[Show abstract][Hide abstract] ABSTRACT: Frontotemporal dementia (FTD) is a clinically and genetically heterogeneous disorder. Rare TREM2 variants have been recently identified in families affected by FTD-like phenotype. However, genetic studies of the role of rare TREM2 variants in FTD have generated conflicting results possibly because of difficulties on diagnostic accuracy. The aim of the present study was to investigate associations between rare TREM2 variants and specific FTD subtypes (FTD-S). The entire coding sequence of TREM2 was sequenced in FTD-S patients of Spanish (n = 539) and German (n = 63) origin. Genetic association was calculated using Fisher exact test. The minor allele frequency for controls was derived from in-house genotyping data and publicly available databases. Seven previously reported rare coding variants (p.A28V, p.W44X, p.R47H, p.R62H, p.T66M, p.T96K, and p.L211P) and 1 novel missense variant (p.A105T) were identified. The p.R47H variant was found in 4 patients with FTD-S. Two of these patients showed cerebrospinal fluid pattern of amyloid beta, tau, and phosphorylated-tau suggesting underlying Alzheimer's disease (AD) pathology. No association was found between p.R47H and FTD-S. A genetic association was found between p.T96K and FTD-S (p = 0.013, odds ratio = 4.23, 95% Confidence Interval [1.17-14.77]). All 6 p.T96K patients also carried the TREM2 variant p.L211P, suggesting linkage disequilibrium. The remaining TREM2 variants were found in 1 patient, respectively, and were absent in controls. The present findings provide evidence that p.T96K is associated with FTD-S and that p.L211P may contribute to its pathogenic effect. The data also suggest that p.R47H is associated with an FTD phenotype that is characterized by the presence of underlying AD pathology.
Neurobiology of Aging 12/2014; · 6.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to determine the relationship between serum albumin, affective prosody, and symptoms of attention-deficit hyperactivity disorder (ADHD) found coincidentally in a recently published study. Here, serum albumin levels were assessed as a covariate. Twenty healthy male adults (controls) and 20 adult male patients with ADHD participated in the study on two study days. Serum albumin levels and performance in an affective prosody task were assessed, and correlations were determined. Serum albumin had a significant correlation with performance on an affective prosody task on both of the two study days. The same correlations were not significant in the healthy control group. There was no difference in the serum albumin level between patients with ADHD and healthy controls. The association between serum albumin and affective prosody in adults with ADHD is a novel finding. However, to date, there is no clear theory that explains this association. Future research should analyze whether serum albumin influences causes changes in performance in affective prosody using experimental designs.
[Show abstract][Hide abstract] ABSTRACT: Large-scale longitudinal neuroimaging studies with diffusion imaging techniques are necessary to test and validate models of white matter neurophysiological processes that change in time, both in healthy and diseased brains. The predictive power of such longitudinal models will always be limited by the reproducibility of repeated measures acquired during different sessions. At present, there is limited quantitative knowledge about the across-session reproducibility of standard diffusion metrics in 3T multi-centric studies on subjects in stable conditions, in particular when using tract based spatial statistics and with elderly people. In this study we implemented a multi-site brain diffusion protocol in 10 clinical 3T MRI sites distributed across 4 countries in Europe (Italy, Germany, France and Greece) using vendor provided sequences from Siemens (Allegra, Trio Tim, Verio, Skyra, Biograph mMR), Philips (Achieva) and GE (HDxt) scanners. We acquired DTI data (2x2x2 mm(3), b=700s/mm(2), 5 b0 and 30 diffusion weighted volumes) of a group of healthy stable elderly subjects (5 subjects per site) in two separate sessions at least a week apart. For each subject and session four scalar diffusion metrics were considered: fractional anisotropy (FA), mean diffusivity (MD), radial (RD) and axial (AD) diffusivity. The diffusion metrics from multiple subjects and sessions at each site were aligned to their common white matter skeleton using tract-based spatial statistics. The reproducibility at each MRI site was examined by looking at group averages of absolute changes relative to the mean (%) on various parameters: i) reproducibility of the signal-to-noise ratio (SNR) of the b0 images in centrum semiovale, ii) full brain test-retest differences of the diffusion metric maps on the white matter skeleton, iii) reproducibility of the diffusion metrics on atlas-based white matter ROIs on the white matter skeleton. Despite the differences of MRI scanner configurations across sites (vendors, models, RF coils and acquisition sequences) we found good and consistent test-retest reproducibility. White matter b0 SNR reproducibility was on average 7±1 % with no significant MRI site effects. Whole brain analysis resulted in no significant test-retest differences at any of the sites with any of the DTI metrics. The atlas-based ROI analysis showed that the mean reproducibility errors largely remained in the range 2-4% for FA and AD and 2-6% for MD and RD, averaged across ROIs. Our results show reproducibility values comparable to those reported in studies using a smaller number of MRI scanners, slightly different DTI protocols and mostly younger populations. We therefore show that the acquisition and analysis protocol used are appropriate for multi-site experimental scenarios.
[Show abstract][Hide abstract] ABSTRACT: Acute tryptophan depletion – converging evidence for decreasing central nervous serotonin synthesis in rodents and humans We read the comment provided by Simon N. Young (1) on the articles (2–5) in the special issue of Acta Psychiatrica Scandi-navica (6) dealing with the acute tryptophan depletion (ATD) methodology with great interest. ATD is a pharmacological method designed to lower central nervous system (CNS) syn-thesis of the neurotransmitter serotonin (5-HT) for a brief per-iod that can also be used in both adults and young people (7). As 5-HT plays an important role in behavioral inhibition (8– 10) and other important processes in the brain (11–14), ATD is a translational method to study the effects of changes in CNS 5-HT function that has particular value, as discussed at a recent symposium dedicated to the role of 5-HT in psychopa-thology (7–11, 15). The author of this particular comment expressed concerns that ATD might not always decrease CNS 5-HT synthesis and that the lack of the amino acid histidine (HIS) in the depletion mixtures used might influence the results due to the potential role of 5-HT–histamine interactions in any observed outcome. We appreciate the comments made and would like to address the issues raised, point by point. Young argues that 'there is no evidence that ATD does always decrease seroto-nin release (in humans)'. This is contradictory by decades of work in rodents and in humans demonstrating that ATD can decrease 5-HT synthesis and release in rodents and lower 5-HIAA in human CSF (16–19). In one of our laboratories, the acute tryptophan depletion (ATD) protocol termed 'Moja-De' has been shown to decrease 5-HT release in rodents (20, 21) and to lower tryptophan (TRP) comparably in humans (22), suggesting that this mixture successfully decreases 5-HT synthesis as postulated. While some experi-ments (23) fail to detect changes in central 5-HT function after ATD, this is the exception rather than the rule in published studies. The author of this comment was also concerned that there would be regional variations in the inhibition of serotonin function. This is logical and consistent with published data on the effects of Moja-De ATD in mice. Mouse studies indicated that depletion of TRP was comparable across different brain areas but that the extent of decrease in 5-HIAA varied by region (20, 21). Regional release of 5-HT is controlled by a combination of cell firing including regionally selective input, the concentration of 5-HT1b receptors on terminals, the amount of tryptophan hydroxylase, and many other factors (24). However, there is no evidence that 5-HT release happens only in selective regions, but we agree the magnitude of ATD effects on release is likely to vary between regions despite comparable depletion of TRP. As regards potential interactions between 5-HT and hista-mine, we agree that measurement of histidine after depletion of TRP or any other formula lacking HIS is of interest. Young has questioned the results of ATD experiments in which HIS was not included, stating that 'histidine is an essential amino acid'. However, the essentiality of this amino acid is not clearly established (25). It has been reported that HIS was not necessary for the maintenance of nitrogen balances in short-term (26, 27). Kriengsunyos et al. (28) observed after a long-term histidine depletion administered to healthy adults that there were no effects on the protein metabolism (urinary nitrogen excretion and nitrogen balance). They suggested that the essentiality of this amino acid in healthy adults is still unclear as there are some components that may serve as sources of HIS, although the data they reported indicate that this amount may not be enough for maintain the HIS pool. The other concern expressed by Young was that effects of ATD could reflect disruption of a histamine–serotonin inter-action, as ATD would cause a dramatic decrease in histamine synthesis. This is possible, as it is well established that the neurotransmitter histamine is formed from HIS (29), and his-tamine turnover seems to occur faster than other biogenic amines, such as norepinephrine or 5-HT (30). Therefore, in the absence of HIS, competition from the amino acid mix-tures could indeed lower histamine production. However, nei-ther the control nor the ATD mixture in most studies contains histidine, and so histamine would not be differen-tially affected by the ATD mixture, but should be compara-bly depleted in both control and ATD mixtures. Nevertheless, it is possible that some interaction between his-tamine depletion and 5-HT depletion could have behavioral effects. Unfortunately, no behavioral effects of histamine depletion have been clearly established in the literature. A study by Young and his collaborators of HIS depletion effects on sensory and motor behavior in healthy adults (31) showed that HIS in plasma decreased 20% and the ratio HIS/ΣLNAA decreased 59%, but there were no behavioral effects of this depletion. Finally, we disagree with the statement that 'the relevance of such animal studies to the far more complex human brain is uncertain'. It is well known that validation of trans-lational methods has allowed modeling many aspects of the neuropsychopathology with the use of appropriate animal models, the majority of them throughout the use of rodents (32, 33). Translation of behavioral findings is challenging, due to limits in extrapolating simple behavioral tasks in rodents to sophisticated behaviors in humans. However, bio-chemical studies of ATD effects in humans and rodents have shown considerable concordance. For example, our studies in humans (5, 22) have been validated in mice (20, 21), consistent with the field as described above (16–19). As Dr. Young points out, detailed anatomic studies of 5-HT synthesis in the human brain are technologically demanding and rarely conducted. However, the concordance between the dependent measures that can be collected in humans (CSF 5-HIAA for example) and comparable measures in
[Show abstract][Hide abstract] ABSTRACT: Alzheimer's disease (AD) is the most common and complex neurodegenerative disease in the elderly individuals. Recently, genome-wide association studies (GWAS) have been used to investigate AD pathogenesis. These GWAS have yielded important new insights into the genetic mechanisms of AD. However, these newly identified AD susceptibility loci exert only very small risk effects and cannot fully explain the underlying AD genetic risk. We hypothesize that combining the findings from different AD GWAS may have greater power than genetic analysis alone. To identify new AD risk factors, we integrated findings from 3 previous large-scale AD GWAS (n = 14,138) using a gene-based meta-analysis and subsequently conducted a pathway analysis using the kyoto encyclopedia of genes and genomes and gene ontology databases. Interestingly, we not only confirmed previous findings, but also highlighted, for the first time, the involvement of cardiovascular disease-related pathways in AD. Our results provided the clues as to the link between these diseases using pathway analysis methods. We believe that these findings will be very useful for future genetic studies of AD.
[Show abstract][Hide abstract] ABSTRACT: Alzheimer´s disease is characterized by pathological aggregation of protein tau and amyloid-β peptides, both of which are considered to be toxic to neurons. Naturally occurring dietary flavonoids have received considerable attention as alternative candidates for Alzheimer´s therapy taking into account their anti-amyloidogenic, anti-oxidative, and anti-inflammatory properties. Experimental evidence supports the hypothesis that certain flavonoids may protect against Alzheimer's disease in part by interfering with the generation and assembly of amyloid-β peptides into neurotoxic oligomeric aggregates and also by reducing tau aggregation. Several mechanisms have been proposed for the ability of flavonoids to prevent the onset or to slow the progression of the disease. Some mechanisms include their interaction with important signalling pathways in the brain like the phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways that regulate prosurvival transcription factors and gene expression. Other processes include the disruption of amyloid-β aggregation and alterations in amyloid precursor protein processing through the inhibition of β-secretase and/or activation of α-secretase, and inhibiting cyclin-dependent kinase-5 and glycogen synthase kinase-3β activation preventing abnormal tau phosphorylation. The interaction of flavonoids with different signalling pathways put forward their therapeutic potential to prevent the onset and progression of Alzheimer´s disease and to promote cognitive performance. Nevertheless, further studies are needed to give additional insight into the specific mechanisms by which flavonoids exert their potential neuroprotective actions in the brain of Alzheimer´s disease patients.
ACS Chemical Neuroscience 12/2013; · 3.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Serum levels of IL-16, IL-33 and the decoy receptor of IL-33, soluble ST2, are elevated in allergic rhinitis. Recent studies show that IL-16, soluble ST2 or anti-IL-33 reduce type 2 cytokines (such as IL-5) and eosinophilia in murine models of allergic asthma or allergic rhinitis respectively.
In this study, we studied the release of IL-5, IL-16, IL-33 and soluble ST2 in allergic rhinitis patients after nasal allergen challenge and natural pollen exposure.
The nasal lavages of 15 allergic and 14 non-allergic volunteers were collected during the pollen allergy season. In addition, six allergic volunteers underwent unilateral nasal allergen and control challenge out of season and nasal secretions and sera were collected. IL-5, IL-16, IL-33 and soluble ST2 in nasal secretions and sera were measured by electrochemiluminescent assay or ELISA, respectively.
Nasal IL-5, IL-16 and soluble ST2 levels were significantly increased in seasonally pollen exposed allergic volunteers compared to control subjects (P < 0.001, P = 0.018 and P = 0.002 respectively), whereas IL-33 remained undetectable. Nasal IL-16 showed a weak inverse correlation trend with nasal symptoms (r = -0.48, P = 0.07). Nasal soluble ST2 concentrations were inversely correlated with nasal symptoms (r = -0.61, P = 0.02) and positively correlated with IL-16 (r = 0.56, P = 0.03). Significant increases of nasal IL-5, IL-16 and ST2 but not IL-33 were observed after nasal allergen challenge. At 24 h after allergen challenge, local ST2 and IL-5 concentrations showed an inverse correlation trend (r = -0.83, P = 0.04). Serum levels of IL-5, IL-16 and soluble ST2 rose in at least five of six volunteers tested at 5 or 24 h post-challenge.
The observed upregulation of soluble ST2 and IL-16 after nasal allergen challenge and during peak pollination season suggests potential regulatory roles of these cytokines in the inflammatory reaction in allergic rhinitis.
[Show abstract][Hide abstract] ABSTRACT: We report on the development of a novel assay protocol for the separation and detection of charge isoforms of DJ-1 in biological samples by automated capillary isoelectric focusing followed by immunological detection. DJ-1 (PARK7) is considered as a biomarker candidate for Parkinson's disease and may potentially support the differentiation of clinical subtypes of the disease. The new method allows for separation and subsequent relative quantitative comparison of different isoforms of DJ-1 in biological samples. The assay was successfully applied to the analysis of DJ-1 isoform patterns in brains from mice subjected to normal or high-fat diet and revealed statistically significant group differences. Furthermore, in a pooled and concentrated sample of human cerebrospinal fluid that was depleted of albumin and IgG, four different charge variants of DJ-1 could be detected. Taken together, the capillary isoelectric focusing immunoassay for DJ-1 represents a promising tool that may ultimately serve in clinical biomarker studies.
[Show abstract][Hide abstract] ABSTRACT: A 64-year-old right-handed Caucasian presented with a four-year history of word-finding deficits and otherwise fluent speech production. Neurological examination remained unremarkable apart from the word finding impairment. Likewise, neuropsychological evaluation confirmed significantly reduced semantic word fluency. While brain MRI depicted only discrete anterior temporal atrophy, 18-fluorodeoxyglucose PET showed clear hypometabolism of the anterior temporal pole bilaterally with left predominance. An imaging-supported diagnosis of the semantic variant of primary progressive aphasia was established in close accordance to recently published diagnostic criteria.The PET findings can be regarded as typical for this condition and PET imaging proved helpful to delineate other variants (non-fluent and logopenic) of primary progressive aphasia.
[Show abstract][Hide abstract] ABSTRACT: Allergic rhinitis is an inflammatory disease characterized by local overproduction of type 2 cytokines and tissue eosinophilia. Recent research suggests the involvement of additional cytokines such as IL-17, chemokine (C-C motif) ligand (CCL) 26/eotaxin-3, and CCL13/monocyte chemoattractant protein-4 (MCP-4) in its pathophysiology. Furthermore, bronchial epithelial cells treated with IL-17 and type 2 cytokines distinctively up-regulated eotaxin-3 gene expression. In this study we investigated the kinetics of IL-4, IL-10, IL-17, eotaxin-3, and MCP-4 in seasonal allergic rhinitis volunteers after nasal allergen challenge (NAC) and their release during natural pollen exposure.
The nasal lavages of 15 symptomatic allergic and 14 nonallergic subjects were collected during the pollination season. Additionally, six allergic subjects underwent a single unilateral nasal allergen and control challenge out of season, and nasal secretions were collected. Levels of IL-4, IL-10, IL-17, eotaxin-3, and MCP-4 in nasal lavages and secretions were measured using an electrochemiluminescent assay.
After NAC, allergic subjects had a significant immediate response of nasal symptoms as well as a significant increase at 5 hours of IL-4, IL-10, and IL-17 and at 2, 5, and 24 hours significantly raising levels of eotaxin-3. IL-17 and eotaxin-3 concentrations at 5 hours were correlated (r = 0.94; p = 0.005). During natural pollen exposure, barely detectable levels of IL-17 in allergic subjects were also correlated with eotaxin-3 (r = 0.62; p = 0.01). Eotaxin-3 and MCP-4 levels were significantly elevated 9- or 3.7-fold, respectively, and IL-10 and, unexpectedly, IL-4 were significantly lower in allergic subjects compared with nonallergic subjects.
Nasal IL-17, MCP-4, and, possibly, eotaxin-3 may aggravate and IL-10 may alleviate nasal mucosal allergy.
American Journal of Rhinology and Allergy 07/2013; 27(4):266-72.
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE: Adults with attention deficit hyperactivity disorder (ADHD) have difficulties processing affective prosody, and research evidence demonstrates the importance of brain serotonin (5-HT) in the neurobiology of ADHD. This study aimed to investigate whether diminished brain 5-HT synthesis, as achieved by acute tryptophan depletion (ATD), can impair the processing of affective prosody in adults with ADHD. METHOD: Twenty male patients with ADHD and twenty male healthy controls received ATD and a tryptophan-balanced control condition on separate days in a double-blind within-subject repeated measures crossover design. In both conditions, the Tübingen Affect Battery was administered in which subjects had to name the affective prosody of sentences with neutral, congruent, or incongruent semantic content. RESULTS: Participants in the group of patients with ADHD perceived affec-tive prosody less accurately than controls. Participants with ADHD showed compromised processing of sentences, committing more errors than healthy controls when identifying affect in instances of incongruent semantic content (P = 0.031). ATD did not contribute to this effect (all P > 0.5). CONCLUSION: The difficulties male adults with ADHD have in accurately processing affective prosody may result from impairments in their ability to inhibit unwanted stimuli and impulses. No clear evidence implicates 5-HT as a cause of these impairments.
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE: To date, the impact of the neurotransmitter serotonin (5-HT) on different neuropsychological functions in adults with attention deficit hyperactivity disorder (ADHD) is underinvestigated. We aimed to examine the effects of acute tryptophan depletion (ATD) and the resulting reduction in central nervous 5-HT synthesis on target/non-target discrimination ability and sustained attention in adults with ADHD using an AX-Continuous Performance Test (AX-CPT). METHOD: Twenty male patients with ADHD (age: M = 30.25 SD = 9.37) and twenty male healthy controls (age: M = 27.90 SD = 6.01) received ATD on one day and a tryptophan-balanced control condition (BAL) on another day in a double-blind within-subject crossover design. A continuous performance test (AX-CPT) with three conditions (AX, AY, and BX) was administered on both days under depleted and sham-depleted conditions. RESULTS: In patients omissions increased after ATD when compared with BAL. Patient's reaction time decreased after ATD when compared with BAL, which was contrasted by opposite effects in controls. Patients showed fewer correct responses (AX condition) and showed a higher rate of errors (condition AX(E) ) independent of ATD or BAL intake. CONCLUSION: The present preliminary results are indicative of the contribution of serotonergic neurotransmission to attentional processes in adults with ADHD.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND:
Three small trials suggest that intravenous immunoglobulin can affect biomarkers and symptoms of mild-to-moderate Alzheimer's disease. We tested the safety, effective dose, and infusion interval of intravenous immunoglobulin in such patients.
We did a multicentre, placebo-controlled phase 2 trial at seven sites in the USA and five in Germany. Participants with probable Alzheimer's disease aged 50-85 years were randomly assigned (by a computer-generated randomisation sequence, with block sizes of eight) to infusions every 4 weeks (0·2, 0·5, or 0·8 g intravenous immunoglobulin per kg bodyweight, or placebo) or infusions every 2 weeks (0·1, 0·25, or 0·4 g/kg, or placebo). Patients, caregivers, investigators assessing outcomes, and staff at imaging facilities and the clinical research organisation were masked to treatment allocation, but dispensing pharmacists, the statistician, and the person responsible for final PET analyses were not. Treatment was masked with opaque pouches and infusion lines. The primary endpoint was median area under the curve (AUC) of plasma amyloid β (Aβ)(1-40) between the last infusion and the final visit (2 weeks or 4 weeks depending on infusion interval) in the intention-to-treat population. The trial is registered at ClinicalTrials.gov (NCT00812565) and controlled-trials.com (ISRCTN64846759).
89 patients were assessed for eligibility, of whom 58 were enrolled and 55 included in the primary analysis. Median AUC of plasma Aβ(1-40) was not significantly different for intravenous immunoglobulin compared with placebo for five of the six intervention groups (-18·0 [range -1347·0 to 1068·5] for 0·2 g/kg, -364·3 [-5834·5 to 1953·5] for 0·5 g/kg, and -351·8 [-1084·0 to 936·5] for 0·8 g/kg every 4 weeks vs -116·3 [-1379·0 to 5266·0] for placebo; and -13·8 [-1729·0 to 307·0] for 0·1 g/kg, and -32·5 [-1102·5 to 451·5] for 0·25 g/kg every 2 weeks vs 159·5 [51·5 to 303·0] for placebo; p>0·05 for all). The difference in median AUC of plasma Aβ(1-40) between the 0·4 g/kg every 2 weeks group (47·0 [range -341·0 to 72·5]) and the placebo group was significant (p=0·0216). 25 of 42 (60%) patients in the intervention group versus nine of 14 (64%) receiving placebo had an adverse event. Four of 42 (10%) patients in the intravenous immunoglobulin group versus four of 14 (29%) receiving placebo had a serious adverse event, including one stroke in the intervention group.
Intravenous immunoglobulin may have an acceptable safety profile. Our results did not accord with those from previous studies. Longer trials with greater power are needed to assess the cognitive and functional effects of intravenous immunoglobulin in patients with Alzheimer's disease.
The Lancet Neurology 01/2013; · 23.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Three small trials suggest that intravenous immunoglobulin can affect biomarkers and symptoms of mild-to-moderate Alzheimer's disease. We tested the safety, effective dose, and infusion interval of intravenous immunoglobulin in such patients. METHODS: We did a multicentre, placebo-controlled phase 2 trial at seven sites in the USA and five in Germany. Participants with probable Alzheimer's disease aged 50-85 years were randomly assigned (by a computer-generated randomisation sequence, with block sizes of eight) to infusions every 4 weeks (0·2, 0·5, or 0·8 g intravenous immunoglobulin per kg bodyweight, or placebo) or infusions every 2 weeks (0·1, 0·25, or 0·4 g/kg, or placebo). Patients, caregivers, investigators assessing outcomes, and staff at imaging facilities and the clinical research organisation were masked to treatment allocation, but dispensing pharmacists, the statistician, and the person responsible for final PET analyses were not. Treatment was masked with opaque pouches and infusion lines. The primary endpoint was median area under the curve (AUC) of plasma amyloid β (Aβ)(1-40) between the last infusion and the final visit (2 weeks or 4 weeks depending on infusion interval) in the intention-to-treat population. The trial is registered at ClinicalTrials.gov (NCT00812565) and controlled-trials.com (ISRCTN64846759). FINDINGS: 89 patients were assessed for eligibility, of whom 58 were enrolled and 55 included in the primary analysis. Median AUC of plasma Aβ(1-40) was not significantly different for intravenous immunoglobulin compared with placebo for five of the six intervention groups (-18·0 [range -1347·0 to 1068·5] for 0·2 g/kg, -364·3 [-5834·5 to 1953·5] for 0·5 g/kg, and -351·8 [-1084·0 to 936·5] for 0·8 g/kg every 4 weeks vs -116·3 [-1379·0 to 5266·0] for placebo; and -13·8 [-1729·0 to 307·0] for 0·1 g/kg, and -32·5 [-1102·5 to 451·5] for 0·25 g/kg every 2 weeks vs 159·5 [51·5 to 303·0] for placebo; p>0·05 for all). The difference in median AUC of plasma Aβ(1-40) between the 0·4 g/kg every 2 weeks group (47·0 [range -341·0 to 72·5]) and the placebo group was significant (p=0·0216). 25 of 42 (60%) patients in the intervention group versus nine of 14 (64%) receiving placebo had an adverse event. Four of 42 (10%) patients in the intravenous immunoglobulin group versus four of 14 (29%) receiving placebo had a serious adverse event, including one stroke in the intervention group. INTERPRETATION: Intravenous immunoglobulin may have an acceptable safety profile. Our results did not accord with those from previous studies. Longer trials with greater power are needed to assess the cognitive and functional effects of intravenous immunoglobulin in patients with Alzheimer's disease. FUNDING: Octapharma AG.
The Lancet Neurology 01/2013; · 23.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study is to implement and examine the feasibility of a cross-institutional mental health intervention to comprehend and advance mental health of elderly long-term unemployed persons.Report on the procedure and on the observational study utilisation in a 14-month period.The structure and processes chosen could be implemented into practice successfully. Utilisation was high but 30% dropped out during the procedure. Of the unemployed persons surveyed, 96% received a psychiatric diagnosis. 85% were not having psychiatric treatment.The method chosen is feasible and was accepted by the target group. Project structure and processes proved to be applicable for the implementation of the project aims. The method chosen reaches an up to now "psychiatry-inexperienced" target group characterised by frequent incidence of mental disorders and low utilisation of psychiatric care. Thus, vocational reintegration programmes should be supported by psychiatric services.
Das Gesundheitswesen 01/2013; · 0.94 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.
[Show abstract][Hide abstract] ABSTRACT: INTRODUCTION: Early after having been diagnosed with relapsing remitting multiple sclerosis (RRMS), young patients coping with the new situation require good social support and interactions. Successful social interaction is critically dependent upon the ability to understand the minds of others and their feelings. Social cognition refers to the ability to understand the mind of others. Theory of mind (ToM) defines the capability to reason about mental states of others. Empathy describes the ability to have insight into emotional stages and feelings of others. Despite the knowledge of cognitive impairment, which can have profound effects on patients daily activities and quality of life in advanced stages of multiple sclerosis, little is known concerning social cognition in early stages of RRMS. METHODS: In this analysis, tests assessing executive functions (working memory, set shifting and inhibition) and instruments measuring theory of mind (the Movie for the Assessment of Social Cognition - MASC) and empathy (Baron-Cohen's Empathy Quotient) were administered to 25 young adult patients at an early stage of RRMS and to 25 healthy controls (HC). Patients and HC were carefully matched according to intellectual level, age, gender, handedness and education. An early stage of the disease was defined as being diagnosed with RRMS in the last 2 years and having an EDSS of 2 or lower. RESULTS: Patients had significantly more incorrect responses ("missing") ToM (P<0.04). Moreover, patients showed a significantly lower level of empathy in the self-rating questionnaire (P<0.02). Of the cognitive tests and depression, ToM and Empathy Quotient (EQ) scores were only significantly correlated with the interference score of the stroop test. CONCLUSIONS: Our findings suggest that theory of mind and empathy are deficient even at early stages of RRMS. Deficits in theory of mind and empathy might negatively influence interpersonal relationships in patients with RRMS.
Clinical neurology and neurosurgery 11/2012; · 1.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cognitive dysfunction is well known in patients suffering from multiple sclerosis (MS) and has been described for many years. Cognitive impairment, memory, and attention deficits seem to be features of advanced MS stages, whereas depression and emotional instability already occur in early stages of the disease. However, little is known about processing of affective prosody in patients in early stages of relapsing-remitting MS (RRMS). In this study, tests assessing attention, memory, and processing of affective prosody were administered to 25 adult patients with a diagnosis of RRMS at an early stage and to 25 healthy controls (HC). Early stages of the disease were defined as being diagnosed with RRMS in the last 2 years and having an Expanded Disability Status Scale (EDSS) of 2 or lower. Patients and HC were comparable in intelligence quotient (IQ), educational level, age, handedness, and gender. Patients with early stages of RRMS performed below the control group with respect to the subtests 'discrimination of affective prosody' and 'matching of affective prosody to facial expression' for the emotion 'angry' of the 'Tübingen Affect Battery'. These deficits were not related to executive performance. Our findings suggest that emotional prosody comprehension is deficient in young patients with early stages of RRMS. Deficits in discriminating affective prosody early in the disease may make misunderstandings and poor communication more likely. This might negatively influence interpersonal relationships and quality of life in patients with RRMS.
Journal of Neuropsychology 11/2012; · 3.82 Impact Factor