Biological Aspects of Late-life Depression

Penninx, B.W.J.H. [Promotor]Vogelzangs, N. [Copromotor]Ferrucci, L. [Copromotor

Arterial stiffness and Vitamin D levels: the Baltimore Longitudinal Study of Aging

CONTEXT: The importance of vitamin D for bone health has long been acknowledged. Recent evidence suggests that vitamin D can also play a role in reducing the risk of several other diseases, including cardiovascular disease. OBJECTIVE: The aim of this study is to test the hypothesis that 25-hydroxyvitamin D (25-OH D) is an independent cross-sectional correlate of central arterial stiffness in a normative aging study population. DESIGN AND SETTINGS: We conducted a cross-sectional analysis. SUBJECTS: We studied 1228 healthy volunteers (50% males; age, 70\ub112 yr) of the Baltimore Longitudinal Study of Aging. MAIN OUTCOME MEASURES: We measured carotid-femoral pulse wave velocity (PWV) and 25-OH D levels. RESULTS: We found a significant inverse association between PWV and 25-OH D levels (adjusted r2=0.27; \u3b2=-0.43; P=0.001). After adjusting for age, gender, ethnicity, season of blood draw, estimated glomerular filtration rate, physical activity level, cardiovascular risk factors score (smoking, visceral obesity, hypercholesterolemia, hypertension, and diabetes), calcium/vitamin D supplementation, serum calcium, and PTH levels, the association between PWV and 25-OH D levels was only slightly reduced and remained statistically significant (adjusted r2=0.34; \u3b2=-0.34; P=0.04). CONCLUSIONS: Vitamin D levels are inversely associated with increased arterial stiffness in a normative aging population, irrespective of traditional risk factor burden. Further research is needed to understand the mechanism of this association and to test the hypothesis that vitamin D supplementation can reduce arterial stiffness

Is the haematopoietic effect of testosterone mediated by erythropoietin? The results of a clinical trial in older men

The stimulatory effects of testosterone on erythropoiesis are very well known, but the mechanisms underlying the erythropoietic action of testosterone are still poorly understood, although erythropoietin has long been considered a potential mediator. A total of 108 healthy men >65 years old with serum testosterone concentration <475 ng/dL were recruited by direct mailings to alumni of the University of Pennsylvania and Temple University, and randomized to receive a 60-cm(2) testosterone or placebo patch for 36 months. Ninety-six subjects completed the trial. We used information and stored serum specimens from this trial to test the hypothesis that increasing testosterone increases haemoglobin by stimulating erythropoietin production. We used information of 67 men, 43 in the testosterone group and 24 in the placebo group who had banked specimens available for assays of testosterone, haemoglobin and erythropoietin at baseline and after 36 months. The original randomized clinical study was primarily designed to verify the effects of testosterone on bone mineral density. The primary outcome of this report was to investigate whether or not transdermal testosterone increases haemoglobin by increasing erythropoietin levels. The mean age +/- SD of the 67 subjects at baseline was 71.8 +/- 4.9 years. Testosterone replacement therapy for 36 months, as compared with placebo, induced a significant increase in haemoglobin (0.86 +/- 0.31 g/dL, p = 0.01), but no change in erythropoietin levels (-0.24 +/- 2.16 mIU/mL, p = 0.91). Included time-varying measure of erythropoietin did not significantly account for the effect of testosterone on haemoglobin (Treatment-by-time: beta = 0.93, SE = 0.33, p = 0.01). No serious adverse effect was observed. Transdermal testosterone treatment of older men for 36 months significantly increased haemoglobin, but not erythropoietin levels. The haematopoietic effect of testosterone does not appear to be mediated by stimulation of erythropoietin production

Obesity and atypical depression symptoms: findings from Mendelian randomization in two European cohorts.

Studies considering the causal role of body mass index (BMI) for the predisposition of major depressive disorder (MDD) based on a Mendelian Randomization (MR) approach have shown contradictory results. These inconsistent findings may be attributable to the heterogeneity of MDD; in fact, several studies have documented associations between BMI and mainly the atypical subtype of MDD. Using a MR approach, we investigated the potential causal role of obesity in both the atypical subtype and its five specific symptoms assessed according to the Statistical Manual of Mental Disorders (DSM), in two large European cohorts, CoLaus|PsyCoLaus (n = 3350, 1461 cases and 1889 controls) and NESDA|NTR (n = 4139, 1182 cases and 2957 controls). We first tested general obesity measured by BMI and then the body fat distribution measured by waist-to-hip ratio (WHR). Results suggested that BMI is potentially causally related to the symptom increase in appetite, for which inverse variance weighted, simple median and weighted median MR regression estimated slopes were 0.68 (SE = 0.23, p = 0.004), 0.77 (SE = 0.37, p = 0.036), and 1.11 (SE = 0.39, p = 0.004). No causal effect of BMI or WHR was found on the risk of the atypical subtype or for any of the other atypical symptoms. Our findings show that higher obesity is likely causal for the specific symptom of increase in appetite in depressed participants and reiterate the need to study depression at the granular level of its symptoms to further elucidate potential causal relationships and gain additional insight into its biological underpinnings

Association of CRTC1 polymorphisms with obesity markers in subjects from the general population with lifetime depression.

Psychiatric disorders have been hypothesized to share common etiological pathways with obesity, suggesting related neurobiological bases. We aimed to examine whether CRTC1 polymorphisms were associated with major depressive disorder (MDD) and to test the association of these polymorphisms with obesity markers in several large case-control samples with MDD. The association between CRTC1 polymorphisms and MDD was investigated in three case-control samples with MDD (PsyCoLaus n1=3,362, Radiant n2=3,148 and NESDA/NTR n3=4,663). The effect of CRTC1 polymorphisms on obesity markers was then explored. CRTC1 polymorphisms were not associated with MDD in the three samples. CRTC1 rs6510997C&gt;T was significantly associated with fat mass in the PsyCoLaus study. In fact, a protective effect of this polymorphism was found in MDD cases (n=1,434, β=-1.32%, 95% CI -2.07 to -0.57, p&lt;0.001), but not in controls. In the Radiant study, CRTC1 polymorphisms were associated with BMI, exclusively in individuals with MDD (n=2,138, β=-0.75kg/m(2), 95% CI -1.30 to -0.21, p=0.007), while no association with BMI was found in the NESDA/NTR study. Estimated fat mass using bioimpedance that capture more accurately adiposity was only present in the PsyCoLaus sample. CRTC1 polymorphisms seem to play a role with obesity markers in individuals with MDD rather than non-depressive individuals. Therefore, the weak association previously reported in the population-based samples was driven by cases diagnosed with lifetime MDD. However, CRTC1 seems not to be implicated directly in the development of psychiatric diseases

The association between plasma tryptophan catabolites and depression: the role of symptom profiles and inflammation

Background: Tryptophan catabolites ("TRYCATs") produced by the kynurenine pathway (KP) may play a role in depression pathophysiology. Studies comparing TRYCATs levels in depressed subjects and controls provided mixed findings. We examined the association of TRYCATs levels with 1) the presence of Major Depressive Disorder (MDD), 2) depressive symptom profiles and 3) inflammatory markers.Methods: The sample from the Netherlands Study of Depression and Anxiety included participants with current (n = 1100) or remitted (n = 753) MDD DSM-IV diagnosis and healthy controls (n = 642). Plasma levels of tryptophan (TRP), kynurenine (KYN), kynurenic acid (KynA), quinolinic acid (QA), C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor (TNF) were measured. Atypical/energy-related symptom (AES), melancholic symptom (MS) and anxious-distress symptom (ADS) profiles were derived from questionnaires.Results: After adjustment for age, sex, education, smoking status, alcohol consumption and chronic diseases, no significant differences in TRYCATs were found comparing MDD cases versus controls. The MS profile was associated (q < 0.05) with lower KynA (beta = -0.05), while AES was associated with higher KYN (beta = 0.05), QA (beta = 0.06) and TRP (beta = 0.06). Inflammatory markers were associated with higher KYN (CRP beta = 0.12, IL-6 beta = 0.08, TNF beta = 0.10) and QA (CRP beta = 0.21, IL-6 beta = 0.12, TNF beta = 0.18). Significant differences against controls emerged after selecting MDD cases with high (top 30%) CRP (KYN d = 0.20, QA d = 0.33) and high TNF (KYN d = 0.24; QA d = 0.39).Conclusions: TRYCATs levels were related to specific clinical and biological features, such as atypical symptoms or a proinflammatory status. Modulation of KP may potentially benefit a specific subset of depressed patients. Clinical studies should focus on patients with clear evidence of KP dysregulations.Stress-related psychiatric disorders across the life spa

Neandertal introgression partitions the genetic landscape of neuropsychiatric disorders and associated behavioral phenotypes

Despite advances in identifying the genetic basis of psychiatric and neurological disorders, fundamental questions about their evolutionary origins remain elusive. Here, introgressed variants from archaic humans such as Neandertals can serve as an intriguing research paradigm. We compared the number of associations for Neandertal variants to the number of associations of frequency-matched non-archaic variants with regard to human CNS disorders (neurological and psychiatric), nervous system drug prescriptions (as a proxy for disease), and related, non-disease phenotypes in the UK biobank (UKBB). While no enrichment for Neandertal genetic variants were observed in the UKBB for psychiatric or neurological disease categories, we found significant associations with certain behavioral phenotypes including pain, chronotype/sleep, smoking and alcohol consumption. In some instances, the enrichment signal was driven by Neandertal variants that represented the strongest association genome-wide. SNPs within a Neandertal haplotype that was associated with smoking in the UKBB could be replicated in four independent genomics datasets

Cosmic microwave background polarization, Faraday rotation and stochastic gravity-waves backgrounds

A magnetic field, coherent over the horizon size at the decoupling and strong enough to rotate the polarization plane of the CMBR, can be generated from the electromagnetic vacuum fluctuations amplified by the space-time evolution of the dilaton coupling. The possible relevance of this result for superstring inspired cosmological models is discussed. Particular attention will be paid to the connection between Faraday rotation signals and stochastic gravity-wave backgrounds.Comment: 24 A4 pages in Latex style plus two figures combined into an eps file, accepted for publication in Physical Review

Supplementation-induced increase in circulating omega-3 serum levels is not associated with a reduction in depressive symptoms: Results from the MooDFOOD depression prevention trial

This is the final version. Available from Wiley via the DOI in this record.The data that support the findings of this study are available from the corresponding author upon reasonable request.Background: There is ambiguity on how omega-3 (n-3) polyunsaturated fatty acids (PUFAs) are associated with depression, and what the temporality of the association might be. The present study aimed to examine whether (intervention-induced changes in) n-3 PUFA levels were associated with (changes in) depressive symptoms. Methods: Baseline, 6- and 12-month follow-up data on 682 overweight and subclinically depressed persons from four European countries that participated in the MooDFOOD depression prevention randomized controlled trial were used. Participants were allocated to four intervention groups: (a) placebos, (b) placebos and food-related behavioral activation therapy (F-BA), (c) multinutrient supplements (fish oil and multivitamin), and (d) multinutrient supplements and F-BA. Depressive symptoms were measured using the inventory of depressive symptomatology. PUFA levels (µmol/L) were measured using gas chromatography. Analyses were adjusted for sociodemographics, lifestyle, and somatic health. Results: Increases in n-3 PUFA, docosahexaenoic acid, and eicosapentaenoic acid levels over time were significantly larger in the supplement groups than in placebo groups. Change in PUFA levels was not significantly associated with the change in depressive symptoms (β =.002, SE = 0.003, p =.39; β =.003, SE = 0.005, p =.64; β =.005, SE = 0.005, p =.29; β = −.0002, SE = 0.0004, p =.69). Baseline PUFA levels did not modify the intervention effects on depressive symptoms. Conclusions: In overweight and subclinical depressed persons, multinutrient supplements led to significant increases in n-3 PUFA levels over time, which were not associated with changes in depressive symptoms. Multinutrient supplements do not seem to be an effective preventive strategy in lowering depressive symptoms over time in these at-risk groups.European UnionNational Institute for Health Research (NIHR