We propose a method to discover couplings in multivariate time series, based on partial mutual information, an information-theoretic generalization of partial correlation. It represents the part of ...mutual information of two random quantities that is not contained in a third one. By suitable choice of the latter, we can differentiate between direct and indirect interactions and derive an appropriate graphical model. An efficient estimator for partial mutual information is presented as well.
Abstract
Advanced brain aging is commonly regarded as a risk factor for neurodegenerative diseases, for example, Alzheimer’s dementia, and it was suggested that sleep disorders such as obstructive ...sleep apnea (OSA) are significantly contributing factors to these neurodegenerative processes. To determine the association between OSA and advanced brain aging, we investigated the specific effect of two indices quantifying OSA, namely the apnea–hypopnea index (AHI) and the oxygen desaturation index (ODI), on brain age, a score quantifying age-related brain patterns in 169 brain regions, using magnetic resonance imaging and overnight polysomnography data from 690 participants (48.8% women, mean age 52.5 ± 13.4 years) of the Study of Health in Pomerania. We additionally investigated the mediating effect of subclinical inflammation parameters on these associations via a causal mediation analysis. AHI and ODI were both positively associated with brain age (AHI std. effect 95% CI: 0.07 0.03; 0.12, p-value: 0.002; ODI std. effect 95% CI: 0.09 0.04; 0.13, p-value: < 0.0003). The effects remained stable in the presence of various confounders such as diabetes and were partially mediated by the white blood cell count, indicating a subclinical inflammation process. Our results reveal an association between OSA and brain age, indicating subtle but widespread age-related changes in regional brain structures, in one of the largest general population studies to date, warranting further examination of OSA in the prevention of neurodegenerative diseases.
White matter lesions (WML) emerge as a consequence of vascular injuries in the brain. While they are commonly observed in aging, associations have been established with neurodegenerative and ...neurological disorders such as dementia or stroke. Despite substantial research efforts, biological mechanisms are incomplete and biomarkers indicating WMLs are lacking. Utilizing data from the population-based
(SHIP), our objective was to identify plasma-circulating micro-RNAs (miRNAs) associated with WMLs, thus providing a foundation for a comprehensive biological model and further research. In linear regression models, direct association and moderating factors were analyzed. In 648 individuals, we identified
-miR-425-5p as directly associated with WMLs. In subsequent analyses,
-miR-425-5p was found to regulate various genes associated with WMLs with particular emphasis on the
gene. Furthermore, miR-425-5p was found to be involved in immunological processes. In addition, noteworthy miRNAs associated with WMLs were identified, primarily moderated by the factors of sex or smoking status. All identified miRNAs exhibited a strong over-representation in neurodegenerative and neurological diseases. We introduced
-miR-425-5p as a promising candidate in WML research probably involved in immunological processes. Mir-425-5p holds the potential as a biomarker of WMLs, shedding light on potential mechanisms and pathways in vascular dementia.
Previous studies suggested that childhood maltreatment is associated with altered memory performance in adulthood. Deficits in identifying and describing feelings as captured by the alexithymia ...construct are strongly linked with childhood trauma and may mediate the associations with memory function.
To investigate the associations of childhood trauma with verbal declarative memory performance and the putative mediating role of alexithymia.
Associations of the different dimensions of childhood trauma with adult declarative memory performance were tested in two large, independent general population samples comprising a total of N = 5574 participants. Moreover, we tested whether associations were mediated by alexithymia.
In both samples, childhood emotional neglect, but not abuse emerged as a negative statistical predictor of early (sample 1: β=-1.79; p < 0.001, sample 2: β=-0.26; p < 0.001) as well as delayed recall (β=-0.78; p < 0.001; β=-0.24; p < 0.05). Likewise, childhood emotional neglect was the strongest predictor for alexithymia (β = 3.2; p < 0.001; β = 3.54; p < 0.001). Finally, the association between childhood emotional neglect and early (Total Mediated Effect (TME): 13.2, CI: 0.087-0.302; TME: 20.1; CI: 0.123-0.619) as well as late recall (TME: 13.2, CI: 0.086-0.301; TME: 9; CI: -0.442-0.699) was significantly mediated by alexithymia.
Our findings suggest that childhood emotional neglect is particularly detrimental to memory functioning in adulthood. In comparison, childhood abuse was not associated with reduced declarative memory capacity. Our results contribute to explain the mechanism underlying the relation of childhood trauma and memory deficits: Finding specific associations with emotional neglect and a mediating role of alexithymia highlights the relevance of emotion processing capacities for memory functioning.
Evidence from previous studies suggests that elevated body mass index (BMI) and genetic risk for obesity is associated with reduced brain volume, particularly in areas of reward-related cognition, ...e.g. the medial prefrontal cortex (AC-MPFC), the orbitofrontal cortex (OFC), the striatum and the thalamus. However, only few studies examined the interplay between these factors in a joint approach. Moreover, previous findings are based on cross-sectional data. We investigated the longitudinal relationship between increased BMI, brain structural magnetic resonance imaging (MRI) parameters and genetic risk scores in a cohort of n = 502 community-dwelling participants from the Study of Health in Pomerania (SHIP) with a mean follow-up-time of 4.9 years. We found that (1) increased BMI values at baseline were associated with decreased brain parameters at follow-up. These effects were particularly pronounced for the OFC and AC-MPFC. (2) The genetic predisposition for BMI had no effect on brain parameters at baseline or follow-up. (3) The interaction between the genetic score for BMI and brain parameters had no effect on BMI at baseline. Finding a significant impact of overweight, but not genetic predisposition for obesity on altered brain structure suggests that metabolic mechanisms may underlie the relationship between obesity and altered brain structure.
It has been shown that Alzheimer's disease (AD) is accompanied by marked structural brain changes that can be detected several years before clinical diagnosis
structural magnetic resonance (MR) ...imaging. In this study, we developed a structural MR-based biomarker for
detection of AD using a supervised machine learning approach. Based on an individual's pattern of brain atrophy a continuous AD score is assigned which measures the similarity with brain atrophy patterns seen in clinical cases of AD.
The underlying statistical model was trained with MR scans of patients and healthy controls from the Alzheimer's Disease Neuroimaging Initiative (ADNI-1 screening). Validation was performed within ADNI-1 and in an independent patient sample from the Open Access Series of Imaging Studies (OASIS-1). In addition, our analyses included data from a large general population sample of the Study of Health in Pomerania (SHIP-Trend).
Based on the proposed AD score we were able to differentiate patients from healthy controls in ADNI-1 and OASIS-1 with an accuracy of 89% (AUC = 95%) and 87% (AUC = 93%), respectively. Moreover, we found the AD score to be significantly associated with cognitive functioning as assessed by the Mini-Mental State Examination in the OASIS-1 sample after correcting for diagnosis, age, sex, age·sex, and total intracranial volume (Cohen's f
= 0.13). Additional analyses showed that the prediction accuracy of AD status based on both the AD score and the MMSE score is significantly higher than when using just one of them. In SHIP-Trend we found the AD score to be weakly but significantly associated with a test of verbal memory consisting of an immediate and a delayed word list recall (again after correcting for age, sex, age·sex, and total intracranial volume, Cohen's f
= 0.009). This association was mainly driven by the immediate recall performance.
In summary, our proposed biomarker well differentiated between patients and healthy controls in an independent test sample. It was associated with measures of cognitive functioning both in a patient sample and a general population sample. Our approach might be useful for defining robust MR-based biomarkers for other neurodegenerative diseases, too.
Although the common pathology of Alzheimer's disease (AD) and white matter hyperintensities (WMH) is disputed, the gene
has been implicated in both conditions: its whole-blood gene expression was ...associated with WMH volume and its missense variant rs3747742 with AD risk. We re-examined those associations within one comprehensive dataset of the general population, additionally searched for cross-relations and illuminated the role of the apolipoprotein E (
) ε4 status in the associations. For our linear regression and linear mixed effect models, we used 1949 participants from the Study of Health in Pomerania (Germany). AD was assessed using a continuous pre-symptomatic MRI-based score evaluating a participant's AD-related brain atrophy. In our study, increased whole-blood
gene expression was significantly associated with reduced WMH volume but not with the AD score. Conversely, rs3747742-C was significantly associated with a reduced AD score but not with WMH volume. The
status did not influence the associations. In sum,
robustly associated with WMH volume and AD-related brain atrophy on different molecular levels. Our results thus underpin
's role in neurodegeneration, might point to its involvement in AD and WMH via different biological mechanisms, and highlight
as a worthwhile target for disentangling the two pathologies.
Abstract
Exposures to life stressors accumulate across the lifespan, with possible impact on brain health. Little is known, however, about the mechanisms mediating age-related changes in brain ...structure. We use a lifespan sample of participants (n = 21 251; 4–97 years) to investigate the relationship between the thickness of cerebral cortex and the expression of the glucocorticoid- and the mineralocorticoid-receptor genes (NR3C1 and NR3C2, respectively), obtained from the Allen Human Brain Atlas. In all participants, cortical thickness correlated negatively with the expression of both NR3C1 and NR3C2 across 34 cortical regions. The magnitude of this correlation varied across the lifespan. From childhood through early adulthood, the profile similarity (between NR3C1/NR3C2 expression and thickness) increased with age. Conversely, both profile similarities decreased with age in late life. These variations do not reflect age-related changes in NR3C1 and NR3C2 expression, as observed in 5 databases of gene expression in the human cerebral cortex (502 donors). Based on the co-expression of NR3C1 (and NR3C2) with genes specific to neural cell types, we determine the potential involvement of microglia, astrocytes, and CA1 pyramidal cells in mediating the relationship between corticosteroid exposure and cortical thickness. Therefore, corticosteroids may influence brain structure to a variable degree throughout life.
Background Hypertrophy of the left ventricle (LV) has recently been associated with adverse changes of brain structure in older adults, notably increased burden of white matter hyperintensities ...(WMHs). Whether greater LV size or mass is also related to WMH burden in middle-aged adults is currently unclear. In addition, its relation with alterations in cortical thickness (CT) has not been studied to date. Methods and Results Data from 1602 participants of the population-based SHIP (Study of Health in Pomerania) with LV ejection fraction >40% and no history of myocardial infarction were included (aged 21-82 years; median age, 49 years; 53% women). Participants underwent both echocardiography and magnetic resonance imaging of the head. Imaging markers of brain aging (ie, CT and WMH volume) were determined from magnetic resonance imaging scans. LV mass and diameter were associated with lower global CT and greater WMH volume, while adjusting for age, sex, body height, fat-free body mass, and intracranial volume. Moreover, thicknesses of the interventricular septum and posterior wall were also associated with lower global CT. These associations could not be explained by cardiovascular risk factors (including hypertension), inflammatory markers, or sociodemographic factors. Regional analyses showed distinct spatial patterns of lower CT in association with LV diameter and posterior wall thickness. Conclusions LV diameter and mass are associated with lower global and regional CT as well as greater WMH burden in the general population. These findings highlight the brain structural underpinnings of the associations of LV hypertrophy with cognitive decline and dementia.
Basal cortisol concentrations vary between men and women. Likewise, previous findings suggest stress-related cortical thickness alterations. Thus, we aimed at elucidating sex differences in the ...association between serum cortisol concentrations and cortical thickness.
Data of 2594 participants (55.55% male; mean age = 53.55 years ± 13.17 years) of the general population were used to investigate sex differences in basal serum cortisol concentrations and associations of serum cortisol concentrations with global and regional cortical thickness. The validity of the results was tested by including sex hormone concentrations as a biological and childhood maltreatment and depressive symptoms as a psychological confounder.
Basal serum cortisol concentrations were higher in men than in women (β = −0.158, t(2575) = -6.852, p = 9.056e-12). Sex differences in serum cortisol concentrations were diminished by including serum concentrations of testosterone, estrone, or estradiol in the models. In men but not in women, serum cortisol concentrations were inversely associated with the global cortical thickness (men: β = −0.064, t(1412) = -3.010, p = .003; women: β = −0.016, t(1131) = -0.607, p = .544). Additionally, these effects were observed in eleven cortical regions after adjusting for multiple testing. The associations were independent of childhood maltreatment and depressive symptoms.
Sex differences in serum cortisol concentrations and the association between serum cortisol concentrations and cortical thickness suggest important sex-specific effects of stress on the brain. Future studies should integrate the interaction between the hypothalamic-pituitary-adrenal (HPA) axis and hypothalamic-pituitary-gonadal (HPG) axis in sex-stratified analyses.
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