Birgitte Fagerlund’s research while affiliated with University of Copenhagen and other places

Identifying early predictors of cognitive decline and at-risk individuals is essential for timely intervention and prevention of dementia. This study aimed to detect neurobiological changes and factors related to cognitive performance in the Metropolit 1953 Danish male birth cohort. We analyzed data from 582 participants, aged 57–68 years, using machine learning techniques to group cognitive trajectories into four clusters differentiating high- and low-performing groups. These clusters were then evaluated with MRI, EEG, and lifestyle/familial risk factors to identify predictors of cognitive decline. Low education and occupation, alcohol consumption, and type 2 diabetes were associated with lower cognitive performance. Declines in neocortical volume and increases in frontotemporal alpha and temporoparietal gamma activity preceded clinical symptoms of cognitive decline. Neocortical atrophy and disruptions in network activity were prominent in lower-performing groups, with higher education and IQ scores and a lower prevalence of lifestyle factors moderating cognitive decline.

Background While several risk factors for schizophrenia have been identified, their individual impacts are rather small. The relative independent and cumulative impacts of multiple risk factors on disease risk and age of onset warrant further investigation. Study design We conducted a register-based case–control study including all individuals receiving a schizophrenia spectrum disorder in Denmark from 1973 to 2018 ( N = 29,142), and a healthy control sample matched 5:1 on age, sex, and parental socioeconomic status ( N = 136,387). Register data included parental history of psychiatric illness, birth weight, gestational age, season of birth, population density of birthplace, immigration, paternal age, and Apgar scores. Data were analysed using logistic regression and machine learning. Results Parental history of psychiatric illness (OR = 2.32 [95%CI 2.21–2.43]), high paternal age (OR = 1.30 [1.16–1.45]), and low birth weight (OR = 1.28 [1.16–1.41]) increased the odds of belonging to the patient group. In contrast, being a second-generation immigrant (OR = 0.65 [0.61–0.69]) and high population density of the birthplace (OR = 0.92 [0.89–0.96]) decreased the odds. The findings were supported by a decision tree analysis where parental history, paternal age, and birth weight contributed most to diagnostic classification (ACC test = 0.69, AUC test = 0.59, p < 0.001). Twenty percent of patients were child-onset cases. Here, female sex (OR = 1.82 [1.69–1.97]) and parental psychiatric illness (OR = 1.62 [1.49–1.77]) increased the odds of receiving the diagnosis <18 years. Conclusion Multiple early factors contribute independently to a higher psychosis risk, suggesting cumulative effects leading to symptom onset. Routine assessments of the most influential risk factors could be incorporated into clinical practise. Being female increased the risk of diagnosis during childhood, suggesting sex differences in the developmental trajectories of the disorder.

Patients with schizophrenia exhibit structural and functional dysconnectivity but the relationship to the well-documented cognitive impairments is less clear. This study investigates associations between structural and functional connectivity and executive functions in antipsychotic-naïve patients experiencing schizophrenia. Sixty-four patients with schizophrenia and 95 matched controls underwent cognitive testing, diffusion weighted imaging and resting state functional magnetic resonance imaging. In the primary analyses, groupwise interactions between structural connectivity as measured by fixel-based analyses and executive functions were investigated using multivariate linear regression analyses. For significant structural connections, secondary analyses examined whether functional connectivity and associations with executive functions also differed for the two groups. In group comparisons, patients exhibited cognitive impairments across all executive functions compared to controls (p < 0.001), but no group difference were observed in the fixel-based measures. Primary analyses revealed a groupwise interaction between planning abilities and fixel-based measures in the left anterior thalamic radiation (p = 0.004), as well as interactions between cognitive flexibility and fixel-based measures in the isthmus of corpus callosum and cingulum (p = 0.049). Secondary analyses revealed increased functional connectivity between grey matter regions connected by the left anterior thalamic radiation (left thalamus with pars opercularis p = 0.018, and pars orbitalis p = 0.003) in patients compared to controls. Moreover, a groupwise interaction was observed between cognitive flexibility and functional connectivity between contralateral regions connected by the isthmus (precuneus p = 0.028, postcentral p = 0.012), all p-values corrected for multiple comparisons. We conclude that structural and functional connectivity appear to associate with executive functions differently in antipsychotic-naïve patients with schizophrenia compared to controls.

Background Targeted treatment is highly warranted for cerebral small vessel disease, a causal factor of one in four strokes and a major contributor to vascular dementia. Patients with cerebral small vessel disease have impaired cerebral blood flow and vessel reactivity. Tadalafil is a specific phosphodiesterase 5 inhibitor shown to improve vascular reactivity in the brain. Methods The ETLAS-2 trial is a phase 2 double-blind, randomized placebo-controlled, parallel trial with the feasibility of tadalafil as the primary outcome. The trial aims to include 100 patients with small vessel occlusion stroke or transitory ischemic attacks and signs of cerebral small vessel disease more than 6 months before administration of study medication. Patients are treated for 3 months with tadalafil 20 mg or placebo daily and undergo magnetic resonance imaging (MRI) to evaluate changes in small vessel disease according to the STandards for ReportIng Vascular changes on nEuroimaging (STRIVE) criteria as well as cerebral blood flow, cerebrovascular reactivity, and neurovascular coupling in a functional MRI sub-study. The investigation includes comprehensive cognitive testing using paper–pencil tests and Cambridge Neuropsychological Test Automated Battery (CANTAB) tests in a cognitive sub-study. Discussion The ETLAS-2 trial tests the feasibility of long-term treatment with tadalafil and explores vascular and cognitive effects in cerebral small vessel disease in trial sub-studies. The study aims to propose a new treatment target and improve the understanding of small vessel disease. Currently, 64 patients have been included and the trial is estimated to be completed in the year 2024. Trial registration Clinicaltrials.gov, NCT05173896. Registered on 30 December 2021.

Background: Targeted treatment is highly warranted for cerebral small vessel disease, a causal factor of one in four strokes and a major contributor to vascular dementia. Patients with cerebral small vessel disease have impaired cerebral blood flow and vessel reactivity. Tadalafil is a specific phosphodiesterase 5 inhibitor shown to improve vascular reactivity in the brain. Methods: The ETLAS-2 trial is a phase 2 double-blind, randomized placebo-controlled, parallel trial with feasibility of tadalafil as the primary outcome. The trial aims to include 100 patients with small vessel occlusion stroke or transitory ischemic attacks and signs of cerebral small vessel disease more than six months before administration of study medication. Patients are treated for three months with tadalafil 20 mg or placebo daily and undergo magnetic resonance imaging (MRI) to evaluate changes in small vessel disease according to the Standards for ReportIng Vascular changes on nEuroimaging (STRIVE) criteria as well as cerebral blood flow, cerebrovascular reactivity, and neurovascular coupling in a functional MRI sub-study. The investigation includes comprehensive cognitive testing using paper-pencil tests and Cambridge Neuropsychological Test Automated Battery (CANTAB)-tests in a cognitive sub-study. Discussion: The ETLAS-2 trial tests the feasibility of long-term treatment with tadalafil and explores vascular and cognitive effects in cerebral small vessel disease in trial sub-studies. The study aims to propose a new treatment target and improve the understanding of small vessel disease. Currently, 64 patients have been included and the trial is estimated to be completed in year 2024. Trial registration: The trial is registered at clinicaltrials.gov (NCT05173896).

Despite the high prevalence of neurodevelopmental disorders, there are a lack of clinical studies examining the impact of pregnancy diet on child neurodevelopment. This observational clinical study examined the associations between pregnancy dietary patterns and neurodevelopmental diagnoses, as well as their symptoms, in a prospective cohort of 10-year-old children (n=508). Data-driven dietary patterns were derived from self-reported food frequency questionnaires. An Unhealthy dietary pattern in pregnancy (per SD change) was significantly associated with attention deficit hyperactivity disorder (ADHD) OR 1.66 [1.21 - 2.27], p=0.002 and autism diagnosis OR 2.22 [1.33 - 3.74], p=0.002 and associated symptoms p<0.001. Findings for ADHD were validated in two large (n=656, n=348), independent mother-child cohorts via blood metabolome modelling. Objective metabolite scores, assessed at five timepoints in mothers and children in two independent mother-child cohorts, indicated that the strongest association with ADHD was during early- to mid- pregnancy. These results provide evidence for targeted prenatal dietary interventions to prevent neurodevelopmental disorders in children.