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1.
Eur J Epidemiol ; 2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31494793

RESUMO

Inferring a person's smoking habit and history from blood is relevant for complementing or replacing self-reports in epidemiological and public health research, and for forensic applications. However, a finite DNA methylation marker set and a validated statistical model based on a large dataset are not yet available. Employing 14 epigenome-wide association studies for marker discovery, and using data from six population-based cohorts (N = 3764) for model building, we identified 13 CpGs most suitable for inferring smoking versus non-smoking status from blood with a cumulative Area Under the Curve (AUC) of 0.901. Internal fivefold cross-validation yielded an average AUC of 0.897 ± 0.137, while external model validation in an independent population-based cohort (N = 1608) achieved an AUC of 0.911. These 13 CpGs also provided accurate inference of current (average AUCcrossvalidation 0.925 ± 0.021, AUCexternalvalidation0.914), former (0.766 ± 0.023, 0.699) and never smoking (0.830 ± 0.019, 0.781) status, allowed inferring pack-years in current smokers (10 pack-years 0.800 ± 0.068, 0.796; 15 pack-years 0.767 ± 0.102, 0.752) and inferring smoking cessation time in former smokers (5 years 0.774 ± 0.024, 0.760; 10 years 0.766 ± 0.033, 0.764; 15 years 0.767 ± 0.020, 0.754). Model application to children revealed highly accurate inference of the true non-smoking status (6 years of age: accuracy 0.994, N = 355; 10 years: 0.994, N = 309), suggesting prenatal and passive smoking exposure having no impact on model applications in adults. The finite set of DNA methylation markers allow accurate inference of smoking habit, with comparable accuracy as plasma cotinine use, and smoking history from blood, which we envision becoming useful in epidemiology and public health research, and in medical and forensic applications.

2.
J Atten Disord ; : 1087054719855691, 2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31271090

RESUMO

Objective: To investigate beliefs and attitudes of the public toward attention deficit hyperactivity disorder (ADHD) in children and adults. Method: In a representative population survey in Germany (N = 1,008) using computer-assisted telephone interviews, we asked participants about causal beliefs, illness recognition, treatment recommendations, and beliefs about ADHD, presenting an unlabelled vignette of a child or an adult with ADHD. Results: The most frequently endorsed causal beliefs for the depicted child with ADHD were "TV or Internet," "lack of parental affection," and "broken home." In comparison with the child vignette, biological causal beliefs were endorsed more often after the adult vignette. In the child vignette, 66% advised against a treatment with stimulant medication. About 90% of respondents had heard of ADHD. Of those, 20% said they believed ADHD to be not a real disease. Conclusion: Beliefs of the German public partly contradict evidence and should be considered in therapeutical and public contexts.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31284290

RESUMO

Childhood traumatization (CT) is associated with the development of several neuropsychiatric disorders in later life. Experimental data in animals and observational data in humans revealed evidence for biological alterations in response to CT that may contribute to its long-term consequences. This includes epigenetic changes in miRNA levels that contribute to complex alterations of gene expression. We investigated the association between CT and 121 miRNAs in a target sample of N = 150 subjects from the general population and patients from the Department of Psychiatry. We hypothesized that CT exhibits a long-term effect on miRNA plasma levels. We supported our findings using bioinformatics tools and databases. Among the 121 miRNAs 22 were nominally significantly associated with CT and four of them (let-7g-5p, miR-103a-3p, miR-107, and miR-142-3p) also after correction for multiple testing; most of them were previously associated with Alzheimer's disease (AD) or depression. Pathway analyses of target genes identified significant pathways involved in neurodevelopment, inflammation and intracellular transduction signaling. In an independent general population sample (N = 587) three of the four miRNAs were replicated. Extended analyses in the general population sample only (N = 687) showed associations of the four miRNAs with gender, memory, and brain volumes. We gained increasing evidence for a link between CT, depression and AD through miRNA alterations. We hypothesize that depression and AD not only share environmental factors like CT but also biological factors like altered miRNA levels. This miRNA pattern could serve as mediating factor on the biological path from CT to adult neuropsychiatric disorders.

4.
Am J Psychiatry ; 176(8): 651-660, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31164008

RESUMO

OBJECTIVE: More than 90% of people who attempt suicide have a psychiatric diagnosis; however, twin and family studies suggest that the genetic etiology of suicide attempt is partially distinct from that of the psychiatric disorders themselves. The authors present the largest genome-wide association study (GWAS) on suicide attempt, using cohorts of individuals with major depressive disorder, bipolar disorder, and schizophrenia from the Psychiatric Genomics Consortium. METHODS: The samples comprised 1,622 suicide attempters and 8,786 nonattempters with major depressive disorder; 3,264 attempters and 5,500 nonattempters with bipolar disorder; and 1,683 attempters and 2,946 nonattempters with schizophrenia. A GWAS on suicide attempt was performed by comparing attempters to nonattempters with each disorder, followed by a meta-analysis across disorders. Polygenic risk scoring was used to investigate the genetic relationship between suicide attempt and the psychiatric disorders. RESULTS: Three genome-wide significant loci for suicide attempt were found: one associated with suicide attempt in major depressive disorder, one associated with suicide attempt in bipolar disorder, and one in the meta-analysis of suicide attempt in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. No significant associations were found in the meta-analysis of all three disorders. Polygenic risk scores for major depression were significantly associated with suicide attempt in major depressive disorder (R2=0.25%), bipolar disorder (R2=0.24%), and schizophrenia (R2=0.40%). CONCLUSIONS: This study provides new information on genetic associations and demonstrates that genetic liability for major depression increases risk for suicide attempt across psychiatric disorders. Further collaborative efforts to increase sample size may help to robustly identify genetic associations and provide biological insights into the etiology of suicide attempt.

5.
Psychoneuroendocrinology ; 107: 232-240, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31174161

RESUMO

OBJECTIVE: Previous evidence suggested lasting and cumulative effects of traumatization on the renin-angiotensin-aldosterone-system (RAAS). However, it is unclear whether traumas during childhood and those experienced in adulthood differentially impact the RAAS. In this study, we sought to investigate main and putative interactive effects of childhood and adulthood trauma on RAAS functioning. METHODS: Plasma concentrations of renin and aldosterone were measured in a general population sample (n = 2016). Childhood trauma was assessed using the Childhood Trauma Questionnaire (CTQ), adulthood trauma was measured using the PTSD module of the Structured Clinical Interview of the DSM-IV. Linear regression models were calculated to assess the relations between childhood or adulthood traumatization with renin and aldosterone concentrations. RESULTS: Exposure to (ß = 0.094; p = 0.01), severity of childhood trauma (ß = 0.004; p = 0.01) were associated with increased aldosterone, but not renin levels. Results were carried by all dimensions of abuse, while childhood neglect was not associated with altered RAAS activity. In contrast, adulthood traumas (ß = 0.113; p < 0.01) were significantly associated with increased renin concentrations. Subjects with PTSD (renin: ß = 0.345; p = 0.01; aldosterone: ß = 0.232; p = 0.04) and those who had been exposed to both childhood and adulthood trauma showed increases in renin (ß = 0.180; p < 0.01) and aldosterone (ß = 0.340; p < 0.01) levels. DISCUSSION: These findings indicate that trauma is associated with differential alterations of the RAAS depending on the time of traumatization. Moreover, exposure to childhood or adulthood trauma may act synergistically on the RAAS, resulting in severe dysregulation of the RAAS. The results contribute to explain associations between trauma and enhanced risk for physical disease.

6.
Psychol Med ; : 1-12, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31084657

RESUMO

BACKGROUND: Childhood maltreatment (CM) plays an important role in the development of major depressive disorder (MDD). The aim of this study was to examine whether CM severity and type are associated with MDD-related brain alterations, and how they interact with sex and age. METHODS: Within the ENIGMA-MDD network, severity and subtypes of CM using the Childhood Trauma Questionnaire were assessed and structural magnetic resonance imaging data from patients with MDD and healthy controls were analyzed in a mega-analysis comprising a total of 3872 participants aged between 13 and 89 years. Cortical thickness and surface area were extracted at each site using FreeSurfer. RESULTS: CM severity was associated with reduced cortical thickness in the banks of the superior temporal sulcus and supramarginal gyrus as well as with reduced surface area of the middle temporal lobe. Participants reporting both childhood neglect and abuse had a lower cortical thickness in the inferior parietal lobe, middle temporal lobe, and precuneus compared to participants not exposed to CM. In males only, regardless of diagnosis, CM severity was associated with higher cortical thickness of the rostral anterior cingulate cortex. Finally, a significant interaction between CM and age in predicting thickness was seen across several prefrontal, temporal, and temporo-parietal regions. CONCLUSIONS: Severity and type of CM may impact cortical thickness and surface area. Importantly, CM may influence age-dependent brain maturation, particularly in regions related to the default mode network, perception, and theory of mind.

11.
Neuropsychopharmacology ; 44(5): 930-938, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30700816

RESUMO

DNA methylation of the FKBP5 gene is assumed to alter FKBP5 expression and hence the synthesis of the FK506 binding protein 51, a central element of a genomic negative feedback loop for glucocorticoid receptor signaling. The present study aimed to replicate and extend previously reported influences of FKBP5 genotypes, childhood maltreatment and depression on methylation levels of five CpG sites in intron 7 of the FKBP5 gene in a large population-based sample. Besides the single nucleotide polymorphism (SNP) rs1360780, associations of the FKBP5 methylation with 22 other, unlinked FKBP5 SNPs as well as associations between FKBP5 methylation levels and transcription levels were investigated. Using whole-blood methylation of 3965 subjects of the Study of Health in Pomerania (SHIP) reduced methylation levels in TT allele carriers of rs1360780 (OR = 0.975, p = .005) and currently depressed subjects (OR = 0.995, p = 0.005) were found. Further, an impact of two yet undescribed SNPs (rs6910300, rs7771727) on methylation levels was observed. However, main and interactive effects for childhood maltreatment and lifetime major depressive disorder observed in previous studies could not be replicated. Finally, FKBP5 methylation levels were not related to FKBP5 transcription levels in whole blood. Thus, the present study verified the associations of FKBP5 genotypes and state depression on the FKBP5 methylation levels of five CpG sites in intron 7. However, FKBP5 methylation of these five CpG sites could not be validated as a valuable clinical biomarker for biological long-term effects of childhood maltreatment or lifetime depression.

12.
Am J Med Genet B Neuropsychiatr Genet ; 180(6): 439-447, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30708398

RESUMO

Major depressive disorder (MDD) is clinically heterogeneous with prevalence rates twice as high in women as in men. There are many possible sources of heterogeneity in MDD most of which are not measured in a sufficiently comparable way across study samples. Here, we assess genetic heterogeneity based on two fundamental measures, between-cohort and between-sex heterogeneity. First, we used genome-wide association study (GWAS) summary statistics to investigate between-cohort genetic heterogeneity using the 29 research cohorts of the Psychiatric Genomics Consortium (PGC; N cases = 16,823, N controls = 25,632) and found that some of the cohort heterogeneity can be attributed to ascertainment differences (such as recruitment of cases from hospital vs. community sources). Second, we evaluated between-sex genetic heterogeneity using GWAS summary statistics from the PGC, Kaiser Permanente GERA, UK Biobank, and the Danish iPSYCH studies but did not find convincing evidence for genetic differences between the sexes. We conclude that there is no evidence that the heterogeneity between MDD data sets and between sexes reflects genetic heterogeneity. Larger sample sizes with detailed phenotypic records and genomic data remain the key to overcome heterogeneity inherent in assessment of MDD.

13.
Nervenarzt ; 90(3): 260-266, 2019 Mar.
Artigo em Alemão | MEDLINE | ID: mdl-30643953

RESUMO

BACKGROUND: In traumatized parents with mental disorders, pregnancy and related medical examinations can lead to high emotional distress and flashbacks and increase the already tense emotional situation. Besides psychiatric burdens, parental insecurity concerning dealing with and reduced sensitivity for the child often exist. The children themselves have a higher risk of being neglected or abused and to also develop mental disorders. OBJECTIVE: How does interventional research take the special needs of traumatized parents with mental disorders into account? What kind of interventions predominate and what impact do they have on parents and children? MATERIAL AND METHODS: Publications on perinatal and postnatal interventions for traumatized and mentally disordered parents were included in the review if at least one intervention was explicitly described, a parental trauma was discussed and the impact of the intervention on the parents and children was analyzed. RESULTS: A total of 2 reviews and 10 interventional studies were included. Interventions were primarily based on professional educational counseling, psychoeducation, nurse home visits, individual and group therapies and inpatient mother-baby units. The interventions led to reduced psychiatric symptoms, enhanced parental sensitivity for the child's needs, enhanced quality of nurturing and care and an improved mother-child bonding. CONCLUSION: Although only few studies focused on the special needs of traumatized, mentally disordered parents, the described interventions show promising effect sizes, especially in combination with several kinds of interventions. Nevertheless, an adequate integration of fathers into the therapies has so far been neglected.

14.
Mol Psychiatry ; 2019 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-30617275

RESUMO

Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10-8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10-8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10-3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.

15.
Psychiatr Serv ; 70(3): 225-228, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30651059

RESUMO

OBJECTIVE:: The study evaluated a telephone call and text message intervention to improve adherence to medication among patients with severe mental illness. METHODS:: A randomized clinical trial was conducted, and outpatients with schizophrenia or bipolar disorder were assigned to the intervention group or to a usual care control group. The intervention was provided by trained nurses. Medication adherence was measured with the Medication Adherence Report Scale. RESULTS:: The study sample comprised 120 participants. Logistic regression analysis showed that intervention group participants were significantly more likely than control group participants to be medication adherent at 6 months (odds ratio=4.11, p=.007). The superiority of the intervention emerged during months 4 to 6. Social desirability, diagnosis, and medication did not affect the results. CONCLUSIONS:: Telemedicine via telephone can deliver low-threshold support to patients who are otherwise at high risk of progressive nonadherence to their psychotropic medication after 6 months.

16.
Curr Biol ; 29(1): 120-127.e5, 2019 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-30554901

RESUMO

One of the features that distinguishes modern humans from our extinct relatives and ancestors is a globular shape of the braincase [1-4]. As the endocranium closely mirrors the outer shape of the brain, these differences might reflect altered neural architecture [4, 5]. However, in the absence of fossil brain tissue, the underlying neuroanatomical changes as well as their genetic bases remain elusive. To better understand the biological foundations of modern human endocranial shape, we turn to our closest extinct relatives: the Neandertals. Interbreeding between modern humans and Neandertals has resulted in introgressed fragments of Neandertal DNA in the genomes of present-day non-Africans [6, 7]. Based on shape analyses of fossil skull endocasts, we derive a measure of endocranial globularity from structural MRI scans of thousands of modern humans and study the effects of introgressed fragments of Neandertal DNA on this phenotype. We find that Neandertal alleles on chromosomes 1 and 18 are associated with reduced endocranial globularity. These alleles influence expression of two nearby genes, UBR4 and PHLPP1, which are involved in neurogenesis and myelination, respectively. Our findings show how integration of fossil skull data with archaic genomics and neuroimaging can suggest developmental mechanisms that may contribute to the unique modern human endocranial shape.

17.
J Psychosom Res ; 115: 14-23, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30470312

RESUMO

OBJECTIVE: Alexithymia, neuroticism, and extraversion have been described as relevant predictors of mental and physical health conditions, but their putative interactive effects remain poorly understood and their prospective effects are not well studied. The present study has investigated the differential contributions of distinct personality traits in predicting mental and somatic health symptoms in cross-sectional and longitudinal analyses. METHODS: Additive and interactive effects of neuroticism and extraversion (NEO-FFI), the TAS-20 total score (20-Item Toronto Alexithymia Scale) and its factors (Difficulty Identifying Feelings (DIF), Difficulty Describing Feelings (DDF) and External Oriented Thinking (EOT)) have been investigated on depressive symptoms, the number of chronic diseases, somatic and mental subjective health complaints. Analyses have been based on data from the population-based "Study of Health in Pomerania" (SHIP) in cross-sectional (N = 1704) and longitudinal (N = 1244) analyses. RESULTS: In cross-sectional and longitudinal analyses, additive associations of the TAS-20 total score and neuroticism on somatic and mental health complaints have been observed. The effects of the TAS-20 total score have been mainly carried by DIF. Further, in interaction effetcs extraversion has attenuated the negative impact of neuroticism, whereas DIF has augmented it. CONCLUSION: The present study is the first demonstrating longitudinal effects of alexithymia, particularly DIF, neuroticism, and extraversion in predicting mental and somatic health symptoms. Associations between DIF, neuroticism, and extraversion have been additive and interactive. Hence, subjects high in neuroticism and DIF but low in extraversion have reported most health symptoms and thus might be in need for prevention strategies. Treatments chould be adapted to the associated combination of the personality characteristics.

18.
EBioMedicine ; 2018 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-30442561

RESUMO

BACKGROUND: DNA methylation at the GFI1-locus has been repeatedly associated with exposure to smoking from the foetal period onwards. We explored whether DNA methylation may be a mechanism that links exposure to maternal prenatal smoking with offspring's adult cardio-metabolic health. METHODS: We meta-analysed the association between DNA methylation at GFI1-locus with maternal prenatal smoking, adult own smoking, and cardio-metabolic phenotypes in 22 population-based studies from Europe, Australia, and USA (n = 18,212). DNA methylation at the GFI1-locus was measured in whole-blood. Multivariable regression models were fitted to examine its association with exposure to prenatal and own adult smoking. DNA methylation levels were analysed in relation to body mass index (BMI), waist circumference (WC), fasting glucose (FG), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), diastolic, and systolic blood pressure (BP). FINDINGS: Lower DNA methylation at three out of eight GFI1-CpGs was associated with exposure to maternal prenatal smoking, whereas, all eight CpGs were associated with adult own smoking. Lower DNA methylation at cg14179389, the strongest maternal prenatal smoking locus, was associated with increased WC and BP when adjusted for sex, age, and adult smoking with Bonferroni-corrected P < 0·012. In contrast, lower DNA methylation at cg09935388, the strongest adult own smoking locus, was associated with decreased BMI, WC, and BP (adjusted 1 × 10-7 < P < 0.01). Similarly, lower DNA methylation at cg12876356, cg18316974, cg09662411, and cg18146737 was associated with decreased BMI and WC (5 × 10-8 < P < 0.001). Lower DNA methylation at all the CpGs was consistently associated with higher TG levels. INTERPRETATION: Epigenetic changes at the GFI1 were linked to smoking exposure in-utero/in-adulthood and robustly associated with cardio-metabolic risk factors. FUND: European Union's Horizon 2020 research and innovation programme under grant agreement no. 633595 DynaHEALTH.

19.
Neurogastroenterol Motil ; : e13511, 2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-30444067

RESUMO

BACKGROUND: Irritable bowel syndrome (IBS) is associated with reduced quality of life and high healthcare costs. This study aimed to assess the prevalence and risk factors for IBS in a general adult population. METHODS: The Study of Health in Pomerania (SHIP) is a population-based cohort study in northeastern Germany. SHIP-Trend-0 participants enrolled from 2008 to 2012 were grouped according to Rome III criteria (main criteria: abdominal discomfort or crampy or bloating pain for at least six months plus 2/3 additional criteria). Factors associated with IBS were assessed using survey-weighted backward stepwise logistic regression. KEY RESULTS: The final data set included 4194 records. IBS prevalence was 3.5% (3.0%-4.2%). Unemployment (OR: 2.02, 1.26-3.21), headaches (OR: 2.37, 1.59-3.52), mental quality of life (OR: 0.95 per unit increase, 0.93-0.97), and interactions between gender and physical quality of life (P = 0.004) and gender and alexithymia (P = 0.002) predicted IBS probability. The model resulted in a good discrimination (area under the curve = 75.4%) and model fit (F = 0.72, P = 0.69). History of depression (OR: 2.77, 1.94-3.95), back pain (OR: 2.38, 1.69-3.35), early trauma (OR: 1.03, 1.02-1.04), and duration of inpatient treatment within the last twelve months (OR: 1.02, 1.01-1.04) lost their significance in multivariable analysis. CONCLUSIONS & INFERENCES: IBS prevalence was relatively low compared to other studies. Factors predicting IBS were of biological, psychological, and social nature. The association between IBS and pain in different areas of the body indicates a potential underlying complex somatic symptom disorder.

20.
Thyroid ; 28(11): 1434-1442, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30259797

RESUMO

BACKGROUND: Previous patient studies suggest that thyroid dysfunction affects volumes of particular regions of the brain. So far, population-based data related to this topic are lacking. The aim of this study was to investigate associations of serum levels of thyrotropin (TSH), free triiodothyronine, and free thyroxine (fT4) with total brain volume, gray matter volume, white matter volume (WMV), and hippocampal volume (HV) in a population-based study. METHODS: Data on 2557 individuals were pooled from two independent population-based surveys of the Study of Health in Pomerania conducted in Northeast Germany. Brain volumes were determined from images derived from 1.5 T magnetic resonance imaging. Low and high TSH were defined using the cutoffs 0.40 and 3.29 mIU/L, respectively. Associations between thyroid hormone levels and segmented brain volumes were analyzed by linear regression models. Further, voxel-based morphometry was conducted to search for associations with thyroid hormone levels in a hypothesis-free way throughout the whole brain. All models were adjusted for confounders. RESULTS: Only 9/70 individuals with high TSH had low free triiodothyronine or fT4 levels. Individuals with high TSH had significantly lower total brain volume (ß = -26.9 [confidence interval (CI) -49.0 to -4.8]; p = 0.017), WMV (ß = -16.1 [CI -29.4 to -2.7]; p = 0.018), and HV (ß = -223 [CI -395 to -50]; p = 0.011) than individuals with TSH within the reference range, while low TSH was not significantly associated with any of the brain volumes. Voxel-based morphometry analyses revealed a significant positive association with serum fT4 levels in the left middle frontal gyrus. CONCLUSIONS: In conclusion, the results of this study indicate that the subclinical hypothyroid state may lead to a reduced brain volume affecting particularly HV in younger subjects and WMV, which might correspond to subtle microstructural changes in white matter fiber tracts or myelination of the axones. Gray matter seems not to be affected by subclinical hypothyroid states.

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