[Show abstract][Hide abstract] ABSTRACT: Emerging data suggest that Electro-Convulsive Treatment (ECT) may reduce depressive symptoms by increasing the expression of Brain-Derived Neurotrophic Factor (BDNF). Yet, conflicting findings have been reported. For this reason we performed a systematic review and meta-analysis of the preclinical and clinical literature on the association between ECT treatment (ECS in animals) and changes in BDNF concentrations and their effect on behavior. In addition, regional brain expression of BDNF in mouse and human brains were compared using Allen Brain Atlas. ECS, over sham, increased BDNF mRNA and protein in animal brain (effect size [Hedge's g]: 0.38-0.54; 258 effect-size estimates, N = 4,284) but not in serum (g = 0.06, 95% CI = -0.05-0.17). In humans, plasma but not serum BDNF increased following ECT (g = 0.72 vs. g = 0.14; 23 effect sizes, n = 281). The gradient of the BDNF increment in animal brains corresponded to the gradient of the BDNF gene expression according to the Allen brain atlas. Effect-size estimates were larger following more ECT sessions in animals (r = 0.37, P < .0001) and in humans (r = 0.55; P = 0.05). There were some indications that the increase in BDNF expression was associated with behavioral changes in rodents, but not in humans. We conclude that ECS in rodents and ECT in humans increase BDNF concentrations but this is not consistently associated with changes in behavior.
PLoS ONE 11/2015; 10(11):e0141564. DOI:10.1371/journal.pone.0141564 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Minor depression is diagnosed when a patient suffers from 2 to 4 depressive symptoms for at least 2 weeks. Though minor depression is a widespread phenomenon, its pathophysiology has hardly been studied. To get a first insight into the pathophysiological mechanisms underlying this disorder we assessed serum levels of biomarkers for plasticity, glial and neuronal function: brain-derived neurotrophic factor (BDNF), S100B and neuron specific enolase (NSE). 27 subjects with minor depressive episode and 82 healthy subjects over 60 years of age were selected from the database of the Leipzig population-based study of civilization diseases (LIFE). Serum levels of BDNF, S100B and NSE were compared between groups, and correlated with age, body-mass index (BMI), and degree of white matter hyperintensities (score on Fazekas scale). S100B was significantly increased in males with minor depression in comparison to healthy males, whereas other biomarkers did not differ between groups (p = 0.10-0.66). NSE correlated with Fazekas score in patients with minor depression (rs = 0.436, p = 0.048) and in the whole sample (rs = 0.252, p = 0.019). S100B correlated with BMI (rs = 0.246, p = 0.031) and with age in healthy subjects (rs = 0.345, p = 0.002). Increased S100B in males with minor depression, without alterations in BDNF and NSE, supports the glial hypothesis of depression. Correlation between white matter hyperintensities and NSE underscores the vascular hypothesis of late life depression.
[Show abstract][Hide abstract] ABSTRACT: Background:
The impact of genetic polymorphisms on cognition is assumed to increase with age as losses of brain resources have to be compensated for. We investigate the relation of catechol-O-methyltransferase (COMT)p.Val158Met polymorphism and cognitive capacity in the course of adult development, healthy aging and the development of mild cognitive impairment (MCI) in two birth cohorts of subjects born between 1930 and 1932 or between 1950 and 1952.
Thorough neuropsychological assessment was conducted in a total of 587 participants across three examination waves between 1993 and 2008. The COMT genotype was determined as a restriction fragment length polymorphism after PCR amplification and digestion with NlaIII.
Significant effects of the COMTp.Val158Met polymorphism were identified for attention and cognitive flexibility in the younger but not the older cohort.
These results confirm the importance of the COMTp.Val158Met genotype on tasks assessing attention and cognitive flexibility in midlife but not in healthy aging and the development of MCI. Our findings suggest that the influence of COMT changes as a function of age, decreasing from midlife to aging.
[Show abstract][Hide abstract] ABSTRACT: Background
The LIFE-Adult-Study is a population-based cohort study, which has recently completed the baseline examination of 10,000 randomly selected participants from Leipzig, a major city with 550,000 inhabitants in the east of Germany. It is the first study of this kind and size in an urban population in the eastern part of Germany. The study is conducted by the Leipzig Research Centre for Civilization Diseases (LIFE). Our objective is to investigate prevalences, early onset markers, genetic predispositions, and the role of lifestyle factors of major civilization diseases, with primary focus on metabolic and vascular diseases, heart function, cognitive impairment, brain function, depression, sleep disorders and vigilance dysregulation, retinal and optic nerve degeneration, and allergies.
The study covers a main age range from 40-79 years with particular deep phenotyping in elderly participants above the age of 60. The baseline examination was conducted from August 2011 to November 2014. All participants underwent an extensive core assessment programme (5-6 h) including structured interviews, questionnaires, physical examinations, and biospecimen collection. Participants over 60 underwent two additional assessment programmes (3-4 h each) on two separate visits including deeper cognitive testing, brain magnetic resonance imaging, diagnostic interviews for depression, and electroencephalography.
The participation rate was 33 %. The assessment programme was accepted well and completely passed by almost all participants. Biomarker analyses have already been performed in all participants. Genotype, transcriptome and metabolome analyses have been conducted in subgroups. The first follow-up examination will commence in 2016.
BMC Public Health 07/2015; 15(1). DOI:10.1186/s12889-015-1983-z · 2.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To date, limited data are available regarding the inter-site consistency of test-retest reproducibility of functional connectivity measurements, in particular with regard to integrity of the Default Mode Network (DMN) in elderly participants. We implemented a harmonized resting-state fMRI protocol on 13 clinical scanners at 3.0T using vendor-provided sequences. Each site scanned a group of 5 healthy elderly participants twice, at least a week apart. We evaluated inter-site differences and test-retest reproducibility of both temporal signal-to-noise ratio (tSNR) and functional connectivity measurements derived from: i) seed-based analysis (SBA) with seed in the posterior cingulate cortex (PCC), ii) group independent component analysis (ICA) separately for each site (site ICA), and iii) consortium ICA, with group ICA across the whole consortium. Despite protocol harmonization, significant and quantitatively important inter-site differences remained in the tSNR of resting-state fMRI data; these were plausibly driven by hardware and pulse sequence differences across scanners which could not be harmonized. Nevertheless, the tSNR test-retest reproducibility in the consortium was high (ICC=0.81). The DMN was consistently extracted across all sites and analysis methods. While significant inter-site differences in connectivity scores were found, there were no differences in the associated test-retest error. Overall, ICA measurements were more reliable than PCC-SBA, with site ICA showing higher reproducibility than consortium ICA. Across the DMN nodes, the PCC yielded the most reliable measurements (≈4% test-retest error, ICC=0.85), the medial frontal cortex the least reliable (≈12%, ICC=0.82) and the lateral parietal cortices were in between (site ICA). Altogether these findings support usage of harmonized multisite studies of resting-state functional connectivity to characterize longitudinal effects in studies that assess disease progression and treatment response.
[Show abstract][Hide abstract] ABSTRACT: In patients with affective disorders, the full-blown symptomatology of a depressive episode can develop very fast (eg, within 1 d) or slowly over weeks or months. These differences in the speed of onset of depression are likely to reflect stable intraindividual differences in neurobiological pathomechanisms. This article presents available data on this issue from published studies and from a recently unpublished study and discusses the relevance of these data for diagnostic, therapeutic, and research purposes.
On the basis a database search, we reviewed the literature on speed of onset of depressive episodes. Results of a study for which only some of the data have previously been published involving 205 patients with unipolar or bipolar depression were also considered.
Five older studies produced data concerning the speed of onset of depressive episodes. In addition, our research group has conducted 2 other more recent studies that used the Onset of Depression Inventory to assess the speed of onset of depressive episodes. The major findings of the studies we examined were that depression developed within 1 week in 50% to 58% of patients with a bipolar disorder, whereas only in 7.4% to 21.4% of those with unipolar depression. Different depressive episodes appeared to develop at a similar speed within individual subjects (correlation coefficients: 0.46 to 0.66).
Consistent evidence from 2 studies that used the Onset of Depression Inventory revealed that rapid onset of a depressive episode is more common in patients with bipolar disorder than in those with unipolar major depressive disorder and may be an indication of a latent, not yet expressed, bipolar disorder. The neurobiology of the speed of onset of depressive episodes is a topic for future research.
[Show abstract][Hide abstract] ABSTRACT: α4β2* nicotinic receptors (α4β2* nAChRs) could provide a biomarker in neuropsychiatric disorders (e.g. Alzheimer´s and Parkinson’s disease, depressive disorders, and nicotine addiction). However, there is a lack of α4β2* nAChR specific PET radioligands with kinetics fast enough to enable quantification of nAChR within a reasonable time frame. Following on from promising preclinical results, the aim of the present study was to evaluate for the first time in humans the novel PET radioligand (-)-[18 F]Flubatine, formerly known as (-)-[18 F]NCFHEB, as a tool for α4β2* nAChR imaging and in vivo quantification.
[Show abstract][Hide abstract] ABSTRACT: The "Onset of Depression Inventory" (ODI) represents a patient interview which aims to register the speed of onset of depression systematically. The purpose of this study was to evaluate the patient-relative agreement regarding the speed of onset of depression in the patients.
The ODI was investigated in 31 patients with a depressive episode. Moreover, 31 patients' relatives participated in an interview for which a modified version of the ODI (for relatives of depressed patients; ODI-A) was applied.
There was a significant association between patients' estimation of the speed of onset of the depressive episode and relatives' estimation of this parameter in the case of patients and relatives living in a common household (rho = 0.68; p = 0.006).
There was an agreement between patients and their relatives regarding the speed of onset of the current depressive episodes, however only if they lived in a common household.
International Journal of Psychiatry in Clinical Practice 03/2015; 19(3):1-11. DOI:10.3109/13651501.2015.1028413 · 1.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives. Alterations in neuronal and glial integrity are considered to be of pathogenic impact on major depressive disorder (MDD). For MDD, data on cerebrospinal fluid (CSF) levels of neuron-specific enolase (NSE) are lacking and scarce for glial protein S100B. Methods. We measured CSF levels of NSE and S100B in 31 patients with MDD and 32 mentally healthy controls using electrochemiluminescence immunoassays (ECLIA). Results. Adjusted means of NSE were significantly elevated in the MDD patients (11.73 ng/ml (9.95-13.52 95% CI) compared to the controls (6.17 ng/ml (4.55-7.78), F = 9.037, P = 0.004. Effect size for adjusted mean group difference of 5.57 ng/ml was found invariably high (Cohen's d = 1.23). Differentiating MDD from controls, a NSE cut-off of 7.94 ng/ml showed sensitivity of 81% (95% CI 63.7-90.8) and specificity of 75% (95% CI 57.9-86.7). Adjusted levels of S100B did not differ significantly between the two groups (1.12 ng/ml (0.77-1.48) in MDD, 0.97 ng/ml (0.64-1.30) in controls). Conclusions. Our results of elevated CSF-NSE levels support neuronal pathology in MDD and the potential use of CSF-NSE as marker in clinical diagnostics. Missing group differences in S100B do not promote a specific glial pathology in depressive disorders.
The World Journal of Biological Psychiatry 02/2015; 16(2):106-113. DOI:10.3109/15622975.2014.952776 · 4.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Unlabelled:
(-)-(18)F-flubatine is a promising tracer for neuroimaging of nicotinic acetylcholine receptors (nAChRs), subtype α4β2, using PET. Radiation doses after intravenous administration of the tracer in mice and piglets were assessed to determine the organ doses (ODs) and the effective dose (ED) to humans. The results were compared with subsequent clinical investigations in human volunteers.
Twenty-seven female CD1 mice (weight ± SD, 28.2 ± 2.1 g) received intravenous injection of 0.75 ± 0.33 MBq of (-)-(18)F-flubatine. Up to 240 min after injection, 3 animals per time point were sacrificed and the organs harvested, weighed, and counted in a γ counter to determine mass and activity, respectively. Furthermore, whole-body PET scans of 5 female piglets (age ± SD, 44 ± 3 d; weight ± SD, 13.7 ± 1.7 kg) and 3 humans (2 men and 1 woman; age ± SD, 59.6 ± 3.9 y; weight ± SD, 74.3 ± 3.1 kg) were obtained up to 236 min (piglets) and 355 min (humans) after injection of 186.6 ± 7.4 and 353.7 ± 10.2 MBq of (-)-(18)F-flubatine, respectively, using a PET/CT scanner. The CT was used for delineation of the organs. Exponential curves were fitted to the time-activity-data, and time and mass scales were adapted to the human anatomy. The ODs were calculated using OLINDA/EXM (version 1.0); EDs were calculated with the tissue-weighting factors of ICRP103.
After the injection of (-)-(18)F-flubatine, there were no adverse or clinically detectable pharmacologic effects in any of the subjects. The highest activities after injection were found in the kidneys, urinary bladder, and liver. The urinary bladder receives the highest OD in all investigated species, followed by the kidneys and the liver for animals and humans, respectively. On the basis of mouse, piglet, and human kinetic data, the projected human ED of (-)-(18)F-flubatine was estimated to be 12.5 μSv/MBq in mice, 14.7 ± 0.7 μSv/MBq in piglets, and 23.4 ± 0.4 μSv/MBq in humans.
As has been demonstrated for other PET radiotracers, preclinical (i.e., animal-derived) dosimetry underestimates the ED to humans, in the current case of (-)-(18)F-flubatine by 34%-44%.
Journal of Nuclear Medicine 10/2014; 55(11). DOI:10.2967/jnumed.114.137059 · 6.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
The relationship between leptin and affective disorders is still unknown.
We measured free and bound leptin in 13 drug naïve subjects.
Leptin did not significantly differ between patients and controls.
As part of future studies, it also appears useful to distinguish between free and bound leptin.
Psychiatry Research 10/2014; 219(2). DOI:10.1016/j.psychres.2014.05.030 · 2.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction
(-)-[18 F]Flubatine is a PET tracer with high affinity and selectivity for the nicotinic acetylcholine α4β2 receptor subtype. A clinical trial assessing the availability of this subtype of nAChRs was performed. From a total participant number of 21 Alzheimer’s disease (AD) patients and 20 healthy controls (HCs), the following parameters were determined: plasma protein binding, metabolism and activity distribution between plasma and whole blood.
Plasma protein binding and fraction of unchanged parent compound were assessed by ultracentrifugation and HPLC, respectively. The distribution of radioactivity (parent compound + metabolites) between plasma and whole blood was determined ex vivo at different time-points after injection by gamma counting after separation of whole blood by centrifugation into the cellular and non-cellular components. In additional experiments in vitro, tracer distribution between these blood components was assessed for up to 90 min.
A fraction of 15 ± 2 % of (-)-[18 F]Flubatine was found to be bound to plasma proteins. Metabolic degradation of (-)-[18 F]Flubatine was very low, resulting in almost 90 % unchanged parent compound at 90 min p.i. with no significant difference between AD and HC. The radioactivity distribution between plasma and whole blood changed in vivo only slightly over time from 0.82 ± 0.03 at 3 min p.i. to 0.87 ± 0.03 at 270 min p.i. indicating the contribution of only a small amount of metabolites. In vitro studies revealed that (-)-[18 F]Flubatine was instantaneously distributed between cellular and non-cellular blood parts.
(-)-[18 F]Flubatine exhibits very favourable characteristics for a PET radiotracer such as slow metabolic degradation and moderate plasma protein binding. Equilibrium of radioactivity distribution between plasma and whole blood is reached instantaneously and remains almost constant over time allowing both convenient sample handling and facilitated fractional blood volume contribution assessment.
Nuclear Medicine and Biology 07/2014; 41(6). DOI:10.1016/j.nucmedbio.2014.03.018 · 2.41 Impact Factor