Biomarkers sensitive to prodromal or early pathophysiological changes in Alzheimer’s disease (AD) symptoms could improve disease detection and enable timely interventions. Changes in brain hemodynamics may be associated with the main clinical AD symptoms. To test this possibility, we measured the variability of blood oxygen level-dependent (BOLD) signal in individuals from three independent datasets (totaling 80 AD patients and 90 controls). We detected a replicable increase in brain BOLD signal variability in the AD populations, which constituted a robust biomarker for clearly differentiating AD cases from controls. Fast BOLD scans showed that the elevated BOLD signal variability in AD arises mainly from cardiovascular brain pulsations. Manifesting in abnormal cerebral perfusion and cerebrospinal fluid convection, present observation presents a mechanism explaining earlier observations of impaired glymphatic clearance associated with AD in humans.
Age plays a crucial role in the performance of schizophrenia vs. controls (SZ-HC) neuroimaging-based machine learning (ML) models as the accuracy of identifying first-episode psychosis from controls is poor compared to chronic patients. Resolving whether this finding reflects longitudinal progression in a disorder-specific brain pattern or a systematic but non-disorder-specific deviation from a normal brain aging (BA) trajectory in schizophrenia would help the clinical translation of diagnostic ML models. We trained two ML models on structural MRI data: an SZ-HC model based on 70 schizophrenia patients and 74 controls and a BA model (based on 561 healthy individuals, age range = 66 years). We then investigated the two models’ predictions in the naturalistic longitudinal Northern Finland Birth Cohort 1966 (NFBC1966) following 29 schizophrenia and 61 controls for nine years. The SZ-HC model’s schizophrenia-specificity was further assessed by utilizing independent validation (62 schizophrenia, 95 controls) and depression samples (203 depression, 203 controls). We found better performance at the NFBC1966 follow-up (sensitivity = 75.9%, specificity = 83.6%) compared to the baseline (sensitivity = 58.6%, specificity = 86.9%). This finding resulted from progression in disorder-specific pattern expression in schizophrenia and was not explained by concomitant acceleration of brain aging. The disorder-specific pattern’s progression reflected longitudinal changes in cognition, outcomes, and local brain changes, while BA captured treatment-related and global brain alterations. The SZ-HC model was also generalizable to independent schizophrenia validation samples but classified depression as control subjects. Our research underlines the importance of taking account of longitudinal progression in a disorder-specific pattern in schizophrenia when developing ML classifiers for different age groups.
1Background and Aims: Prepregnancy maternal obesity is a global health problem and has been 2 associated with offspring metabolic and mental ill-health. However, there is a knowledge gap in 3 understanding potential neurobiological factors. This study explored the relation between 4 maternal prepregnancy body mass index (BMI) and offspring brain white matter microstructure 5 at the age of 6, 10 and 26 years in three independent cohorts. 6Subjects and Methods: The study used data from three European birth cohorts (n=116 children 7 aged 6 years, n=2466 children aged 10 years, and n=437 young adults aged 26 years). 8Information on maternal prepregnancy BMI was measured before or during pregnancy and 9 offspring brain white matter microstructure was measured at age 6, 10 or 26 years. Magnetic 10 resonance imaging derived fractional anisotropy (FA) and mean diffusivity (MD) were used as 11 measures of white matter microstructure in the brainstem, callosal, limbic, association and 12 projection tracts. Linear regressions were fitted to examine the association of maternal BMI and 13 offspring white matter microstructure, adjusting for several socioeconomic and lifestyle-related 14 confounders, including education, smoking and alcohol use.15Results: Maternal BMI was associated with higher FA and lower MD in multiple brain tracts, for 16 example association and projection fibers, in offspring aged 10 and 26 years, but not at 6 years. 17In each cohort maternal BMI was related to different white matter tract and thus no common 18 associations across cohorts were found. 19Conclusions: Maternal BMI was associated with higher FA and lower MD in multiple brain 20 tracts in offspring aged 10 and 26 years, but not at 6 years of age. Future longitudinal studies 21 should examine whether these associations persist in later stages of development and explore the 22 causal nature of the findings.23 17associated to structural and functional brain connectivity in neonates (15, 16). In addition, 18 newborns of mothers with obesity had lower fractional anisotropy (FA) in several white matter 19 tracts, including projection, association, callosal, thalamic and limbic system fibers when 20 compared to controls (16). Furthermore, exposure to maternal obesity was related to differences 21 in resting-state functional connectivity in the dorsal anterior cingulate cortex (i.e. a brain region 22 that is connected with the prefrontal and parietal cortex) in newborns (15). These two studies 10 11 Methods 12 The present study consists of participants drawn from three birth cohorts, including the PREOBE 13 Study from Granada, Spain, the Generation R Study from Rotterdam, Netherlands, and the 14 Northern Finland Birth Cohort 1986 (NFBC 1986), from the Northern Finland. Detailed 15 information about inclusion and exclusion criteria for each cohort is included in the 16 supplementary material. All studies were approved by their local Medical Ethics Committee. 17 18 Setting & participants 19The PREOBE Study 20The PREOBE study (17) was designed as a prosp...
It has remained unclear what factors relate to primary nonadherence to antipsychotic treatment and whether specific agents and routes of administration differ in how patients adhere to them. We collected electronic prescriptions and their dispensings from the Finnish electronic prescription database for 29 956 patients with schizophrenia prescribed antipsychotics via electronic prescription during 2015–2016. We defined primary nonadherence as being prescribed an antipsychotic, which was not dispensed from the pharmacy within one year from prescription. Using logistic regression, we analyzed whether several sociodemographic and clinical factors related to nonadherence. We found that 31.7% (N = 9506) of the patients demonstrated primary nonadherence to any of their prescribed antipsychotics. We found that young age (OR = 1.77, 95%CI = 1.59–1.96), concomitant benzodiazepines (OR = 1.47, 95%CI = 1.40–1.55) and mood stabilizers (OR = 1.29, 95%CI = 1.21–1.36), substance abuse (OR = 1.26 95%CI = 1.19–1.35), previous suicide attempt (OR = 1.21, 95%CI = 1.11–1.31), diabetes (OR = 1.15, 95%CI = 1.06–1.25), asthma/COPD (OR = 1.14, 95%CI = 1.04–1.25), and cardiovascular disease (OR = 1.12, 95%CI = 1.05–1.19), were related to primary nonadherence to antipsychotic treatment. Patients using clozapine showed the lowest nonadherence (4.77%, 95%CI = 4.66–4.89), and patients using long-acting injectables were more adherent to treatment (7.27%, 95%CI = 6.85–7.71) when compared to respective oral agents (10.26%, 95%CI = 10.02–10.49). These results suggest that selection between different pharmacological agents and routes of administration while taking into account patients’ concomitant medications (benzodiazepines in particular) and comorbidities play a key role in primary nonadherence to antipsychotic treatment.
Objective: Schizophrenia has one of the highest heritability estimates in psychiatry, but the geneticallybased underlying neuropathology has mainly remained unclear. We conducted a multimodal coordinatebased meta-analysis (CBMA) to investigate brain structural and functional alterations in individuals with high familial risk for schizophrenia, i.e. in first-degree relatives of schizophrenia patients (FRs). Methods:We conducted a systematic literature search from two electronic databases to find studies that examined differences between FRs and healthy controls using whole-brain functional magnetic resonance imaging (fMRI) or voxel-based morphometry (VBM). A CBMA of 30 fMRI (754 FRs; 959 controls) and 11 VBM (885 FRs; 775 controls) datasets were conducted using the anisotropic effect-size version of signed differential mapping. Further, we conducted separate meta-analyses about functional alterations in different cognitive tasks: social cognition, executive functioning, working memory, and inhibitory control. Results:When compared to healthy controls, FRs showed higher fMRI activation in the right frontal gyrus during cognitive tasks. In VBM studies, there were no differences in grey matter density between FRs and healthy controls. Furthermore, multi-modal meta-analysis obtained no differences between FRs and healthy controls. Finally, by utilizing the BrainMap database, we showed that the brain region which showed functional alterations in FRs (i) overlapped only slightly with the brain regions that were affected in the meta-analysis of schizophrenia patients and (ii) correlated positively with the brain regions that exhibited increased activity during cognitive tasks in healthy individuals. Conclusions: Based on this meta-analysis, FRs may exhibit only minor functional alterations in the brain during cognitive tasks, and the alterations are much more restricted and only slightly overlapping with the regions that are affected in schizophrenia patients. The familial risk did not relate to structural alterations in the grey matter.
Early stressors play a key role in shaping interindividual differences in vulnerability to various psychopathologies, which according to the diathesis-stress model might relate to the elevated glucocorticoid secretion and impaired responsiveness to stress. Furthermore, previous studies have shown that individuals exposed to early adversity have deficits in emotion processing from faces. This study aims to explore whether early adversities associate with brain response to faces and whether this association might associate with the regional variations in mRNA expression of the glucocorticoid receptor gene (NR3C1). A total of 104 individuals drawn from the Northern Finland Brith Cohort 1986 participated in a face-task functional magnetic resonance imaging (fMRI) study. A large independent dataset (IMAGEN, N = 1739) was utilized for reducing fMRI data-analytical space in the NFBC 1986 dataset. Early adversities were associated with deviant brain response to fearful faces (MANCOVA, P = 0.006) and with weaker performance in fearful facial expression recognition (P = 0.01). Glucocorticoid receptor gene expression (data from the Allen Human Brain Atlas) correlated with the degree of associations between early adversities and brain response to fearful faces (R = 0.25, P = 0.01) across different brain regions. Our results suggest that early adversities contribute to brain response to faces and that this association is mediated in part by the glucocorticoid system. Hum Brain Mapp 38:4470-4478, 2017. © 2017 Wiley Periodicals, Inc.
The Northern Finland Birth Cohort 1986 is a large population-based birth cohort, which aims to promote health and wellbeing of the population. In this paper, we systematically review the psychiatric research performed in the cohort until today, i.e. at the age of 32 years of the cohort (2018). We conducted a systematic literature search using the databases of PubMed and Scopus and complemented it with a manual search. We found a total of 94 articles, which were classified as examining ADHD, emotional and behavioural problems, psychosis risk or other studies relating to psychiatric subjects. The articles are mainly based on two large comprehensive follow-up studies of the cohort and several substudies. The studies have often used also nationwide register data. The studies have found several early predictors for the aforementioned psychiatric outcomes, such as problems at pregnancy and birth, family factors in childhood, physical inactivity and substance use in adolescence. There are also novel findings relating to brain imaging and cognition, for instance regarding familial risk of psychosis in relation to resting state functional MRI. The Northern Finland Birth Cohort 1986 has been utilised frequently in psychiatric research and future data collections are likely to lead to new scientifically important findings.Abbreviations: attention deficit hyperactivity disorder (ADHD); magnetic resonance imaging (MRI)
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