RESUMEN
BACKGROUND: Eighty percent of all patients suffering from major depressive disorder (MDD) relapse at least once in their lifetime. Thus, understanding the neurobiological underpinnings of the course of MDD is of utmost importance. A detrimental course of illness in MDD was most consistently associated with superior longitudinal fasciculus (SLF) fiber integrity. As similar associations were, however, found between SLF fiber integrity and acute symptomatology, this study attempts to disentangle associations attributed to current depression from long-term course of illness. METHODS: A total of 531 patients suffering from acute (N = 250) or remitted (N = 281) MDD from the FOR2107-cohort were analyzed in this cross-sectional study using tract-based spatial statistics for diffusion tensor imaging. First, the effects of disease state (acute v. remitted), current symptom severity (BDI-score) and course of illness (number of hospitalizations) on fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity were analyzed separately. Second, disease state and BDI-scores were analyzed in conjunction with the number of hospitalizations to disentangle their effects. RESULTS: Disease state (pFWE < 0.042) and number of hospitalizations (pFWE< 0.032) were associated with decreased FA and increased MD and RD in the bilateral SLF. A trend was found for the BDI-score (pFWE > 0.067). When analyzed simultaneously only the effect of course of illness remained significant (pFWE < 0.040) mapping to the right SLF. CONCLUSIONS: Decreased FA and increased MD and RD values in the SLF are associated with more hospitalizations when controlling for current psychopathology. SLF fiber integrity could reflect cumulative illness burden at a neurobiological level and should be targeted in future longitudinal analyses.
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Trastorno Depresivo Mayor , Sustancia Blanca , Humanos , Trastorno Depresivo Mayor/patología , Sustancia Blanca/patología , Imagen de Difusión Tensora/métodos , Estudios Transversales , Anisotropía , Encéfalo/patologíaRESUMEN
BACKGROUND: Schizotypy is a putative risk phenotype for psychosis liability, but the overlap of its genetic architecture with schizophrenia is poorly understood. METHODS: We tested the hypothesis that dimensions of schizotypy (assessed with the SPQ-B) are associated with a polygenic risk score (PRS) for schizophrenia in a sample of 623 psychiatrically healthy, non-clinical subjects from the FOR2107 multi-centre study and a second sample of 1133 blood donors. RESULTS: We did not find correlations of schizophrenia PRS with either overall SPQ or specific dimension scores, nor with adjusted schizotypy scores derived from the SPQ (addressing inter-scale variance). Also, PRS for affective disorders (bipolar disorder and major depression) were not significantly associated with schizotypy. CONCLUSIONS: This important negative finding demonstrates that despite the hypothesised continuum of schizotypy and schizophrenia, schizotypy might share less genetic risk with schizophrenia than previously assumed (and possibly less compared to psychotic-like experiences).
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Trastorno Bipolar , Trastornos Psicóticos , Esquizofrenia , Trastorno de la Personalidad Esquizotípica , Humanos , Esquizofrenia/genética , Trastorno de la Personalidad Esquizotípica/psicología , Trastornos Psicóticos/psicología , FenotipoRESUMEN
INTRODUCTION: The investigation of disease course-associated brain structural alterations in Major Depressive Disorder (MDD) have resulted in heterogeneous findings, possibly due to low reliability of single clinical variables used for defining disease course. The present study employed a principal component analysis (PCA) on multiple clinical variables to investigate effects of cumulative lifetime illness burden on brain structure in a large and heterogeneous sample of MDD patients. METHODS: Gray matter volumes (GMV) was estimated in n = 681 MDD patients (mean age: 35.87 years; SD = 12.89; 66.6% female) using voxel-based-morphometry. Five clinical variables were included in a PCA to obtain components reflecting disease course to associate resulting components with GMVs. RESULTS: The PCA yielded two main components: Hospitalization reflected by patients' frequency and duration of inpatient treatment and Duration of Illness reflected by the frequency and duration of depressive episodes. Hospitalization revealed negative associations with bilateral dorsolateral prefrontal cortex (DLPFC) and left insula volumes. Duration of Illness showed significant negative associations with left hippocampus and right DLPFC volumes. Results in the DLPFC and hippocampus remained significant after additional control for depressive symptom severity, psychopharmacotherapy, psychiatric comorbidities, and remission status. CONCLUSION: This study shows that a more severe and chronic lifetime disease course in MDD is associated with reduced volume in brain regions relevant for executive and cognitive functions and emotion regulation in a large sample of patients representing the broad heterogeneity of MDD disease course. These findings were only partly influenced by other clinical characteristics (e.g., remission status, psychopharmacological treatment).
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Trastorno Depresivo Mayor , Adulto , Encéfalo/diagnóstico por imagen , Trastorno Depresivo Mayor/diagnóstico por imagen , Trastorno Depresivo Mayor/tratamiento farmacológico , Progresión de la Enfermedad , Femenino , Sustancia Gris , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Reproducibilidad de los ResultadosRESUMEN
Major depressive disorder (MDD) is associated to affected brain wiring. Little is known whether these changes are stable over time and hence might represent a biological predisposition, or whether these are state markers of current disease severity and recovery after a depressive episode. Human white matter network ("connectome") analysis via network science is a suitable tool to investigate the association between affected brain connectivity and MDD. This study examines structural connectome topology in 464 MDD patients (mean age: 36.6 years) and 432 healthy controls (35.6 years). MDD patients were stratified categorially by current disease status (acute vs. partial remission vs. full remission) based on DSM-IV criteria. Current symptom severity was assessed continuously via the Hamilton Depression Rating Scale (HAMD). Connectome matrices were created via a combination of T1-weighted magnetic resonance imaging (MRI) and tractography methods based on diffusion-weighted imaging. Global tract-based metrics were not found to show significant differences between disease status groups, suggesting conserved global brain connectivity in MDD. In contrast, reduced global fractional anisotropy (FA) was observed specifically in acute depressed patients compared to fully remitted patients and healthy controls. Within the MDD patients, FA in a subnetwork including frontal, temporal, insular, and parietal nodes was negatively associated with HAMD, an effect remaining when correcting for lifetime disease severity. Therefore, our findings provide new evidence of MDD to be associated with structural, yet dynamic, state-dependent connectome alterations, which covary with current disease severity and remission status after a depressive episode.
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Conectoma , Trastorno Depresivo Mayor/patología , Remisión Espontánea , Adulto , Depresión/diagnóstico por imagen , Depresión/patología , Trastorno Depresivo Mayor/diagnóstico por imagen , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patologíaRESUMEN
BACKGROUND: Major depressive disorder (MDD) and type 2 diabetes mellitus (T2D) are known to share clinical comorbidity and to have genetic overlap. Besides their shared genetics, both diseases seem to be associated with alterations in brain structural connectivity and impaired cognitive performance, but little is known about the mechanisms by which genetic risk of T2D might affect brain structure and function and if they do, how these effects could contribute to the disease course of MDD. METHODS: This study explores the association of polygenic risk for T2D with structural brain connectome topology and cognitive performance in 434 nondiabetic patients with MDD and 539 healthy control subjects. RESULTS: Polygenic risk score for T2D across MDD patients and healthy control subjects was found to be associated with reduced global fractional anisotropy, a marker of white matter microstructure, an effect found to be predominantly present in MDD-related fronto-temporo-parietal connections. A mediation analysis further suggests that this fractional anisotropy variation may mediate the association between polygenic risk score and cognitive performance. CONCLUSIONS: Our findings provide preliminary evidence of a polygenic risk for T2D to be linked to brain structural connectivity and cognition in patients with MDD and healthy control subjects, even in the absence of a direct T2D diagnosis. This suggests an effect of T2D genetic risk on white matter integrity, which may mediate an association of genetic risk for diabetes and cognitive impairments.
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Conectoma , Trastorno Depresivo Mayor , Diabetes Mellitus Tipo 2 , Encéfalo , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/genética , Humanos , Factores de RiesgoRESUMEN
Apolipoprotein E (APOE) genotype is the strongest single gene predictor of Alzheimer's disease (AD) and has been frequently associated with AD-related brain structural alterations before the onset of dementia. While previous research has primarily focused on hippocampal morphometry in relation to APOE, sporadic recent findings have questioned the specificity of the hippocampus and instead suggested more global effects on the brain. With the present study we aimed to investigate associations between homozygous APOE ε4 status and cortical gray matter structure as well as white matter microstructure. In our study, we contrasted n = 31 homozygous APOE ε4 carriers (age=34.47 years, including a subsample of n = 12 subjects with depression) with a demographically matched sample without an ε4 allele (resulting total sample: N = 62). Morphometry analyses included a) Freesurfer based cortical segmentations of thickness and surface area measures and b) tract based spatial statistics of DTI measures. We found pronounced and widespread reductions in cortical surface area of ε4 homozygotes in 57 out of 68 cortical brain regions. In contrast, no differences in cortical thickness were observed. Furthermore, APOE ε4 homozygous carriers showed significantly lower fractional anisotropy in the corpus callosum, the right internal and external capsule, the left corona radiata and the right fornix. The present findings support a global rather than regionally specific effect of homozygous APOE ε4 allele status on cortical surface area and white matter microstructure. Future studies should aim to delineate the clinical implications of these findings.
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Enfermedad de Alzheimer , Apolipoproteína E4 , Sustancia Blanca , Adulto , Alelos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Apolipoproteína E4/genética , Apolipoproteínas E/genética , Encéfalo/diagnóstico por imagen , Imagen de Difusión Tensora/métodos , Genotipo , Homocigoto , Humanos , Imagen por Resonancia Magnética , Sustancia Blanca/diagnóstico por imagenRESUMEN
It has been difficult to find robust brain structural correlates of the overall severity of major depressive disorder (MDD). We hypothesized that specific symptoms may better reveal correlates and investigated this for the severity of insomnia, both a key symptom and a modifiable major risk factor of MDD. Cortical thickness, surface area and subcortical volumes were assessed from T1-weighted brain magnetic resonance imaging (MRI) scans of 1053 MDD patients (age range 13-79 years) from 15 cohorts within the ENIGMA MDD Working Group. Insomnia severity was measured by summing the insomnia items of the Hamilton Depression Rating Scale (HDRS). Symptom specificity was evaluated with correlates of overall depression severity. Disease specificity was evaluated in two independent samples comprising 2108 healthy controls, and in 260 clinical controls with bipolar disorder. Results showed that MDD patients with more severe insomnia had a smaller cortical surface area, mostly driven by the right insula, left inferior frontal gyrus pars triangularis, left frontal pole, right superior parietal cortex, right medial orbitofrontal cortex, and right supramarginal gyrus. Associations were specific for insomnia severity, and were not found for overall depression severity. Associations were also specific to MDD; healthy controls and clinical controls showed differential insomnia severity association profiles. The findings indicate that MDD patients with more severe insomnia show smaller surfaces in several frontoparietal cortical areas. While explained variance remains small, symptom-specific associations could bring us closer to clues on underlying biological phenomena of MDD.