tools in decoding physiological stressors stimulated by training paradigms. Acute physiological changes induced by three diverse exercise protocols known to elicit similar levels of muscle hypertrophy were evaluated using muscle functional magnetic resonance imaging (mfMRI). The study was a cross-over study with participants ( = 10) performing three acute unilateral knee extensor exercise protocols to failure and a work matched control exercise protocol. Participants were scanned after each exercise protocol; 70% 1 repetition maximum (RM) (FF70); 20% 1RM (FF20); 20% 1RM with blood flow restriction (BFR20); free-flow (FF) control work matched to BFR20 (FF20). Post exercise mfMRI scans were used to obtain interleaved measures of muscle R2 (indicator of edema), R2' (indicator of deoxyhemoglobin), muscle cross sectional area (CSA) blood flow, and diffusion. Both BFR20 and FF20 exercise resulted in a larger acute decrease in R2, decrease in R2', and expansion of the extracellular compartment with slower rates of recovery. BFR20 caused greater acute increases in muscle CSA than FF20 and FF70. Only BFR20 caused acute increases in intracellular volume. Postexercise muscle blood flow was higher after FF70 and FF20 exercise than BFR20. Acute changes in mean diffusivity were similar across all exercise protocols. This study was able to differentiate the acute physiological responses between anabolic exercise protocols. Low-load exercise protocols, known to have relatively higher energy contributions from glycolysis at task failure, elicited a higher mfMRI response. Noninvasive mfMRI represents a promising tool for decoding mechanisms of anabolic adaptation in muscle. Using muscle functional MRI (mfMRI), this study was able to differentiate the acute physiological responses following three established hypertrophic resistance exercise strategies. Low-load exercise protocols performed to failure, with or without blood flow restriction, resulted in larger changes in R (i.e. greater T-shifts) with a slow rate of return to baseline indicative of myocellular fluid shifts. These data were cross evaluated with interleaved measures of macrovascular blood flow, water diffusion, muscle cross sectional area (i.e. acute macroscopic muscle swelling), and intracellular water fraction measured using MRI.
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http://dx.doi.org/10.1152/japplphysiol.01012.2020DOI Listing
June 2021

Association and Familial Coaggregation of Type 1 Diabetes and Eating Disorders: A Register-Based Cohort Study in Denmark and Sweden.

Diabetes Care 2021 05 6;44(5):1143-1150. Epub 2021 Apr 6.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden.

Objective: To ascertain the association and coaggregation of eating disorders and childhood-onset type 1 diabetes in families.

Research Design And Methods: Using population samples from national registers in Sweden ( = 2,517,277) and Demark ( = 1,825,920), we investigated the within-individual association between type 1 diabetes and eating disorders and their familial coaggregation among full siblings, half siblings, full cousins, and half cousins. On the basis of clinical diagnoses, we classified eating disorders into any eating disorder (AED), anorexia nervosa (AN) and atypical AN, and other eating disorder (OED). Associations were determined with hazard ratios (HRs) with 95% CIs from Cox regressions.

Results: Swedish and Danish individuals with a type 1 diabetes diagnosis had a greater risk of receiving an eating disorder diagnosis (HR [95% CI] Sweden: AED 2.02 [1.80-2.27], AN 1.63 [1.36-1.96], OED 2.34 [2.07-2.63]; Denmark: AED 2.19 [1.84-2.61], AN 1.78 [1.36-2.33], OED 2.65 [2.20-3.21]). We also meta-analyzed the results: AED 2.07 (1.88-2.28), AN 1.68 (1.44-1.95), OED 2.44 (2.17-2.72). There was an increased risk of receiving an eating disorder diagnosis in full siblings in the Swedish cohort (AED 1.25 [1.07-1.46], AN 1.28 [1.04-1.57], OED 1.28 [1.07-1.52]); these results were nonsignificant in the Danish cohort.

Conclusions: Patients with type 1 diabetes are at a higher risk of subsequent eating disorders; however, there is conflicting support for the relationship between having a sibling with type 1 diabetes and an eating disorder diagnosis. Diabetes health care teams should be vigilant about disordered eating behaviors in children and adolescents with type 1 diabetes.
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http://dx.doi.org/10.2337/dc20-2989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132321PMC
May 2021

Prediction of treatment dosage and duration from free-text prescriptions: an application to ADHD medications in the Swedish prescribed drug register.

Evid Based Ment Health 2021 Apr 1. Epub 2021 Apr 1.

Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.

Background: Accurate estimation of daily dosage and duration of medication use is essential to pharmacoepidemiological studies using electronic healthcare databases. However, such information is not directly available in many prescription databases, including the Swedish Prescribed Drug Register.

Objective: To develop and validate an algorithm for predicting prescribed daily dosage and treatment duration from free-text prescriptions, and apply the algorithm to ADHD medication prescriptions.

Methods: We developed an algorithm to predict daily dosage from free-text prescriptions using 8000 ADHD medication prescriptions as the training sample, and estimated treatment periods while taking into account several features including titration, stockpiling and non-perfect adherence. The algorithm was implemented to all ADHD medication prescriptions from the Swedish Prescribed Drug Register in 2013. A validation sample of 1000 ADHD medication prescriptions, independent of the training sample, was used to assess the accuracy for predicted daily dosage.

Findings: In the validation sample, the overall accuracy for predicting daily dosage was 96.8%. Specifically, the natural language processing model (NLP1 and NLP2) have an accuracy of 99.2% and 96.3%, respectively. In an application to ADHD medication prescriptions in 2013, young adult ADHD medication users had the highest probability of discontinuing treatments as compared with other age groups. The daily dose of methylphenidate use increased with age substantially.

Conclusions: The algorithm provides a flexible approach to estimate prescribed daily dosage and treatment duration from free-text prescriptions using register data. The algorithm showed a good performance for predicting daily dosage in external validation.

Clinical Implications: The structured output of the algorithm could serve as basis for future pharmacoepidemiological studies evaluating utilization, effectiveness, and safety of medication use, which would facilitate evidence-based treatment decision-making.
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http://dx.doi.org/10.1136/ebmental-2020-300231DOI Listing
April 2021

Editorial: Attention-Deficit/Hyperactivity Disorder Polygenic Scores in Context: Interpretations, Implications, and Directions for Future Research.

J Am Acad Child Adolesc Psychiatry 2021 Oct 25;60(10):1178-1180. Epub 2021 Mar 25.

Dr. Du Rietz and Larsson are with Karolinska Institutet, Stockholm, Sweden. Dr. Larsson is also with the School of Medical Sciences, Örebro University, Örebro, Sweden.

During the past 15 years, genome-wide association studies (GWASs) have been instrumental for identifying common genetic variants that influence complex traits. The latest attention-deficit/hyperactivity disorder (ADHD) GWAS, published in 2019, identified for the first time 12 loci significantly associated with ADHD. Since then a large number of studies have used the summary statistics of this GWAS to calculate individual polygenic scores (PGSs) in independent genotyped samples to explore how the ADHD PGS associates with relevant outcomes. The study by Ronald et al. synthesized the available literature on ADHD PGS and concluded that the ADHD PGS is robust and reliable, but not yet useful in clinical practice.
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http://dx.doi.org/10.1016/j.jaac.2021.03.007DOI Listing
October 2021

Healthcare utilization and costs of psychiatric and somatic comorbidities associated with newly diagnosed adult ADHD.

Acta Psychiatr Scand 2021 07 4;144(1):50-59. Epub 2021 May 4.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Background: Psychiatric and somatic problems in young adulthood have been found to be main drivers of costs in individuals with childhood ADHD. However, knowledge of the patterns of healthcare utilization and costs of comorbidities in middle-aged adults with newly diagnosed ADHD is very limited.

Method: We studied individuals born 1966-1978 (from the Swedish Total Population Register) with newly diagnosed ADHD between the ages of 30-45 years and individuals without ADHD matched on birthdate, birth county, and sex. Healthcare utilization and expenditure for psychiatric and somatic disorders were obtained over four years (two years pre- and post-initial ADHD diagnosis).

Results: Middle-aged adults with newly diagnosed ADHD showed higher levels of healthcare utilization and costs (outpatient, inpatient, medications) for psychiatric and somatic comorbidities relative to adults without ADHD, both before and after the initial diagnosis. Females showed greater average group differences across the study period for medication prescriptions than males. Total incremental annual costs per capita were €2478.76 in adults with ADHD relative to those without, and costs were mainly driven by inpatient care. Psychiatric outpatient visits were statistically significantly higher the year before the ADHD diagnosis compared with two years before and after the diagnosis.

Conclusion: This study demonstrates the substantial burden of psychiatric and somatic comorbidities in middle-aged adults newly diagnosed with ADHD. Psychiatric outpatient visits peaked in the year leading up to the ADHD diagnosis. Findings further suggested that females with ADHD may seek more treatment for comorbidities than males, which may reflect a general female tendency.
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http://dx.doi.org/10.1111/acps.13297DOI Listing
July 2021

Association Between Hypertensive Disorders of Pregnancy and Neurodevelopmental Outcomes Among Offspring.

JAMA Pediatr 2021 Jun;175(6):577-585

Clinical Epidemiology and Biostatistics, School of Medical Sciences, Örebro University, Örebro, Sweden.

Importance: Hypertensive disorders of pregnancy (HDP) have been associated with poorer neurodevelopmental outcomes in offspring, but the role of familial confounding in these associations is unclear.

Objective: To investigate associations of maternal HDP with risks in offspring of autism spectrum disorders (ASDs), attention-deficit/hyperactivity disorder (ADHD), and intellectual disability (ID), as well as variation in overall cognitive performance in offspring.

Design, Setting, And Participants: This Swedish register-based study used data from a birth cohort divided into 1 085 024 individuals born between 1987 and 1996 and followed up until December 31, 2014, and 285 901 men born between 1982 and 1992 who attended assessments for military conscription, including a cognitive function test. Statistical analysis was performed from April 1, 2019, to June 1, 2020.

Exposures: Diagnoses of HDP, which were provided by the Medical Birth Register.

Main Outcomes And Measures: Diagnoses of ASDs, ADHD, and ID were extracted from the National Patient Register. Cognitive function was assessed using written tests and summarized as a single 9-point score. Whole-cohort and within-sibship analyses were performed; the latter accounted for unmeasured familial confounding factors shared by siblings.

Results: The study included 1 085 024 individuals (556 912 male participants [51.3%]) born between 1987 and 1996 and 285 901 men born between 1982 and 1992 who attended assessments for military conscription. The prevalence of maternal HDP was 4.0% in the 1987-1996 birth cohort (n = 42 980) and 5.1% in the military conscription cohort (n = 14 515). A total of 15 858 participants received a diagnosis of ASD, 36 852 received a diagnosis of ADHD, and 8454 received a diagnosis of ID. The mean (SD) cognitive score among the men in the conscription cohort was 5.1 (1.9). In whole-cohort analyses with multivariable adjustment, HDP were associated with offspring ASDs (hazard ratio [HR], 1.22; 95% CI, 1.13-1.31), ADHD (HR, 1.10; 95% CI, 1.05-1.16), and ID (HR, 1.39; 95% CI, 1.27-1.53). Analyses comparing siblings discordant for HDP were less statistically powered but indicated estimates of similar magnitude for ASDs (HR, 1.19; 95% CI, 1.00-1.42) and possibly ADHD (HR, 1.09; 95% CI, 0.95-1.24), but not for ID (HR, 1.04; 95% CI, 0.83-1.29). Hypertensive disorders of pregnancy were associated with somewhat lower cognitive scores in whole-cohort analysis (mean difference comparing offspring exposed with those unexposed, -0.10; 95% CI, -0.13 to -0.07), but in within-sibship analysis, the association was null (mean difference, 0.00; 95% CI, -0.09 to 0.08).

Conclusions And Relevance: The study results suggest that HDP are associated with small increased risks of ASDs and possibly ADHD in offspring, whereas associations with ID and cognitive performance are likely confounded by shared familial (environmental or genetic) factors.
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http://dx.doi.org/10.1001/jamapediatrics.2020.6856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985818PMC
June 2021

Attention-deficit/hyperactivity disorder and occupational outcomes: The role of educational attainment, comorbid developmental disorders, and intellectual disability.

PLoS One 2021 17;16(3):e0247724. Epub 2021 Mar 17.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Background: Individuals with ADHD are at increased risk for poor occupational outcomes. Educational attainment and psychiatric comorbidity may be important contributing factors for these outcomes, but the role of these factors is not well characterized. This study aimed to investigate the associations between ADHD and occupational outcomes, and to examine the influence of educational attainment, comorbid developmental disorders and intellectual disability on these associations.

Methods: We linked the Swedish population graduating from compulsory school 1998-2008 (N = 1.2 millions) to population-wide register-based data on clinical psychiatric diagnoses and medications, objective annual measures of educational, and occupational outcomes. Individuals were followed for between 6 to 16 years after graduation.

Results: Individuals with ADHD had annually on average 17 percent lower income, ratio = 0.83 (95% CI 0.83-0.84), 12.19 (11.89-12.49) more days of unemployment, and a higher likelihood of receiving disability pension, odds-ratio = 19.0 (18.4-19.6), compared to controls. Comorbid diagnoses of intellectual disability and developmental disorder explained most of the association between ADHD and disability pension, while lifetime educational attainment partially explained associations between ADHD and all occupational outcomes. Analyses of occupational trajectories found that income was lower and unemployment elevated relative to controls with the same educational attainment. Higher educational attainment correlated with higher income similarly among individuals with ADHD and controls after accounting for individual background factors.

Conclusions: The occupational burden associated with ADHD is substantial. Comorbid developmental disorders, intellectual disability and educational difficulties (e.g., failing grades) from childhood to adulthood are important factors to consider when designing interventions to improve occupational outcomes in individuals with ADHD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247724PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968636PMC
September 2021
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