Tryptophan catabolites and depression in the general population: results from the Gutenberg Health Study.

Previous studies reported significantly altered tryptophan catabolite concentrations in major depression. Thus, tryptophan catabolites were considered as potential biomarkers of depression and their modulators as potential targets for psychopharmacotherapy. However, the results were based mainly on studies with small sample sizes limiting their generalizability. Against this background, we investigated the relationship of peripheral tryptophan catabolites with depression in a population-based sample with n = 3,389 participants (with fasting status ≥ 8 h and C-reactive protein < 10 mg/L). N = 248 had clinically significant depression according to a PHQ-9 score of ≥ 10, n = 1,101 subjects had mild depressive symptoms with PHQ-9 scores between 5 and 9, and n = 2,040 had no depression. After multivariable adjustment, clinically significant depression was associated with lower kynurenine and kynurenic acid. Spearman correlation coefficients of the tryptophan catabolites with the severity of depression were very small (rho ≤ 0.080, p ≤ 0.015). None of the tryptophan catabolites could diagnostically separate depressed from not depressed persons. Concerning linear associations, kynurenine and kynurenic acid were associated only with the severity and the cognitive dimension of depression but not its somatic dimension. Tryptophan catabolites were not associated with persistence or recurrence of depression at the 5 year follow-up. The results replicated the association between kynurenine and kynurenic acid with depression. However, the associations were small raising doubts about their clinical utility. Findings underline the complexity of the relationships between depression and tryptophan catabolites. The search for subgroups of depression with a potentially higher impact of depression might be warranted.

New onset of depression in aging women and men: contributions of social, psychological, behavioral, and somatic predictors in the community.

BACKGROUND: Based on the vulnerability-stress model, we aimed to (1) determine new onset of depression in individuals who had not shown evidence of depression at baseline (5 years earlier) and (2) identify social, psychological, behavioral, and somatic predictors. METHODS: Longitudinal data of N = 10 036 participants (40-79 years) were evaluated who had no evidence of depression at baseline based on Patient Health Questionnaire (PHQ-9), no history of depression, or intake of antidepressants. Multivariate logistic regression models were used to predict the onset of depression. RESULTS: Prevalence of new cases of depression was 4.4%. Higher rates of women (5.1%) than men (3.8%) were due to their excess incidence <60 years of age. Regression analyses revealed significant social, psychological, behavioral, and somatic predictors: loneliness [odds ratio (OR) 2.01; 95% confidence interval (CI) 1.48-2.71], generalized anxiety (OR 2.65; 1.79-3.85), social phobia (OR 1.87; 1.34-2.57), panic (OR 1.67; 1.01-2.64), type D personality (OR 1.85; 1.47-2.32), smoking (OR 1.35; 1.05-1.71), and comorbid cancer (OR 1.58; 1.09-2.24). Protective factors were age (OR 0.88; 0.83-0.93) and social support (OR 0.93; 0.90-0.95). Stratified by sex, cancer was predictive for women; for men smoking and life events. Entered additionally, the PHQ-9 baseline score was strongly predictive (OR 1.40; 1.34-1.47), generalized anxiety became only marginally, and panic was no longer predictive. Other predictors remained significant, albeit weaker. CONCLUSIONS: Psychobiological vulnerability, stress, and illness-related factors were predictive of new onset of depression, whereas social support was protective. Baseline subclinical depression was an additional risk weakening the relationship between anxiety and depression by taking their overlap into account. Vulnerability factors differed between men and women.

Investigation of the predictive validity of laser-EPs in normal, UVB-inflamed and capsaicin-irritated skin with four analgesic compounds in healthy volunteers.

AIMS: The aim of the present study was to assess the predictivity of laser-(radiant-heat)-evoked potentials (LEPs) from the vertex electroencephalogram, using an algesimetric procedure, testing the anti-nociceptive/anti-hyperalgesic effects of single oral doses of four marketed analgesics (of different compound classes) vs. placebo, in healthy volunteers with three skin types. METHODS: This was a randomized, placebo-controlled, single-blind, five-way-crossover trial. Twenty-five healthy male/female Caucasians were included (receiving celecoxib 200 mg, pregabalin 150 mg, duloxetine 60 mg, lacosamide 100 mg or placebo) in a Williams design, with CO2 laser-induced painful stimuli to normal, ultraviolet (UV) B-inflamed and capsaicin-irritated skin. LEPs and visual analogue scale ratings were taken at baseline and hourly for 6 h postdose from all three skin types. RESULTS: In normal skin, the averaged postdose LEP peak-to-peak-(PtP)-amplitudes were reduced by pregabalin (-2.68 µV; 95% confidence interval (CI) -4.16, 1.19) and duloxetine (-1.73 µV; 95% CI -3.21, -0.26) but not by lacosamide and celecoxib vs. placebo. On UVB-irradiated skin, reflecting inflammatory pain, celecoxib induced a pronounced reduction in LEP PtP amplitudes vs. placebo (-6.2 µV; 95% CI -7.88, -4.51), with a smaller reduction by duloxetine (-4.54 µV; 95% CI -6.21, -2.87) and pregabalin (-3.72 µV; 95% CI -5.40, -2.04), whereas lacosamide was inactive. LEP PtP amplitudes on capsaicin-irritated skin, reflecting peripheral/spinal sensitization, as in neuropathic pain, were reduced by pregabalin (-3.78 µV; 95% CI -5.31, -2.25) and duloxetine (-2.32 µV; 95% CI -3.82, -0.82) but not by celecoxib or lacosamide vs. placebo, which was in agreement with known clinical profiles. Overall, PtP amplitude reductions were in agreement with subjective ratings. CONCLUSIONS: LEP algesimetry is sensitive to analgesics with different modes of action and may enable the effects of novel analgesics to be assessed during early clinical development.

A new dopaminergic nigro-olfactory projection.

Parkinson disease (PD) is a neurodegenerative disorder characterized by massive loss of midbrain dopaminergic neurons. Whereas onset of motor impairments reflects a rather advanced stage of the disorder, hyposmia often marks the beginning of the disease. Little is known about the role of the nigro-striatal system in olfaction under physiological conditions and the anatomical basis of hyposmia in PD. Yet, the early occurrence of olfactory dysfunction implies that pathogens such as environmental toxins could incite the disease via the olfactory system. In the present study, we demonstrate a dopaminergic innervation from neurons in the substantia nigra to the olfactory bulb by axonal tracing studies. Injection of two dopaminergic neurotoxins-1-methyl-4-phenylpyridinium and 6-hydroxydopamine-into the olfactory bulb induced a decrease in the number of dopaminergic neurons in the substantia nigra. In turn, ablation of the nigral projection led to impaired olfactory perception. Hyposmia following dopaminergic deafferentation was reversed by treatment with the D1/D2/D3 dopamine receptor agonist rotigotine. Hence, we demonstrate for the first time the existence of a direct dopaminergic projection into the olfactory bulb and identify its origin in the substantia nigra in rats. These observations may provide a neuroanatomical basis for invasion of environmental toxins into the basal ganglia and for hyposmia as frequent symptom in PD.

Inflammation predicts new onset of depression in men, but not in women within a prospective, representative community cohort.

Depression has been associated with increased inflammation. However, only few large-scale, prospective studies have evaluated whether inflammation leads to new cases of depression and whether this association can be found in men and women. Longitudinal data of N = 10,357 adult participants with no evidence of depression at baseline (based on Patient Health Questionnaire (PHQ-9), lifetime diagnoses, and current antidepressant medication) were evaluated for depression 5 years later. Multivariate logistic regression models were used to predict the onset of depression based on C-reactive protein (CRP) and white blood cell count (WBC). We used interaction terms and separate analyses in men and women to investigate gender-dependent associations. Based on both markers, inflammation was predictive of new cases of depression 5 years later, even when adjusting for sociodemographic, physical health, health behavior variables, and baseline depression symptoms. As established by interaction terms and separate analyses, inflammatory markers were predictive of depression in men, but not in women. Additional predictors of new onset of depression were younger age, loneliness, smoking (only in men), cancer and less alcohol consumption (only in women). The study indicates gender differences in the etiology of depressive disorders within the community, with a greater role of physical factors in men.

Course of depressive symptoms in men and women: differential effects of social, psychological, behavioral and somatic predictors.

In this study, we aimed to identify the most important and sex-specific social, psychological, behavioral and somatic predictors of recurrent depressive symptoms. Data was obtained at two measurement points within five years by the Gutenberg Health Study (GHS). Out of N = 12,061 individuals, a sample of 877 (age 52.3 ± 9.9) who reported clinically relevant depressive symptoms at baseline was analyzed. Univariate analyses and multiple logistic regression analyses were conducted. Almost half of participants depressed at baseline also reported depressive symptoms five years later. Sex-stratified multivariate analyses revealed that solely social support remained a significant protective predictor against recurrence of depression in men (OR = 0.93; CI95% = 0.87-0.99), whereas in women smoking (OR = 1.97; CI95% = 1.23-3.22), and Type D personality (OR = 1.65; CI95% = 1.10-2.49) were significant risk factors. However, when analyzing the entire sample, no interaction effect between sex and each predictor turned out to be significant. Only social support was retained as an overall predictive factor. As depressive symptoms recur, depressive vulnerability is established involving personality, health behavior and social factors. Although no significant sex-specific interactions were observed, sex-stratified analyses point out different patterns for relevant predictors of recurrent depressive symptoms in men and women.

Gray matter networks and clinical progression in subjects with predementia Alzheimer's disease.

We studied whether gray matter network parameters are associated with rate of clinical progression in nondemented subjects who have abnormal amyloid markers in the cerebrospinal fluid (CSF), that is, predementia Alzheimer's disease. Nondemented subjects (62 with subjective cognitive decline; 160 with mild cognitive impairment (MCI); age = 68 ± 8 years; Mini-Mental State Examination (MMSE) = 28 ± 2.4) were selected from the Amsterdam Dementia Cohort when they had abnormal amyloid in CSF (<640 pg/mL). Networks were extracted from gray matter structural magnetic resonance imaging (MRI), and 9 parameters were calculated. Cox proportional hazards models were used to test associations between each connectivity predictor and rate of progression to MCI or dementia. After a median time of 2.2 years, 122 (55%) subjects showed clinical progression. Lower network parameter values were associated with increased risk for progression, with the strongest hazard ratio of 0.29 for clustering (95% confidence interval = 0.12-0.70; p < 0.01). Results remained after correcting for tau, hippocampal volume, and MMSE scores. Our results suggest that at predementia stages, gray matter network parameters may have use to identify subjects who will show fast clinical progression.

EEG spectral analysis as a putative early prognostic biomarker in nondemented, amyloid positive subjects.

We studied whether electroencephalography (EEG)-derived measures of brain oscillatory activity are related to clinical progression in nondemented, amyloid positive subjects. We included 205 nondemented amyloid positive subjects (63 subjective cognitive decline [SCD]; 142 mild cognitive impairment [MCI]) with a baseline resting-state EEG data and ≥1-year follow-up. Peak frequency and relative power of 4 frequency bands were calculated. Relationships between normalized EEG measures and time to clinical progression (conversion from SCD to MCI/dementia or from MCI to dementia) were analyzed using Cox proportional hazard models. One hundred eight (53%) subjects clinically progressed after 2.1 (IQR 1.3-3.0) years. In the total sample, none of the EEG spectral measures were significant predictors. Stratified for baseline diagnosis, we found that in SCD patients higher delta and theta power (HR [95% CI] = 1.7 [1.0-2.7] resp. 2.3 [1.2-4.4]), and lower alpha power and peak frequency (HR [95% CI] = 0.5 [0.3-1.0] resp. 0.6 [0.4-1.0]) were associated with clinical progression over time. In amyloid positive subjects with normal cognition, slowing of oscillatory brain activity is related to clinical progression.

Novel Blood-Based Biomarkers of Cognition, Stress, and Physical or Cognitive Training in Older Adults at Risk of Dementia: Preliminary Evidence for a Role of BDNF, Irisin, and the Kynurenine Pathway.

 Psychosocial stress and physical, cognitive, and social activity predict the risk of cognitive decline and dementia. The aim of this study was to elucidate brain-derived neurotrophic factor (BDNF), irisin, and the kynurenine pathway (KP) as potential underlying biological correlates. We evaluated associations of irisin and the KP with BDNF in serum and with cognition, stress, and activities. Furthermore, changes in serum concentrations of BDNF, irisin, and KP metabolites were investigated after physical or cognitive training. Forty-seven older adults at risk of dementia were assigned to 10 weeks of physical training, cognitive training, or a wait-list control condition. Previous physical, cognitive, and social activities and stressful life events were recorded; global cognition, episodic memory, and executive functions were assessed. Serum levels of L-kynurenine, kynurenic acid, 3-hydroxykynurenine (3-HK), and quinolinic acid (QUIN) were determined by validated assays based on liquid chromatography coupled to tandem mass spectrometry. BDNF and irisin serum levels were determined with enzyme-linked immunosorbent assays. BDNF and irisin correlated positively with global cognition and episodic memory, while the neurotoxic metabolite QUIN correlated negatively with executive functions. Stressful life events were associated with reduced BDNF and increased 3-HK. 3-HK decreased after cognitive training, while BDNF tended to increase after physical training. This suggests that psychosocial stress as well as cognitive and physical training may impact BDNF serum levels and the KP. Irisin and QUIN may constitute novel serum biomarkers of cognitive impairment, in addition to BDNF. Larger scale trials are needed to replicate and extend these novel findings.

Analysis of behavioral asymmetries in the elevated plus-maze and in the T-maze.

When studying functional asymmetries in normal laboratory rats, several behavioral tests have been applied and proven their utility, including turning in rotometers or open-fields, handedness in paw usage, T-maze alternation, and others. Here, we analyzed male Wistar rats in two tests, namely the elevated plus-maze and the T-maze. In these tests, behavioral asymmetries are rather likely to occur, since the animals have to show several types of turns towards the left or right when ambulating through these environments. In a first study using the plus-maze, we provide detailed data on (A) the types of turns which the animals showed when changing their direction within arms (i.e., 180 degrees turns), and (B) the types of turns when proceeding from one arm to an adjacent one (i.e., 90 degrees turns). With respect to asymmetry, we found moderate biases in favor of the right. On the 1st day of plus-maze testing, there was a trend for more rightward turns within arms. On the 2nd day of testing, there was a trend for turns towards the right when alternating between arms of the plus-maze. In a 2nd study, we asked for asymmetries in the plus-maze in animals, which had been treated acutely with the psychostimulatory amphetamine analogue 3,4-methylene-dioxymethamphetamine (MDMA). Psychostimulants drugs, especially amphetamine, have repeatedly been used before in work on functional asymmetry, since they can enhance or reveal asymmetries in normal rats. MDMA had dose-dependent effects on activity, which affected turns within arms, and turns between arms; however, there was only sparse evidence with respect to asymmetry. Interestingly, and if at all, asymmetry was in favor of the right. Finally, we present data for behavior in the T-maze, where we used a spontaneous test version, that is, the animals could explore the maze but had no task to solve. Asymmetries were measured as turns within the start arm (180 degrees), and as left- or rightward turns between arms (90 degrees ) at the T-point of the maze. In both measures, we again obtained evidence for asymmetries in favor of the right. This work supports previous studies showing that the T-maze is suitable to analyze behavioral asymmetries in rats. In addition, it provides new evidence with respect to the elevated plus-maze, indicating that this standard tool of anxiety research may also be useful in research on behavioral asymmetries and their underlying brain mechanisms. Behavioral biases in favor of the right, as shown here, have often been reported before, especially with Wistar rats. Such biases should be taken into account, since they can serve as an approach to study brain/behavior relationships, and since they may affect the outcome of physiological manipulations or behavioral trainings.

Inhibitory avoidance, pain reactivity, and plus-maze behavior in Wistar rats with high versus low rearing activity.

Substantial work has shown that rats although identical in strain, sex, age and housing conditions can differ considerably in terms of behavior and physiology. Such individual differences can be rather stable and may be detected by behavioral screening tests. Here, the degree of behavioral activation in a novel open-field situation has been shown to serve as a useful predictor to classify animals of a given population into sub-groups with high or low activity, based on measures like locomotion or rearing activity. We used such a screening test and assigned larger samples of male adult Wistar rats into those with high versus low rearing activity (HRA/LRA). They were then tested in the elevated plus-maze, in an inhibitory avoidance task, and in two tests of pain reactivity (hot-plate, tail-flick). In the open field, HRA rats not only showed more rearing behavior, but also more locomotor activity than LRA rats. In the plus-maze, HRA rats again showed more rearing behavior. Also, they spent less time in the open arms, and entered the closed arm more often than low responder rats, which is indicative of more anxiety-related behavior than in LRA rats. In the inhibitory avoidance test, HRA and LRA rats showed similar basal step-in latencies, whereas HRA rats had shorter retention scores than LRA rats after experience of footshock, especially when using a higher (0.5 mA) shock intensity. In contrast, repeated exposure to the avoidance apparatus without shock did not affect step-in latencies in either group. In the pain test, HRA and LRA rats behaved similarly, indicating that their differences in inhibitory avoidance behavior were probably not determined on the level of pain processing. The relevance of these findings is discussed in the context of previous work, especially with respect to the role of processing of aversive experiences.

Post-trial treatment with the nicotinic agonist metanicotine: Differential effects in Wistar rats with high versus low rearing activity.

Laboratory rats, although identical in strain, sex, age and housing conditions, can differ considerably in behavior and physiology. When screened in an open-field, for example, Wistar rats can be assigned to subgroups, based on the measure of rearing activity (high, low rearing activity; HRA/LRA). Such rats have previously been found to differ in dopaminergic and cholinergic brain mechanisms, reactivity to cholinergic drugs, and in tests of learning and memory. Here, we asked whether HRA and LRA rats might respond differently to nicotinic treatment, when given during the consolidation of an aversive experience. Therefore, we tested them for performance in an inhibitory avoidance task where they received post-trial injections of either saline, or the nicotinic agonist metanicotine (RJR-2403, 0.017-1.7 mg/kg, i.p.). In support of previous findings, saline-treated LRA rats showed a trend for higher step-in latencies than HRA rats after shock experience. Furthermore, metanicotine was effective only in LRA rats: Compared to their respective saline-treated controls, the retention scores of LRA rats were decreased after post-trial treatment with the highest dose (1.7 mg/kg). Thus, the nicotinic agonist had an amnestic-like effect dependent on dose and subject-dependent factors (HRA/LRA). These findings are discussed with respect to possible drug actions on mnestic and non-mnestic mechanisms, and the importance of taking subject-dependent variability into account when analysing drug effects.

Dopamine and adult neurogenesis.

Dopamine is an important neurotransmitter implicated in the regulation of mood, motivation and movement. We have reviewed here recent data suggesting that dopamine, in addition to being a neurotransmitter, also plays a role in the regulation of endogenous neurogenesis in the adult mammalian brain. In addition, we approach a highly controversial question: can the adult human brain use neurogenesis to replace the dopaminergic neurones in the substantia nigra that are lost in Parkinson's disease?

Overt behavior and ultrasonic vocalization in a fear conditioning paradigm: a dose-response study in the rat.

The behavioral analysis of laboratory rats is usually confined to the level of overt behavior, like locomotion, behavioral inhibition, instrumental responses, and others. Apart from such visible outcome, however, behaviorally relevant information can also be obtained when analyzing the animals' ultrasonic vocalization, which is typically emitted in highly motivational situations, like 22-kHz calls in response to acute or conditioned threat. To further investigate such vocalizations and their relationship with overt behavior, we tested male Wistar rats in a paradigm of Pavlovian fear conditioning, where a tone stimulus (CS) was preceding an aversive foot-shock (US) in a distinct environment. Importantly, the shock dose was varied between groups (0-1.1 mA), and its acute and conditioned outcome were determined. The analysis of visible behavior confirms the usefulness of immobility as a measure of fear conditioning, especially when higher shock doses were used. Rearing and grooming, on the other hand, were more useful to detect conditioned effects with lower shock levels. Ultrasonic vocalization occurred less consistently than changes in overt behavior; however, dose-response relationships were also observed during the phase of conditioning, for example, in latency, call rate and lengths, intervals between calls, and sound amplitude. Furthermore, total calling time (and rate) were highly correlated with overt behavior, namely behavioral inhibition as measured through immobility. These correlations were observed during the phase of fear conditioning, and the subsequent tests. Importantly, conditioned effects in overt behavior were observed, both, to the context and to the CS presented in this context, whereas conditioned vocalization to the context was not observed (except for one rat). In support and extent of previous results, the present data show that a detailed analysis of ultrasonic vocalization can substantially broaden and refine the spectrum of analysis in behavioral work with rats, since it can provide information about situational-, state-, and subject-dependent factors which are partly distinct from what is visible to the experimenter.