[Show abstract][Hide abstract] ABSTRACT: Neuron-specific enolase (NSE) is a neuronal glycolytic enzyme of which cerebrospinal fluid (CSF) levels are found altered following acute or prolonged neuronal damage. Investigations concerning the role of NSE in Alzheimer's disease (AD) are conflicting with both elevated and reduced levels. We measured CSF-levels of NSE in 32 patients with AD and 32 healthy subjects (HS) using an electrochemiluminescence immunoassay (ECLIA). Mean levels of adjusted NSE were significantly elevated in AD (18.12ng/mL (95% CI 15.63-20.60), HS 8.46ng/mL (95% CI 5.98-10.94), p=0.00002) and effect size for mean group differences high (1.84). NSE alone (cut-off score 15.80ng/mL, 94% sensitivity, 97% specificity) and in combination with T-tau and P-Tau had high diagnostic accuracy to differentiate AD from HS. NSE correlated significantly with T-tau (r≥0.87, p<0.000001) and P-tau (r≥0.88, p<0.000001) in both AD and HS. Our results indicate elevated CSF-NSE levels to reflect altered neuronal metabolism in AD that may be used in supporting AD diagnostics.
[Show abstract][Hide abstract] ABSTRACT: The functional organization of the brain in segregated neuronal networks has become a leading paradigm in the study of brain diseases. Diffusion tensor imaging (DTI) allows testing the validity and clinical utility of this paradigm on the structural connectivity level. DTI in Alzheimer's disease (AD) suggests a selective impairment of intracortical projecting fiber tracts underlying the functional disorganization of neuronal networks supporting memory and other cognitive functions. These findings have already been tested for their utility as clinical markers of AD in large multicenter studies. Affective disorders, including major depressive disorder (MDD) and bipolar disorder (BP), show a high comorbidity with AD in geriatric populations and may even have a pathogenetic overlap with AD. DTI studies in MDD and BP are still limited to small-scale monocenter studies, revealing subtle abnormalities in cortico-subcortial networks associated with affect regulation and reward/aversion control. The clinical utility of these findings remains to be further explored. The present paper presents the methodological background of diffusion imaging, including DTI and diffusion spectrum imaging, and discusses key findings in AD and affective disorders. The results of our review strongly point toward the necessity of large-scale multicenter multimodal transnosological networks to study the structural and functional basis of neuronal disconnection underlying different neuropsychiatric diseases.
European Archives of Psychiatry and Clinical Neuroscience 03/2014; · 2.75 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 01/2014; · 2.52 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.
[Show abstract][Hide abstract] ABSTRACT: Structural and metabolic alterations in prefrontal brain areas, including the subgenual (SGPFC), medial (MPFC) and dorsolateral prefrontal cortex (DLPFC), have been shown in major depressive disorder (MDD). Still it remains largely unknown how brain connectivity within these regions is altered at the level of neuronal oscillations. Therefore, the goal was to analyze prefrontal electroencephalographic phase synchronization in MDD and its changes after antidepressant treatment. In 60 unmedicated patients and 60 healthy controls (HC), a 15-min resting electroencephalogram (EEG) was recorded in subjects at baseline and in a subgroup of patients after 2 weeks of antidepressant medication. EEG functional connectivity between the SGPFC and the MPFC/DLPFC was assessed with eLORETA (low resolution brain electromagnetic tomography) by means of lagged phase synchronization. At baseline, patients revealed increased prefrontal connectivity at the alpha frequency between the SGPFC and the left DLPFC/MPFC. After treatment, an increased connectivity between the SGPFC and the right DLPFC/MPFC at the beta frequency was found for MDD. A positive correlation was found for baseline beta connectivity and reduction in scores on the Hamilton Depression Rating Scale. MDD is characterized by increased EEG functional connectivity within frontal brain areas. These EEG markers of disturbed neuronal communication might have potential value as biomarkers.
Psychiatry Research Neuroimaging 01/2014; · 3.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Animal epidemiological and clinical studies suggest that cholesterol is a risk factor for Alzheimer's disease (AD). Nevertheless, the relation of cholesterol to mild cognitive impairment (MCI), influence of APOE genotype and its changes in lifespan is controversial. We investigated the potential impact of plasma total cholesterol (TC) on development of MCI and AD in the interdisciplinary longitudinal study on adult development and aging, a representative birth cohort (born 1930-1932), examined in 1993/1994 (VT1), 1997/1998 (VT2), and 2005/2007 (VT3). Of 500 participants at baseline, 381 survived and were examined at VT3. After exclusion of participants with lifetime prevalence of major psychiatric diseases or mild cognitive disorder due to a medical condition, 222 participants were included in the analysis. At VT3, 82 participants had MCI, 22 participants had AD, and 118 were in good health. Participants with MCI and AD at VT3 evidenced higher TC levels at VT1 than those who were healthy. Higher TC levels at baseline were associated with an increased risk for cognitive disorders at VT3 (highest vs. lowest quartile: OR 2.64, 95 % CI 1.12-6.23, p < 0.05). Over the 14 year follow-up, TC levels declined in those with MCI and AD, but remained stable in those who remained healthy. These findings were not modified by APOE genotype or use of cholesterol-lowering medications. Our findings demonstrate that higher TC levels are observed long before the clinical manifestation of MCI and AD in patients without psychiatric or somatic comorbidities and are independent of APOE genotype.
European Archives of Psychiatry and Clinical Neuroscience 11/2013; · 2.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Minor depression (MinD) and mild cognitive impairment (MCI) are common disorders in late life that often coexist. The aim of the present review is to demonstrate prevalence rates of minor depression in older patients with and without MCI.
Electronic database searches were performed through Medline, ISI Web of Knowledge, Psycinfo, and Cochrane library. Two independent reviewers extracted the original studies based on inclusion criteria: representative study population aged 55 and older, diagnostics of MinD according to DSM. Data on prevalence rates, risk factors, comorbidity and health care usage were analyzed.
Point prevalence for MinD is higher in medical settings (median 14.4%) than in the community-based settings (median 10.4%) and primary care patients (median 7.7%). Although minor depression is rarely investigated in elderly persons with MCI, nearly 20% of patients with MCI seem to suffer from MinD. No data was found on the prevalence of MCI in patients with MinD. Risk factors associated with MinD include female gender, history of cerebrovascular diseases, generalized anxiety disorder, loneliness, and long-term institutional care.
Methodological differences of included studies resulted in a broad range of prevalence rates. No data is shown regarding the prevalence of MCI in MinD group due to insufficient evidence.
Our review indicates that MinD is frequent in elderly population. MCI among those subjects has not been sufficiently investigated. Future studies based on clinical structured interviews should be performed in longitudinal design in order to differentiate late-life depression from progressive MCI or early manifestation of Alzheimer's disease.
Journal of affective disorders 09/2013; · 3.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Typical hallmarks of Alzheimer's disease (AD) are pathologic deposits in cortical and subcortical regions consisting of self-aggregated proteins such as amyloid-beta (Aβ) or tau. Tissue transglutaminase (tTG) catalyses calcium-dependent cross-linking between proteins (transamidation) resulting in protease-resistant isopeptide bonds. Because of this ability, tTG was suspected to participate in AD pathogenesis. Aβ and tau can be cross-linked by tTG in vitro. In AD neocortex, messenger RNA expression of tTG is increased. However, data on transamidation in AD specimens-activity of not only tTG but also other transglutaminases-are contradictory. The aim of our study was to investigate if tTG is involved in AD development and may be useful as biomarker for AD. We studied human brain samples for tTG concentration, tTG localization, and transamidation activity and cerebrospinal fluid (CSF) for tTG content by novel sensitive and highly specific methods. Neither tTG concentration nor transamidation was increased in AD brain homogenates. Immunohistologically, we found no colocalization of tTG in neocortex sections with tau or Aβ deposits but with blood vessels. Only in rare cases, tTG was detectable in CSF samples. This could be attributed to liberation from erythrocytes. Our data contradict the view that tTG is a potential biochemical marker for AD.
Neurobiology of aging 06/2013; · 5.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to assess regional cerebral perfusion distribution in patients with Alzheimer disease (AD) or mild cognitive impairment (MCI) using dynamic susceptibility contrast magnetic resonance imaging.
Regional changes of perfusion were evaluated in 34 patients with AD, 51 patients with MCI, and 23 healthy controls (HCs). Using region of interest analyses, regional cerebral blood flow (CBF), cerebral blood volume, and mean transit time were measured bilaterally in the hippocampus; the temporal, temporoparietal, frontal, and sensomotoric cortices; the anterior and posterior cingulate gyri; the lentiform nucleus; and the cerebellum.
A significant reduction of CBF in patients with AD compared to HCs was shown in the frontal and temporoparietal cortices bilaterally, the lentiform nuclei bilaterally, the left posterior cingulate gyrus, and the cerebellum. Compared with patients with MCI, patients with AD presented a reduction of CBF in the frontal cortices bilaterally, the left temporoparietal cortex, and the left anterior and posterior cingulate gyrus. In both hippocampi and the posterior cingulate gyrus, a trend to a slight increase of CBF in patients with MCI was noticed with a decrease in patients with AD.
Using dynamic susceptibility contrast magnetic resonance imaging, pathologic alterations of regional brain perfusion can be demonstrated in patients with AD compared to patients with MCI or HCs.
[Show abstract][Hide abstract] ABSTRACT: Recently, mood disorders have been discussed to be characterized by glial pathology. The protein S100B, a growth and differentiation factor, is located in, and may actively be released by astro- and oligodendrocytes. This protein is easily assessed in human serum and provides a useful parameter for glial activation or injury. Here, we review studies investigating the glial marker S100B in serum of patients with mood disorders. Studies consistently show that S100B is elevated in mood disorders; more strongly in major depressive than bipolar disorder. Consistent with the glial hypothesis of mood disorders, serum S100B levels interact with age with higher levels in elderly depressed subjects. Successful antidepressive treatment has been associated with serum S100B reduction in major depression, whereas there is no evidence of treatment effects in mania. In contrast to the glial marker S100B, the neuronal marker protein neuron-specific enolase is unaltered in mood disorders. Recently, serum S100B has been linked to specific imaging parameters in the human white matter suggesting a role for S100B as an oligodendrocytic marker protein. In sum, serum S100B can be regarded as a promising in vivo biomarker for mood disorders deepening the understanding of the pathogenesis and plasticity-changes in these disorders. Future longitudinal studies combining serum S100B with other cell-specific serum parameters and multimodal imaging are warranted to further explore this serum protein in the development, monitoring and treatment of mood disorders.
Current drug targets 05/2013; · 3.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: The 'Onset of Depression Inventory' (ODI) is a patient interview developed for systematically registering the speed of onset of depression. The ODI might contribute to the detection of hidden bipolarity because in previous studies a more rapid depression onset was found in patients with bipolar compared to unipolar depression. The aim of this study was to evaluate the test-retest stability of the ODI. Patients were asked concerning the speed of onset at the time of hospitalization and again before discharge. Sampling and Methods: Test-retest stability of the ODI was investigated in 37 patients with a depressive episode. Each patient was interviewed concerning his present depressive episode by the same person at two different time points. Severity of depression at the different time points was assessed using the Hamilton Depression Rating Scale (HAMD-17) and the Inventory of Depressive Symptomatology (IDS-C). Results: The speed of onset as assessed with the ODI showed good test-retest stability (rho = 0.83, p < 0.001). This parameter was not influenced by changes in depression severity. Conclusions: The ODI allows reliable assessment of the speed of onset of depressive episodes. The instrument might be useful for the detection of hidden bipolarity.
[Show abstract][Hide abstract] ABSTRACT: The hypothalamus and its subdivisions are involved in many neuropsychiatric conditions such as affective disorders, schizophrenia, or narcolepsy, but parcellations of hypothalamic subnuclei have hitherto been feasible only with histological techniques in postmortem brains. In an attempt to map subdivisions of the hypothalamus in vivo, we analyzed the directionality information from high-resolution diffusion-weighted magnetic resonance images of healthy volunteers. We acquired T1-weighted and diffusion-weighted scans in ten healthy subjects at 3 T. In the T1-weighted images, we manually delineated an individual mask of the hypothalamus in each subject and computed in the co-registered diffusion-weighted images the similarity of the principal diffusion direction for each pair of mask voxels. By clustering the similarity matrix into three regions with a k-means algorithm, we obtained an anatomically coherent arrangement of subdivisions across hemispheres and subjects. In each hypothalamus mask, we found an anterior region with dorsoventral principal diffusion direction, a posteromedial region with rostro-caudal direction, and a lateral region with mediolateral direction. A comparative analysis with microstructural hypothalamus parcellations from the literature reveals that each of these regions corresponds to a specific group of hypothalamic subnuclei as defined in postmortem brains. This is to our best knowledge the first in vivo study that attempts a delineation of hypothalamic subdivisions by clustering diffusion-weighted magnetic resonance imaging data. When applied in a larger sample of neuropsychiatric patients, a structural analysis of hypothalamic subnuclei should contribute to a better understanding of the pathogenesis of neuropsychiatric conditions such as affective disorders.
European Archives of Psychiatry and Clinical Neuroscience 01/2013; · 2.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Ancillary to decline in cognitive abilities, patients with Alzheimer's disease (AD) frequently suffer from behavioural and psychological symptoms of dementia (BPSD). Hypothalamic polypeptides such as melanin-concentrating hormone (MCH) and hypocretin-1 (HCRT-1, orexin-A) are promoters of sleep-wake regulation and energy homeostasis and are found to impact on cognitive performance. To investigate the role of MCH and HCRT-1 in AD, cerebrospinal fluid (CSF) levels were measured in 33 patients with AD and 33 healthy subjects (HS) using a fluorescence immunoassay (FIA). A significant main effect of diagnosis (F(1,62) = 8.490, p<0.01) on MCH levels was found between AD (93.76±13.47 pg/mL) and HS (84.65±11.40 pg/mL). MCH correlated with T-tau (r = 0.47; p<0.01) and P-tau (r = 0.404; p<0.05) in the AD but not in the HS. CSF-MCH correlated negatively with MMSE scores in the AD (r = -0.362, p<0.05) and was increased in more severely affected patients (MMSE≤20) compared to HS (p<0.001) and BPSD-positive patients compared to HS (p<0.05). In CSF-HCRT-1, a significant main effect of sex (F(1,31) = 4.400, p<0.05) with elevated levels in females (90.93±17.37 pg/mL vs. 82.73±15.39 pg/mL) was found whereas diagnosis and the sex*diagnosis interaction were not significant. Elevated levels of MCH in patients suffering from AD and correlation with Tau and severity of cognitive impairment point towards an impact of MCH in AD. Gender differences of CSF-HCRT-1 controversially portend a previously reported gender dependence of HCRT-1-regulation. Histochemical and actigraphic explorations are warranted to further elucidate alterations of hypothalamic transmitter regulation in AD.
PLoS ONE 01/2013; 8(5):e63136. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Post mortem studies have shown volume changes of the hypothalamus in psychiatric patients. With 7T magnetic resonance imaging this effect can now be investigated in vivo in detail. To benefit from the sub-millimeter resolution requires an improved segmentation procedure. The traditional anatomical landmarks of the hypothalamus were refined using 7T T1-weighted magnetic resonance images. A detailed segmentation algorithm (unilateral hypothalamus) was developed for colour-coded, histogram-matched images, and evaluated in a sample of 10 subjects. Test-retest and inter-rater reliabilities were estimated in terms of intraclass-correlation coefficients (ICC) and Dice's coefficient (DC). The computer-assisted segmentation algorithm ensured test-retest reliabilities of ICC≥.97 (DC≥96.8) and inter-rater reliabilities of ICC≥.94 (DC = 95.2). There were no significant volume differences between the segmentation runs, raters, and hemispheres. The estimated volumes of the hypothalamus lie within the range of previous histological and neuroimaging results. We present a computer-assisted algorithm for the manual segmentation of the human hypothalamus using T1-weighted 7T magnetic resonance imaging. Providing very high test-retest and inter-rater reliabilities, it outperforms former procedures established at 1.5T and 3T magnetic resonance images and thus can serve as a gold standard for future automated procedures.
PLoS ONE 01/2013; 8(7):e66394. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Large-scale longitudinal multi-site MRI brain morphometry studies are becoming increasingly crucial to characterize both normal and clinical population groups using fully automated segmentation tools. The test–retest reproducibility of morphometry data acquired across multiple scanning sessions, and for different MR vendors, is an important reliability indicator since it defines the sensitivity of a protocol to detect longitudinal effects in a consortium. There is very limited knowledge about how across-session reliability of morphometry estimates might be affected by different 3 T MRI systems. Moreover, there is a need for optimal acquisition and analysis protocols in order to reduce sample sizes. A recent study has shown that the longitudinal FreeSurfer segmentation offers improved within session test–retest reproducibility relative to the cross-sectional segmentation at one 3 T site using a nonstandard multi-echo MPRAGE sequence. In this study we implement a multi-site 3 T MRI morphometry protocol based on vendor provided T1 structural sequences from different vendors (3D MPRAGE on Siemens and Philips, 3D IR-SPGR on GE) implemented in 8 sites located in 4 European countries. The protocols used mild acceleration factors (1.5–2) when possible. We acquired across-session test–retest structural data of a group of healthy elderly subjects (5 subjects per site) and compared the across-session reproducibility of two full-brain automated segmentation methods based on either longitudinal or cross-sectional FreeSurfer processing. The segmentations include cortical thickness, intracranial, ventricle and subcortical volumes. Reproducibility is evaluated as absolute changes relative to the mean (%), Dice coefficient for volume overlap and intraclass correlation coefficients across two sessions. We found that this acquisition and analysis protocol gives comparable reproducibility results to previous studies that used longer acquisitions without acceleration. We also show that the longitudinal processingis systematically more reliable across sites regardless of MRI system differences. The reproducibility errors of the longitudinal segmentations are on average approximately half of those obtained with the cross sectional analysis for all volume segmentations and for entorhinal cortical thickness. No significant differences in reliability are found between the segmentation methods for the other cortical thickness estimates. The average of two MPRAGE volumes acquired within each test–retest session did not systematically improve the across-session reproducibility of morphometry estimates. Our results extend those from previous studies that showed improved reliability of the longitudinal analysis at single sites and/or with non-standard acquisition methods. The multi-site acquisition and analysis protocol presented here is promising for clinical applications since it allows for smaller sample sizes per MRI site or shorter trials in studies evaluating the role of potential biomarkers to predict disease progression or treatment effects.