Acylcarnitines metabolism in depression: association with diagnostic status, depression severity and symptom profile in the NESDA cohort.

Background: Acylcarnitines (ACs) are involved in bioenergetics processes that may play a role in the pathophysiology of depression. Studies linking AC levels to depression are few and provide mixed findings. We examined the association of circulating ACs levels with Major Depressive Disorder (MDD) diagnosis, overall depression severity and specific symptom profiles. Methods: The sample from the Netherlands Study of Depression and Anxiety included participants with current (n=1035) or remitted (n=739) MDD and healthy controls (n=800). Plasma levels of four ACs (short-chain: acetylcarnitine C2 and propionylcarnitine C3; medium-chain: octanoylcarnitine C8 and decanoylcarnitine C10) were measured. Overall depression severity as well as atypical/energy-related (AES), anhedonic and melancholic symptom profiles were derived from the Inventory of Depressive Symptomatology. Results: As compared to healthy controls, subjects with current or remitted MDD presented similarly lower mean C2 levels (Cohen's d=0.2, p≤1e-4). Higher overall depression severity was significantly associated with higher C3 levels (ß=0.06, SE=0.02, p=1.21e-3). No associations were found for C8 and C10. Focusing on symptom profiles, only higher AES scores were linked to lower C2 (ß=-0.05, SE=0.02, p=1.85e-2) and higher C3 (ß=0.08, SE=0.02, p=3.41e-5) levels. Results were confirmed in analyses pooling data with an additional internal replication sample from the same subjects measured at 6-year follow-up (totaling 4195 observations). Conclusions: Small alterations in levels of short-chain acylcarnitine levels were related to the presence and severity of depression, especially for symptoms reflecting altered energy homeostasis. Cellular metabolic dysfunctions may represent a key pathway in depression pathophysiology potentially accessible through AC metabolism.

Neural correlates of anxious distress in depression: A neuroimaging study of reactivity to emotional faces and resting-state functional connectivity.

BACKGROUND: Comorbid anxiety disorders and anxious distress are highly prevalent in major depressive disorder (MDD). The presence of the DSM-5 anxious distress specifier (ADS) has been associated with worse treatment outcomes and chronic disease course. However, little is known about the neurobiological correlates of anxious distress in MDD. METHODS: We probed the relation between the DSM-5 ADS and task-related reactivity to emotional faces, as well as resting-state functional connectivity patterns of intrinsic salience and basal ganglia networks in unmedicated MDD patients with (MDD/ADS+, N = 24) and without ADS (MDD/ADS-, N = 48) and healthy controls (HC, N = 59). Both categorical and dimensional measures of ADS were investigated. RESULTS: MDD/ADS+ patients had higher left amygdala responses to emotional faces compared to MDD/ADS- patients (p = .015)-part of a larger striato-limbic cluster. MDD/ADS+ did not differ from MDD/ADS- or controls in resting-state functional connectivity of the salience or basal ganglia networks. CONCLUSIONS: Current findings suggest that amygdala and striato-limbic hyperactivity to emotional faces may be a neurobiological hallmark specific to MDD with anxious distress, relative to MDD without anxious distress. This may provide preliminary indications of the underlying mechanisms of anxious distress in depression, and underline the importance to account for heterogeneity in depression research.

White matter architecture in major depression with anxious distress symptoms.

BACKGROUND: Comorbid anxious distress is common in Major Depressive Disorder (MDD), and associated with significantly worse clinical course and treatment response. While DSM-5 recently introduced the Anxious Distress (AD) specifier as a potentially useful symptom-based subtyping scheme for MDD, its neurobiological underpinnings remain unclear. The current study hence uniquely probed whether MDD with co-occurring AD (MDD/AD+) relates to distinct perturbations in frontolimbic white matter (WM) pathways tentatively theorized in MDD/AD+ pathophysiology. METHODS: Tract-based spatial statistics (TBSS) was therefore used to analyze diffusion tensor imaging data on WM microstructure, in MDD/AD+ patients (N = 20) relative to MDD patients without AD (MDD/AD-; N = 29) and healthy controls (HC; N = 39). Using TBSS, we probed fractional anisotropy and axial/radial/mean diffusivity as proxies for WM integrity. Categorical (between-groups) and dimensional (within-patients) analyses subsequently assessed how Anxious Distress in MDD impacts frontolimbic WM connectivity. Receiver-Operating Characteristics additionally assessed classification capabilities of between-groups WM effects. RESULTS: Compared to MDD/AD- and HC participants, MDD/AD+ patients exhibited diminished integrity within the anterior thalamic radiation (ATR). Higher AD specifier scores within MDD patients additionally related to diminished integrity of the uncinate fasciculus and cingulum pathways. These effects were not confounded by key clinical (e.g., comorbid anxiety disorder) and sociodemographic (e.g., age/sex) factors, with altered ATR integrity moreover successfully classifying MDD/AD+ patients from MDD/AD- and HC participants (90% sensitivity | 73% specificity | 77% accuracy). CONCLUSIONS: These findings collectively link MDD/AD+ to distinct WM anomalies in frontolimbic tracts important to adaptive emotional functioning, and may as such provide relevant, yet preliminary, clues on MDD/AD+ pathophysiology.

Seasonality in depressive and anxiety symptoms among primary care patients and in patients with depressive and anxiety disorders; results from the Netherlands Study of Depression and Anxiety.

BACKGROUND: Little is known about seasonality of specific depressive symptoms and anxiety symptoms in different patient populations. This study aims to assess seasonal variation of depressive and anxiety symptoms in a primary care population and across participants who were classified in diagnostic groups 1) healthy controls 2) patients with a major depressive disorder, 3) patients with any anxiety disorder and 4) patients with a major depression and any anxiety disorder. METHODS: Data were used from the Netherlands Study of Depression and Anxiety (NESDA). First, in 5549 patients from the NESDA primary care recruitment population the Kessler-10 screening questionnaire was used and data were analyzed across season in a multilevel linear model. Second, in 1090 subjects classified into four groups according to psychiatric status according to the Composite International Diagnostic Interview, overall depressive symptoms and atypical versus melancholic features were assessed with the Inventory of Depressive Symptoms. Anxiety and fear were assessed with the Beck Anxiety Inventory and the Fear questionnaire. Symptom levels across season were analyzed in a linear regression model. RESULTS: In the primary care population the severity of depressive and anxiety symptoms did not show a seasonal pattern. In the diagnostic groups healthy controls and patients with any anxiety disorder, but not patients with a major depressive disorder, showed a small rise in depressive symptoms in winter. Atypical and melancholic symptoms were both elevated in winter. No seasonal pattern for anxiety symptoms was found. There was a small gender related seasonal effect for fear symptoms. CONCLUSIONS: Seasonal differences in severity or type of depressive and anxiety symptoms, as measured with a general screening instrument and symptom questionnaires, were absent or small in effect size in a primary care population and in patient populations with a major depressive disorder and anxiety disorders.

Clinical and physiological correlates of irritability in depression: results from the Netherlands study of depression and anxiety.

Objective. Irritable and nonirritable depressed patients differ on demographic and clinical characteristics. We investigated whether this extends to psychological and physiological measures. Method. We compared irritable and nonirritable unipolar depressed patients on symptomatology, personality, and (psycho)physiological measures (cortisol, cholesterol, and heart rate variability). Symptomatology was reassessed after one year, and we also compared depressed patients who were irritable or non-irritable at both time points (Irr++ versus Irr--). Results. Almost half (46%; N = 420) of the sample was classified as irritable. These patients scored higher on depression severity, anxiety, hypomanic symptoms, and psychological variables. No differences were observed on physiological markers after correction for depression severity. The same pattern was found when comparing Irr++ and Irr-- groups. Conclusion. Irritable and non-irritable depressed patients differ on clinical and psychological variables, but not on the currently investigated physiological markers. The clinical relevance of the distinction and the significance of the hypomanic symptoms remain to be demonstrated.

Physical exercise and comorbidity. Results from the Fitness and Arthritis in Seniors Trial (FAST).

BACKGROUND AND AIMS: Physical exercise is associated with a lower risk of disability. The impact of comorbidity on the benefits from physical exercise has not been clearly investigated. Elders with comorbidity may benefit from physical exercise to preserve physical function. METHODS: Data are from 435 participants with knee osteoarthritis aged > or = 60 years enrolled in the Fitness and Arthritis in Seniors Trial (FAST), who were randomly assigned to 18-month health educational (HE), weight training (WT), or aerobic exercise (AE) interventions. Comorbidity was defined as the presence of osteoarthritis and > or = 2 clinical conditions. Percent changes in the 6-minute walk test, self-reported disability and knee pain from baseline to 3-, 9-, and 18-month follow-up visits were analyzed according to comorbidity, using analysis of variance. Significances were adjusted using the Bonferroni method. RESULTS: Mean age of the sample was 68.7 years. In participants with comorbidity (n=197), those in the AE intervention showed significant improvement in walking speed, compared to WT and HE groups, since the beginning of follow-up. Subjects with comorbidity in AE and WT groups showed improvement of the disability score at the 3-month follow-up visit compared to those in the HE group. This improvement was maintained at the end of the follow-up by the only AE group compared to the HE one (p=0.06). In participants with comorbidity, the pain score was improved by the AE intervention. CONCLUSIONS: AE and WT interventions improve physical function in individuals with comorbidity. AE improves physical function and knee pain independently of the presence of comorbidity.

Lipoprotein peroxidation and mobility limitation: results from the Health, Aging, and Body Composition Study.

BACKGROUND: Oxidative damage plays an important role in leading to major health-related events. The aim of this study was to assess the predictive value of a lipoprotein peroxidation marker, oxidized low-density lipoprotein (oxLDL) for incident mobility limitation (ML). METHODS: Data are from 2985 well-functioning elders enrolled in the Health ABC study (median follow-up, 4.1 years). All oxLDL levels were measured at the baseline assessment. The oxLDL/LDL cholesterol (LDL-C) ratio (log value) was used as a measure of lipoprotein peroxidation. Mobility limitation was defined by 2 consecutive semiannual reports of any difficulty either walking 1/4 mile or climbing up 10 steps without resting. Severe ML was defined by 2 consecutive reports of great difficulty or inability to do the same tasks. Cox proportional hazards models were performed to assess hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: The mean (SD) age of the sample was 74.2 (2.9) years. After adjustment for potential confounders (sociodemographic factors, smoking, physical activity, body mass index, clinical conditions, biological markers, and medications), the relationship between the oxLDL/LDL-C ratio and disability events was statistically significant (per log-unit difference in the oxLDL/LDL-C ratio) (for ML: HR, 1.22; 95% CI, 1.06-1.41; for severe ML: HR, 1.43; 95% CI, 1.15-1.79). Consistent results were found when interleukin 6 level was included as a covariate in the adjusted models (ML: HR, 1.13; 95% CI, 0.98-1.31; severe ML: HR, 1.31; 95% CI, 1.05-1.64). No significant sex, race, interleukin 6 level, or clinical conditions interaction was found with the oxLDL/LDL-C ratio and mobility disability. CONCLUSIONS: Lipoprotein peroxidation predicts the onset of ML in older persons. The oxLDL predictive value for ML is partly explained by interleukin 6 levels.

Prognostic value of usual gait speed in well-functioning older people--results from the Health, Aging and Body Composition Study.

OBJECTIVES: To define clinically relevant cutpoints for usual gait speed and to investigate their predictive value for health-related events in older persons. DESIGN: Prospective cohort study. SETTING: Health, Aging and Body Composition Study. PARTICIPANTS: Three thousand forty-seven well-functioning older persons (mean age 74.2). MEASUREMENTS: Usual gait speed on a 6-m course was assessed at baseline. Participants were randomly divided into two groups to identify (Sample A; n=2,031) and then validate (Sample B; n=1,016) usual gait-speed cutpoints. Rates of persistent lower extremity limitation events (mean follow-up 4.9 years) were calculated according to gait speed in Sample A. A cutpoint (defining high- (< 1 m/s) and low risk (> or = 1 m/s) groups) was identified based on persistent lower extremity limitation events. The predictive value of the identified cutpoints for major health-related events (persistent severe lower extremity limitation, death, and hospitalization) was evaluated in Sample B using Cox regression analyses. RESULTS: A graded response was seen between risk groups and health-related outcomes. Participants in the high-risk group had a higher risk of persistent lower extremity limitation (rate ratio (RR)=2.20, 95% confidence interval (CI)=1.76-2.74), persistent severe lower extremity limitation (RR=2.29, 95% CI=1.63-3.20), death (RR=1.64, 95% CI=1.14-2.37), and hospitalization (RR=1.48, 95% CI=1.02-2.13) than those in the low-risk group. CONCLUSION: Usual gait speed of less than 1 m/s identifies persons at high risk of health-related outcomes in well-functioning older people. Provision of a clinically meaningful cutpoint for usual gait speed may facilitate its use in clinical and research settings.

Sarcopenia, obesity, and inflammation--results from the Trial of Angiotensin Converting Enzyme Inhibition and Novel Cardiovascular Risk Factors study.

BACKGROUND: Age-related body-composition changes are associated with health-related outcomes in elders. This relation may be explained by inflammation and hemostatic abnormalities. OBJECTIVES: Our objectives were to evaluate the relation between body-composition measures [body mass index (BMI), total fat mass, and appendicular lean mass (aLM)] and C-reactive protein (CRP), interleukin 6 (IL-6), and plasminogen activator inhibitor 1 (PAI-1) and to explore the effect of obesity and sarcopenia on CRP, IL-6, and PAI-1 concentrations. DESIGN: The data are from the Trial of Angiotensin Converting Enzyme Inhibition and Novel Cardiovascular Risk Factors (TRAIN) study baseline visit (n = 286; mean age = 66.0 y). Total fat mass and aLM were assessed with a dual-energy X-ray absorptiometry scan. Linear regressions were performed between body-composition measures and CRP, IL-6, or PAI-1 concentrations. The effect of sarcopenia and obesity (defined as the percentage of fat mass) on CRP, IL-6, and PAI-1 concentrations was evaluated with the use of analyses of covariance. RESULTS: CRP and IL-6 were positively associated with both BMI [beta = 0.027 (P = 0.03) and beta = 0.048 (P < 0.001), respectively] and total fat mass [beta = 0.049 (P < 0.001) and beta = 0.055 (P < 0.001), respectively] and were inversely associated with fat-adjusted aLM [beta = -0.629 (P = 0.002) and beta = -0.467 (P = 0.02), respectively]. PAI-1 was positively associated with both BMI (beta = 0.038, P = 0.005) and total fat mass (beta = 0.032, P = 0.007). No significant interaction was found between either obesity or sarcopenia and CRP, IL-6, and PAI-1 concentrations. Obesity remained significantly associated with high CRP and IL-6 concentrations after adjustments for sarcopenia. CONCLUSIONS: CRP and IL-6 are positively associated with total fat mass and negatively associated with aLM. Obesity-associated inflammation may play an important role in the age-related process that leads to sarcopenia. The relation of inflammation with sarcopenia was not independent of any of the considered obesity indexes.

Bone density and hemoglobin levels in older persons: results from the InCHIANTI study.

Hypoxemia has been recognized as a risk factor for bone loss. The aim of the present study is to investigate the relationship of bone mass and density measures with anemia and hemoglobin levels in a large sample of older community-dwelling persons. The study is based on data from 950 participants enrolled in the "Invecchiare in Chianti" (Aging in the Chianti area, InCHIANTI) study. All the analyses were performed considering continuous hemoglobin levels as well as the dichotomous anemia variable (defined according to WHO criteria as hemoglobin < 12 g/dl in women and < 13 g/dl in men). A peripheral quantitative computerized tomography (pQCT) scan of the right calf was performed in all participants to evaluate total bone density, trabecular bone density, cortical bone density, and the ratio between cortical and total bone area. Linear regression analyses were used to assess the multivariate relationship of pQCT bone measures with anemia and hemoglobin levels after adjustment for demographics, chronic conditions, muscle strength and biological variables. Participants were 75.0 (SD 6.9) years old. In our sample, 101 participants (10.6%) were anemic. In women, coefficients from adjusted linear regression analyses evaluating the association between pQCT bone measures (per SD increase) and hemoglobin levels/anemia showed significant associations of anemia with total bone density (beta = -0.335, SE = 0.163; P = 0.04) and cortical bone density (beta = -0.428, SE = 0.160; P = 0.008). Relationships with borderline significance were found for the associations of anemia with trabecular bone density and the ratio between cortical and total bone area. Significant associations were found between hemoglobin levels and trabecular bone density (beta = 0.112, SE = 0.049; P = 0.02), total bone density (beta = 0.101, SE = 0.046; P = 0.03), cortical bone density (beta = 0.100, SE = 0.046; P = 0.03) and the ratio between cortical bone and total area (beta = 0.092, SE = 0.045; P = 0.04). In men, significant associations were found for hemoglobin levels with total bone density (beta = 0.076, SE = 0.036; P = 0.03) and cortical bone density (beta = 0.095, SE = 0.41; P = 0.02). A borderline significance was reported for the association between anemia and cortical bone density. We concluded that anemia and low hemoglobin levels are negatively and independently associated with bone mass and density. The bone loss associated with hemoglobin levels mainly occurs in the cortical bone. Women with lower hemoglobin levels demonstrate a higher bone loss than male counterparts.