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1.  Flavonoids as Therapeutic Compounds Targeting Key Proteins Involved in Alzheimer’s Disease 
ACS Chemical Neuroscience  2013;5(2):83-92.
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 antiamyloidogenic, antioxidative, 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 signaling 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 signaling 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.
doi:10.1021/cn400213r
PMCID: PMC3930994  PMID: 24328060
Flavonoids; Alzheimer’s disease; amyloid precursor protein; amyloid beta; BACE-1; tau; signaling
2.  Structural Brain Alterations Associated With Schizophrenia Preceded by Conduct Disorder: A Common and Distinct Subtype of Schizophrenia? 
Schizophrenia Bulletin  2012;39(5):1115-1128.
Conduct disorder (CD) prior to age 15 is a precursor of schizophrenia in a minority of cases and is associated with violent behavior through adulthood, after taking account of substance misuse. The present study used structural magnetic imaging to examine gray matter (GM) volumes among 27 men with schizophrenia preceded by CD (SZ+CD), 23 men with schizophrenia but without CD (SZ–CD), 27 men with CD only (CD), and 25 healthy (H) men. The groups with schizophrenia were similar in terms of age of onset and duration of illness, levels of psychotic symptoms, and medication. The 2 groups with CD were similar as to number of CD symptoms, lifelong aggressive behavior, and number of criminal convictions. Men with SZ+CD, relative to those with SZ–CD, displayed (1) increased GM volumes in the hypothalamus, the left putamen, the right cuneus/precuneus, and the right inferior parietal cortex after controlling for age, alcohol, and drug misuse and (2) decreased GM volumes in the inferior frontal region. Men with SZ+CD (relative to the SZ–CD group) and CD (relative to the H group) displayed increased GM volumes of the hypothalamus and the inferior and superior parietal lobes, which were not associated with substance misuse. Aggressive behavior, both prior to age 15 and lifetime tendency, was positively correlated with the GM volume of the hypothalamus. Thus, among males, SZ+CD represents a distinct subtype of schizophrenia. Although differences in behavior emerge in childhood and remain stable through adulthood, further research is needed to determine whether the differences in GM volumes result from abnormal neural development distinct from that of other males developing schizophrenia.
doi:10.1093/schbul/sbs115
PMCID: PMC3756783  PMID: 23015687
conduct problems; antisocial behavior; violence; structural brain alterations
3.  The Role of Variation at AβPP, PSEN1, PSEN2, and MAPT in Late Onset Alzheimer’s Disease 
Gerrish, Amy | Russo, Giancarlo | Richards, Alexander | Moskvina, Valentina | Ivanov, Dobril | Harold, Denise | Sims, Rebecca | Abraham, Richard | Hollingworth, Paul | Chapman, Jade | Hamshere, Marian | Pahwa, Jaspreet Singh | Dowzell, Kimberley | Williams, Amy | Jones, Nicola | Thomas, Charlene | Stretton, Alexandra | Morgan, Angharad R. | Lovestone, Simon | Powell, John | Proitsi, Petroula | Lupton, Michelle K. | Brayne, Carol | Rubinsztein, David C. | Gill, Michael | Lawlor, Brian | Lynch, Aoibhinn | Morgan, Kevin | Brown, Kristelle S. | Passmore, Peter A. | Craig, David | McGuinness, Bernadette | Todd, Stephen | Johnston, Janet A. | Holmes, Clive | Mann, David | Smith, A. David | Love, Seth | Kehoe, Patrick G. | Hardy, John | Mead, Simon | Fox, Nick | Rossor, Martin | Collinge, John | Maier, Wolfgang | Jessen, Frank | Kölsch, Heike | Heun, Reinhard | Schürmann, Britta | van den Bussche, Hendrik | Heuser, Isabella | Kornhuber, Johannes | Wiltfang, Jens | Dichgans, Martin | Frölich, Lutz | Hampel, Harald | Hüll, Michael | Rujescu, Dan | Goate, Alison M. | Kauwe, John S. K. | Cruchaga, Carlos | Nowotny, Petra | Morris, John C. | Mayo, Kevin | Livingston, Gill | Bass, Nicholas J. | Gurling, Hugh | McQuillin, Andrew | Gwilliam, Rhian | Deloukas, Panagiotis | Davies, Gail | Harris, Sarah E. | Starr, John M. | Deary, Ian J. | Al-Chalabi, Ammar | Shaw, Christopher E. | Tsolaki, Magda | Singleton, Andrew B. | Guerreiro, Rita | Mühleisen, Thomas W. | Nöthen, Markus M. | Moebus, Susanne | Jöckel, Karl-Heinz | Klopp, Norman | Wichmann, H-Erich | Carrasquillo, Minerva M | Pankratz, V Shane | Younkin, Steven G. | Jones, Lesley | Holmans, Peter A. | O’Donovan, Michael C. | Owen, Michael J. | Williams, Julie
Rare mutations in AβPP, PSEN1, and PSEN2 cause uncommon early onset forms of Alzheimer’s disease (AD), and common variants in MAPT are associated with risk of other neurodegenerative disorders. We sought to establish whether common genetic variation in these genes confer risk to the common form of AD which occurs later in life (>65 years). We therefore tested single-nucleotide polymorphisms at these loci for association with late-onset AD (LOAD) in a large case-control sample consisting of 3,940 cases and 13,373 controls. Single-marker analysis did not identify any variants that reached genome-wide significance, a result which is supported by other recent genome-wide association studies. However, we did observe a significant association at the MAPT locus using a gene-wide approach (p = 0.009). We also observed suggestive association between AD and the marker rs9468, which defines the H1 haplotype, an extended haplotype that spans the MAPT gene and has previously been implicated in other neurodegenerative disorders including Parkinson’s disease, progressive supranuclear palsy, and corticobasal degeneration. In summary common variants at AβPP, PSEN1, and PSEN2 and MAPT are unlikely to make strong contributions to susceptibility for LOAD. However, the gene-wide effect observed at MAPT indicates a possible contribution to disease risk which requires further study.
doi:10.3233/JAD-2011-110824
PMCID: PMC4118466  PMID: 22027014
Alzheimer’s disease; amyloid-β protein precursor; genetics; human; MAPT protein; PSEN1 protein; PSEN2 protein
4.  Memory Concerns, Memory Performance and Risk of Dementia in Patients with Mild Cognitive Impairment 
PLoS ONE  2014;9(7):e100812.
Background
Concerns about worsening memory (“memory concerns”; MC) and impairment in memory performance are both predictors of Alzheimer's dementia (AD). The relationship of both in dementia prediction at the pre-dementia disease stage, however, is not well explored. Refined understanding of the contribution of both MC and memory performance in dementia prediction is crucial for defining at-risk populations. We examined the risk of incident AD by MC and memory performance in patients with mild cognitive impairment (MCI).
Methods
We analyzed data of 417 MCI patients from a longitudinal multicenter observational study. Patients were classified based on presence (n = 305) vs. absence (n = 112) of MC. Risk of incident AD was estimated with Cox Proportional-Hazards regression models.
Results
Risk of incident AD was increased by MC (HR = 2.55, 95%CI: 1.33–4.89), lower memory performance (HR = 0.63, 95%CI: 0.56–0.71) and ApoE4-genotype (HR = 1.89, 95%CI: 1.18–3.02). An interaction effect between MC and memory performance was observed. The predictive power of MC was greatest for patients with very mild memory impairment and decreased with increasing memory impairment.
Conclusions
Our data suggest that the power of MC as a predictor of future dementia at the MCI stage varies with the patients' level of cognitive impairment. While MC are predictive at early stage MCI, their predictive value at more advanced stages of MCI is reduced. This suggests that loss of insight related to AD may occur at the late stage of MCI.
doi:10.1371/journal.pone.0100812
PMCID: PMC4096405  PMID: 25019225
5.  Early Diagnosis of Neurodegenerative Diseases – The Long Awaited Holy Grail and Bottleneck of Modern Brain Research – 19th HUPO BPP Workshop 
Proteomics  2013;13(20):2938-2941.
The HUPO Brain Proteome Project (HUPO BPP) held its 19th workshop in Dortmund, Germany, from May 22 to 24, 2013. The focus of the spring workshop was on strategies and developments concerning early diagnosis of neurodegenerative diseases
doi:10.1002/pmic.201370164
PMCID: PMC4086650  PMID: 24108682
Alzheimer; Brain; Brain Proteome Project; HUPO; Neurodegeneration; Parkinson
6.  Spot quantification in two dimensional gel electrophoresis image analysis: comparison of different approaches and presentation of a novel compound fitting algorithm 
BMC Bioinformatics  2014;15:181.
Background
Various computer-based methods exist for the detection and quantification of protein spots in two dimensional gel electrophoresis images. Area-based methods are commonly used for spot quantification: an area is assigned to each spot and the sum of the pixel intensities in that area, the so-called volume, is used a measure for spot signal. Other methods use the optical density, i.e. the intensity of the most intense pixel of a spot, or calculate the volume from the parameters of a fitted function.
Results
In this study we compare the performance of different spot quantification methods using synthetic and real data. We propose a ready-to-use algorithm for spot detection and quantification that uses fitting of two dimensional Gaussian function curves for the extraction of data from two dimensional gel electrophoresis (2-DE) images. The algorithm implements fitting using logical compounds and is computationally efficient. The applicability of the compound fitting algorithm was evaluated for various simulated data and compared with other quantification approaches. We provide evidence that even if an incorrect bell-shaped function is used, the fitting method is superior to other approaches, especially when spots overlap. Finally, we validated the method with experimental data of urea-based 2-DE of Aβ peptides andre-analyzed published data sets. Our methods showed higher precision and accuracy than other approaches when applied to exposure time series and standard gels.
Conclusion
Compound fitting as a quantification method for 2-DE spots shows several advantages over other approaches and could be combined with various spot detection methods.
The algorithm was scripted in MATLAB (Mathworks) and is available as a supplemental file.
doi:10.1186/1471-2105-15-181
PMCID: PMC4085234  PMID: 24915860
Two dimensional gel electrophoresis; Beta amyloid; Image analysis; Spot quantification
7.  Mismatch Negativity Latency and Cognitive Function in Schizophrenia 
PLoS ONE  2014;9(4):e84536.
Background
The Mismatch Negativity (MMN) is an event-related potential (ERP) sensitive to early auditory deviance detection and has been shown to be reduced in schizophrenia patients. Moreover, MMN amplitude reduction to duration deviant tones was found to be related to functional outcomes particularly, to neuropsychological (working memory and verbal domains) and psychosocial measures. While MMN amplitude is thought to be correlated with deficits of early sensory processing, the functional significance of MMN latency remains unclear so far. The present study focused on the investigation of MMN in relation to neuropsychological function in schizophrenia.
Method
Forty schizophrenia patients and 16 healthy controls underwent a passive oddball paradigm (2400 binaural tones; 88% standards [1 kHz, 80 db, 80 ms], 11% frequency deviants [1.2 kHz], 11% duration deviants [40 ms]) and a neuropsychological test-battery. Patients were assessed with regard to clinical symptoms.
Results
Compared to healthy controls schizophrenia patients showed diminished MMN amplitude and shorter MMN latency to both deviants as well as an impaired neuropsychological test performance. Severity of positive symptoms was related to decreased MMN amplitude to duration deviants. Furthermore, enhanced verbal memory performance was associated with prolonged MMN latency to frequency deviants in patients.
Conclusion
The present study corroborates previous results of a diminished MMN amplitude and its association with positive symptoms in schizophrenia patients. Both, the findings of a shorter latency to duration and frequency deviants and the relationship of the latter with verbal memory in patients, emphasize the relevance of the temporal aspect of early auditory discrimination processing in schizophrenia.
doi:10.1371/journal.pone.0084536
PMCID: PMC3989165  PMID: 24740391
8.  Differential Sialylation of Serpin A1 in the Early Diagnosis of Parkinson’s Disease Dementia 
PLoS ONE  2012;7(11):e48783.
The prevalence of Parkinson’s disease (PD) increases with age. Up to 50% of PD show cognitive decline in terms of a mild cognitive impairment already in early stages that predict the development of dementia, which can occur in up to 80% of PD patients over the long term, called Parkinson’s disease dementia (PDD). So far, diagnosis of PD/PDD is made according to clinical and neuropsychological examinations while laboratory data is only used for exclusion of other diseases. The aim of this study was the identification of possible biomarkers in cerebrospinal fluid (CSF) of PD, PDD and controls (CON) which predict the development of dementia in PD. For this, a proteomic approach optimized for CSF was performed using 18 clinically well characterized patients in a first step with subsequent validation using 84 patients. Here, we detected differentially sialylated isoforms of Serpin A1 as marker for differentiation of PD versus PDD in CSF. Performing 2D-immunoblots, all PDD patients could be identified correctly (sensitivity 100%). Ten out of 24 PD patients showed Serpin A1 isoforms in a similar pattern like PDD, indicating a specificity of 58% for the test-procedure. In control samples, no additional isoform was detected. On the basis of these results, we conclude that differentially sialylated products of Serpin A1 are an interesting biomarker to indicate the development of a dementia during the course of PD.
doi:10.1371/journal.pone.0048783
PMCID: PMC3493604  PMID: 23144969
9.  Neurochemical biomarkers in Alzheimer’s disease and related disorders 
Neurochemical biomarkers for diagnosing dementias are currently under intensive investigation and the field is rapidly expanding. The main protagonists and the best defined among them are cerebrospinal fluid levels of Aβ42, tau and its phosphorylated forms (p-tau). In addition, novel cerebrospinal fluid biomarkers are emerging and their multiparametric assessment seems most promising for increasing the accuracy in neurochemical dementia diagnostics. The combined assessment of Aβ42 and p-tau has recently shown value for diagnosing prodromal states of Alzheimer’s dementia, that is, mild cognitive impairment. Disease-specific biomarkers for other degenerative dementias are still missing, but some progress has recently been made. As lumbar puncture is an additional burden for the patient, blood-based neurochemical biomarkers are definitely warranted and promising new discoveries have been made in this direction. These diagnostic developments have implicit therapeutic consequences and give rise to new requirements for future neurochemical dementia diagnostics.
doi:10.1177/1756285612455367
PMCID: PMC3487531  PMID: 23139704
Alzheimer’s disease; biomarker; blood; cerebrospinal fluid; dementia
10.  No consistent evidence for association between mtDNA variants and Alzheimer disease 
Hudson, G. | Sims, R. | Harold, D. | Chapman, J. | Hollingworth, P. | Gerrish, A. | Russo, G. | Hamshere, M. | Moskvina, V. | Jones, N. | Thomas, C. | Stretton, A. | Holmans, P.A. | O'Donovan, M.C. | Owen, M.J. | Williams, J. | Chinnery, P.F. | Harold, Denise | Abraham, Richard | Hollingworth, Paul | Sims, Rebecca | Gerrish, Amy | Chapman, Jade | Russo, Giancarlo | Hamshere, Marian | Pahwa, Jaspreet Singh | Moskvina, Valentina | Dowzell, Kimberley | Williams, Amy | Jones, Nicola | Thomas, Charlene | Stretton, Alexandra | Morgan, Angharad | Lovestone, Simon | Powell, John | Proitsi, Petroula | Lupton, Michelle K | Brayne, Carol | Rubinsztein, David C. | Gill, Michael | Lawlor, Brian | Lynch, Aoibhinn | Morgan, Kevin | Brown, Kristelle | Passmore, Peter | Craig, David | McGuinness, Bernadette | Todd, Stephen | Johnston, Janet | Holmes, Clive | Mann, David | Smith, A. David | Love, Seth | Kehoe, Patrick G. | Hardy, John | Mead, Simon | Fox, Nick | Rossor, Martin | Collinge, John | Maier, Wolfgang | Jessen, Frank | Heun, Reiner | Kölsch, Heike | Schürmann, Britta | van den Bussche, Hendrik | Heuser, Isabella | Kornhuber, Johannes | Wiltfang, Jens | Dichgans, Martin | Frölich, Lutz | Hampel, Harald | Hüll, Michael | Rujescu, Dan | Goate, Alison | Kauwe, John S.K. | Cruchaga, Carlos | Nowotny, Petra | Morris, John C. | Mayo, Kevin | Livingston, Gill | Bass, Nicholas J. | Gurling, Hugh | McQuillin, Andrew | Gwilliam, Rhian | Deloukas, Panagiotis | Holmans, Peter | O'Donovan, Michael | Owen, Michael J. | Williams, Julie
Neurology  2012;78(14):1038-1042.
Objective:
Although several studies have described an association between Alzheimer disease (AD) and genetic variation of mitochondrial DNA (mtDNA), each has implicated different mtDNA variants, so the role of mtDNA in the etiology of AD remains uncertain.
Methods:
We tested 138 mtDNA variants for association with AD in a powerful sample of 4,133 AD case patients and 1,602 matched controls from 3 Caucasian populations. Of the total population, 3,250 case patients and 1,221 elderly controls met the quality control criteria and were included in the analysis.
Results:
In the largest study to date, we failed to replicate the published findings. Meta-analysis of the available data showed no evidence of an association with AD.
Conclusion:
The current evidence linking common mtDNA variations with AD is not compelling.
doi:10.1212/WNL.0b013e31824e8f1d
PMCID: PMC3317529  PMID: 22442439
11.  The release of IL-31 and IL-13 after nasal allergen challenge and their relation to nasal symptoms 
Background
IL-31, a recently discovered member of the gp130/IL-6 cytokine family, is mainly expressed by human mast cells and T helper type 2 cells. IL-31 is a key trigger of atopic dermatitis. Recent studies also suggest a role of IL-31 in the pathogenesis of other allergic diseases including allergic rhinitis. In the present study we studied the release of IL-31 and IL-13 in allergen-challenged allergic rhinitis patients.
Methods
Seven seasonal allergic volunteers underwent unilateral nasal provocation with allergen (and a control challenge) with the disc method out of the allergy season. Nasal symptom scores (rhinorrhea, itching, sneezing, obstruction) and bilateral nasal secretions were quantified before and after allergen provocation. IL-13 and IL-31 in nasal secretions and serum were measured by electrochemiluminescent immunoassay or ELISA, respectively.
Results
Nasal allergen challenge induced the typical clinical symptoms and physiological changes. IL-31 and IL-13 in nasal secretions increased in four and five, respectively, volunteers at 5 h after allergen but not after control challenge. We observed correlation trends between nasal IL-31 concentrations and IL-13 concentrations (r = 0.9, p = 0.002), and IL-31 contents and symptom scores (r = 0.9, p = 0.013) 5 h after allergen provocation. No IL-31 could be detected contralaterally or systemically in the sera.
Conclusions
The observed local upregulation of IL-31 mainly during the late phase reaction after nasal allergen challenge suggests a role of IL-31 in allergic rhinitis. In which way IL-31 modulates the inflammatory reaction and type 2 responses in allergic rhinitis remains to be investigated.
doi:10.1186/2045-7022-2-13
PMCID: PMC3509028  PMID: 22853438
Nasal allergen; Nasal secretion; IL-13; IL-31; Kinetics
12.  Cerebrospinal fluid amyloid-β 2-42 is decreased in Alzheimer’s, but not in frontotemporal dementia 
Journal of Neural Transmission  2012;119(7):805-813.
Alzheimer’s dementia (AD) and frontotemporal dementias (FTD) are common and their clinical differential diagnosis may be complicated by overlapping symptoms, which is why biomarkers may have an important role to play. Cerebrospinal fluids (CSF) Aβ2-42 and 1-42 have been shown to be similarly decreased in AD, but 1-42 did not display sufficient specificity for exclusion of other dementias from AD. The objective of the present study was to clarify the diagnostic value of Aβ2-42 peptides for the differential diagnosis of AD from FTD. For this purpose, 20 non-demented disease controls (NDC), 22 patients with AD and 17 with FTD were comparatively analysed by a novel sequential aminoterminally and carboxyterminally specific immunoprecipitation protocol with subsequent Aβ-SDS-PAGE/immunoblot, allowing the quantification of peptides 1-38ox, 2-40 and 2-42 along with Aβ 1-37, 1-38, 1-39, 1-40, 1-40ox and 1-42. CSF Aβ1-42 was decreased in AD as compared to NDC, but not to FTD. In a subgroup of the patients analyzed, the decrease of Abeta2-42 in AD was evident as compared to both NDC and FTD. Aβ1-38 was decreased in FTD as compared to NDC and AD. For differentiating AD from FTD, Aβ1-42 demonstrated sufficient diagnostic accuracies only when combined with Aβ1-38. Aβ2-42 yielded diagnostic accuracies of over 85 % as a single marker. These accuracy figures could be improved by combining Aβ2-42 to Aβ1-38. Aβ2-42 seems to be a promising biomarker for differentiating AD from other degenerative dementias, such as FTD.
doi:10.1007/s00702-012-0801-3
PMCID: PMC3605494  PMID: 22527776
Alzheimer’s dementia; Frontotemporal dementia; Cerebrospinal fluid; Aminoterminally truncated; Amyloid-β peptides; Aβ2-42
13.  The mechanism of γ-Secretase dysfunction in familial Alzheimer disease 
The EMBO Journal  2012;31(10):2261-2274.
The mechanism of γ-Secretase dysfunction in familial Alzheimer disease
Mutations in presenilin (PSEN) and amyloid precursor protein (APP) cause dominant early-onset Alzheimer's disease (AD), but the mechanism involved is debated. Here, such mutations are shown to alter γ-secretase activity, leading to changes in Aβ peptide cleavage patterns.
The mechanisms by which mutations in the presenilins (PSEN) or the amyloid precursor protein (APP) genes cause familial Alzheimer disease (FAD) are controversial. FAD mutations increase the release of amyloid β (Aβ)42 relative to Aβ40 by an unknown, possibly gain-of-toxic-function, mechanism. However, many PSEN mutations paradoxically impair γ-secretase and ‘loss-of-function' mechanisms have also been postulated. Here, we use kinetic studies to demonstrate that FAD mutations affect Aβ generation via three different mechanisms, resulting in qualitative changes in the Aβ profiles, which are not limited to Aβ42. Loss of ɛ-cleavage function is not generally observed among FAD mutants. On the other hand, γ-secretase inhibitors used in the clinic appear to block the initial ɛ-cleavage step, but unexpectedly affect more selectively Notch than APP processing, while modulators act as activators of the carboxypeptidase-like (γ) activity. Overall, we provide a coherent explanation for the effect of different FAD mutations, demonstrating the importance of qualitative rather than quantitative changes in the Aβ products, and suggest fundamental improvements for current drug development efforts.
doi:10.1038/emboj.2012.79
PMCID: PMC3364747  PMID: 22505025
Alzheimer; amyloid; FAD mutations; γ-secretase; presenilin
15.  The Effects of Acute Tryptophan Depletion on Reactive Aggression in Adults with Attention-Deficit/Hyperactivity Disorder (ADHD) and Healthy Controls 
PLoS ONE  2012;7(3):e32023.
Background
The neurotransmitter serotonin (5-HT) has been linked to the underlying neurobiology of aggressive behavior, particularly with evidence from studies in animals and humans. However, the underlying neurobiology of aggression remains unclear in the context of attention-deficit/hyperactivity disorder (ADHD), a disorder known to be associated with aggression and impulsivity. We investigated the effects of acute tryptophan depletion (ATD), and the resulting diminished central nervous serotonergic neurotransmission, on reactive aggression in healthy controls and adults with ADHD.
Methodology/Principal Findings
Twenty male patients with ADHD and twenty healthy male controls were subjected to ATD with an amino acid (AA) beverage that lacked tryptophan (TRP, the physiological precursor of 5-HT) and a TRP-balanced AA beverage (BAL) in a double-blind, within-subject crossover-study over two study days. We assessed reactive aggression 3.25 hours after ATD/BAL intake using a point-subtraction aggression game (PSAG) in which participants played for points against a fictitious opponent. Point subtraction was taken as a measure for reactive aggression. Lowered rates of reactive aggression were found in the ADHD group under ATD after low provocation (LP), with controls showing the opposite effect. In patients with ADHD, trait-impulsivity was negatively correlated with the ATD effect on reactive aggression after LP. Statistical power was limited due to large standard deviations observed in the data on point subtraction, which may limit the use of this particular paradigm in adults with ADHD.
Conclusions/Significance
Together with previous findings, the data provide preliminary evidence of an inverse association between trait-impulsivity and the ATD effect on reactive aggression after LP (as assessed by the PSAG) in patients with ADHD and that this relationship can be found in both adolescents and adults. Because of limited statistical power larger sample sizes are needed to find main effects of ATD/BAL administration on reactive aggression in adults with ADHD.
doi:10.1371/journal.pone.0032023
PMCID: PMC3303767  PMID: 22431971
16.  Evidence for Elevated Cerebrospinal Fluid ERK1/2 Levels in Alzheimer Dementia 
Cerebrospinal fluid (CSF) samples from 33 patients with Alzheimer dementia (AD), 21 patients with mild cognitive impairment who converted to AD during followup (MCI-AD), 25 patients with stable mild cognitive impairment (MCI-stable), and 16 nondemented subjects (ND) were analyzed with a chemiluminescence immunoassay to assess the levels of the mitogen-activated protein kinase ERK1/2 (extracellular signal-regulated kinase 1/2). The results were evaluated in relation to total Tau (tTau), phosphorylated Tau (pTau), and beta-amyloid 42 peptide (Aβ42). CSF-ERK1/2 was significantly increased in the AD group as compared to stable MCI patients and the ND group. Western blot analysis of a pooled cerebrospinal fluid sample revealed that both isoforms, ERK1 and ERK2, and low amounts of doubly phosphorylated ERK2 were detectable. As a predictive diagnostic AD biomarker, CSF-ERK1/2 was inferior to tTau, pTau, and Aβ42.
doi:10.4061/2011/739847
PMCID: PMC3227514  PMID: 22145083
17.  Common variants in ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease 
Hollingworth, Paul | Harold, Denise | Sims, Rebecca | Gerrish, Amy | Lambert, Jean-Charles | Carrasquillo, Minerva M | Abraham, Richard | Hamshere, Marian L | Pahwa, Jaspreet Singh | Moskvina, Valentina | Dowzell, Kimberley | Jones, Nicola | Stretton, Alexandra | Thomas, Charlene | Richards, Alex | Ivanov, Dobril | Widdowson, Caroline | Chapman, Jade | Lovestone, Simon | Powell, John | Proitsi, Petroula | Lupton, Michelle K | Brayne, Carol | Rubinsztein, David C | Gill, Michael | Lawlor, Brian | Lynch, Aoibhinn | Brown, Kristelle S | Passmore, Peter A | Craig, David | McGuinness, Bernadette | Todd, Stephen | Holmes, Clive | Mann, David | Smith, A David | Beaumont, Helen | Warden, Donald | Wilcock, Gordon | Love, Seth | Kehoe, Patrick G | Hooper, Nigel M | Vardy, Emma R. L. C. | Hardy, John | Mead, Simon | Fox, Nick C | Rossor, Martin | Collinge, John | Maier, Wolfgang | Jessen, Frank | Schürmann, Britta | Rüther, Eckart | Heun, Reiner | Kölsch, Heike | van den Bussche, Hendrik | Heuser, Isabella | Kornhuber, Johannes | Wiltfang, Jens | Dichgans, Martin | Frölich, Lutz | Hampel, Harald | Hüll, Michael | Gallacher, John | Rujescu, Dan | Giegling, Ina | Goate, Alison M | Kauwe, John S K | Cruchaga, Carlos | Nowotny, Petra | Morris, John C | Mayo, Kevin | Sleegers, Kristel | Bettens, Karolien | Engelborghs, Sebastiaan | De Deyn, Peter P | Van Broeckhoven, Christine | Livingston, Gill | Bass, Nicholas J | Gurling, Hugh | McQuillin, Andrew | Gwilliam, Rhian | Deloukas, Panagiotis | Al-Chalabi, Ammar | Shaw, Christopher E | Tsolaki, Magda | Singleton, Andrew B | Guerreiro, Rita | Mühleisen, Thomas W | Nöthen, Markus M | Moebus, Susanne | Jöckel, Karl-Heinz | Klopp, Norman | Wichmann, H-Erich | Pankratz, V Shane | Sando, Sigrid B | Aasly, Jan O | Barcikowska, Maria | Wszolek, Zbigniew K | Dickson, Dennis W | Graff-Radford, Neill R | Petersen, Ronald C | van Duijn, Cornelia M | Breteler, Monique MB | Ikram, M Arfan | DeStefano, Anita L | Fitzpatrick, Annette L | Lopez, Oscar | Launer, Lenore J | Seshadri, Sudha | Berr, Claudine | Campion, Dominique | Epelbaum, Jacques | Dartigues, Jean-François | Tzourio, Christophe | Alpérovitch, Annick | Lathrop, Mark | Feulner, Thomas M | Friedrich, Patricia | Riehle, Caterina | Krawczak, Michael | Schreiber, Stefan | Mayhaus, Manuel | Nicolhaus, S | Wagenpfeil, Stefan | Steinberg, Stacy | Stefansson, Hreinn | Stefansson, Kari | Snædal, Jon | Björnsson, Sigurbjörn | Jonsson, Palmi V. | Chouraki, Vincent | Genier-Boley, Benjamin | Hiltunen, Mikko | Soininen, Hilkka | Combarros, Onofre | Zelenika, Diana | Delepine, Marc | Bullido, Maria J | Pasquier, Florence | Mateo, Ignacio | Frank-Garcia, Ana | Porcellini, Elisa | Hanon, Olivier | Coto, Eliecer | Alvarez, Victoria | Bosco, Paolo | Siciliano, Gabriele | Mancuso, Michelangelo | Panza, Francesco | Solfrizzi, Vincenzo | Nacmias, Benedetta | Sorbi, Sandro | Bossù, Paola | Piccardi, Paola | Arosio, Beatrice | Annoni, Giorgio | Seripa, Davide | Pilotto, Alberto | Scarpini, Elio | Galimberti, Daniela | Brice, Alexis | Hannequin, Didier | Licastro, Federico | Jones, Lesley | Holmans, Peter A | Jonsson, Thorlakur | Riemenschneider, Matthias | Morgan, Kevin | Younkin, Steven G | Owen, Michael J | O’Donovan, Michael | Amouyel, Philippe | Williams, Julie
Nature genetics  2011;43(5):429-435.
We sought to identify new susceptibility loci for Alzheimer’s disease (AD) through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer’s Disease Genetic Consortium (ADGC). First, we undertook a combined analysis of four genome-wide association datasets (Stage 1) and identified 10 novel variants with P≤1×10−5. These were tested for association in an independent sample (Stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (Stage 3). Meta-analyses of all data provide compelling evidence that ABCA7 (meta-P 4.5×10−17; including ADGC meta-P=5.0×10−21) and the MS4A gene cluster (rs610932, meta-P=1.8×10−14; including ADGC meta-P=1.2×10−16; rs670139, meta-P=1.4×10−9; including ADGC meta-P=1.1×10−10) are novel susceptibility loci for AD. Second, we observed independent evidence for association for three suggestive loci reported by the ADGC GWAS, which when combined shows genome-wide significance: CD2AP (GERAD+ P=8.0×10−4; including ADGC meta-P=8.6×10−9), CD33 (GERAD+ P=2.2×10−4; including ADGC meta-P=1.6×10−9) and EPHA1 (GERAD+ P=3.4×10−4; including ADGC meta-P=6.0×10−10). These findings support five novel susceptibility genes for AD.
doi:10.1038/ng.803
PMCID: PMC3084173  PMID: 21460840
18.  Correction: Genetic Evidence Implicates the Immune System and Cholesterol Metabolism in the Aetiology of Alzheimer's Disease 
Jones, Lesley | Holmans, Peter A. | Hamshere, Marian L. | Harold, Denise | Moskvina, Valentina | Ivanov, Dobril | Pocklington, Andrew | Abraham, Richard | Hollingworth, Paul | Sims, Rebecca | Gerrish, Amy | Pahwa, Jaspreet Singh | Jones, Nicola | Stretton, Alexandra | Morgan, Angharad R. | Lovestone, Simon | Powell, John | Proitsi, Petroula | Lupton, Michelle K. | Brayne, Carol | Rubinsztein, David C. | Gill, Michael | Lawlor, Brian | Lynch, Aoibhinn | Morgan, Kevin | Brown, Kristelle S. | Passmore, Peter A. | Craig, David | McGuinness, Bernadette | Todd, Stephen | Holmes, Clive | Mann, David | Smith, A. David | Love, Seth | Kehoe, Patrick G. | Mead, Simon | Fox, Nick | Rossor, Martin | Collinge, John | Maier, Wolfgang | Jessen, Frank | Schürmann, Britta | van den Bussche, Hendrik | Heuser, Isabella | Peters, Oliver | Kornhuber, Johannes | Wiltfang, Jens | Dichgans, Martin | Frölich, Lutz | Hampel, Harald | Hüll, Michael | Rujescu, Dan | Goate, Alison M. | Kauwe, John S. K. | Cruchaga, Carlos | Nowotny, Petra | Morris, John C. | Mayo, Kevin | Livingston, Gill | Bass, Nicholas J. | Gurling, Hugh | McQuillin, Andrew | Gwilliam, Rhian | Deloukas, Panos | Al-Chalabi, Ammar | Shaw, Christopher E. | Singleton, Andrew B. | Guerreiro, Rita | Mühleisen, Thomas W. | Nöthen, Markus M. | Moebus, Susanne | Jöckel, Karl-Heinz | Klopp, Norman | Wichmann, H.-Erich | Rüther, Eckhard | Carrasquillo, Minerva M. | Pankratz, V. Shane | Younkin, Steven G. | Hardy, John | O'Donovan, Michael C. | Owen, Michael J. | Williams, Julie
PLoS ONE  2011;6(2):10.1371/annotation/a0bb886d-d345-4a20-a82e-adce9b047798.
doi:10.1371/annotation/a0bb886d-d345-4a20-a82e-adce9b047798
PMCID: PMC3039022
19.  Genetic Evidence Implicates the Immune System and Cholesterol Metabolism in the Aetiology of Alzheimer's Disease 
Jones, Lesley | Holmans, Peter A. | Hamshere, Marian L. | Harold, Denise | Moskvina, Valentina | Ivanov, Dobril | Pocklington, Andrew | Abraham, Richard | Hollingworth, Paul | Sims, Rebecca | Gerrish, Amy | Pahwa, Jaspreet Singh | Jones, Nicola | Stretton, Alexandra | Morgan, Angharad R. | Lovestone, Simon | Powell, John | Proitsi, Petroula | Lupton, Michelle K. | Brayne, Carol | Rubinsztein, David C. | Gill, Michael | Lawlor, Brian | Lynch, Aoibhinn | Morgan, Kevin | Brown, Kristelle S. | Passmore, Peter A. | Craig, David | McGuinness, Bernadette | Todd, Stephen | Holmes, Clive | Mann, David | Smith, A. David | Love, Seth | Kehoe, Patrick G. | Mead, Simon | Fox, Nick | Rossor, Martin | Collinge, John | Maier, Wolfgang | Jessen, Frank | Schürmann, Britta | van den Bussche, Hendrik | Heuser, Isabella | Peters, Oliver | Kornhuber, Johannes | Wiltfang, Jens | Dichgans, Martin | Frölich, Lutz | Hampel, Harald | Hüll, Michael | Rujescu, Dan | Goate, Alison M. | Kauwe, John S. K. | Cruchaga, Carlos | Nowotny, Petra | Morris, John C. | Mayo, Kevin | Livingston, Gill | Bass, Nicholas J. | Gurling, Hugh | McQuillin, Andrew | Gwilliam, Rhian | Deloukas, Panos | Al-Chalabi, Ammar | Shaw, Christopher E. | Singleton, Andrew B. | Guerreiro, Rita | Mühleisen, Thomas W. | Nöthen, Markus M. | Moebus, Susanne | Jöckel, Karl-Heinz | Klopp, Norman | Wichmann, H.-Erich | Rüther, Eckhard | Carrasquillo, Minerva M. | Pankratz, V. Shane | Younkin, Steven G. | Hardy, John | O'Donovan, Michael C. | Owen, Michael J. | Williams, Julie
PLoS ONE  2010;5(11):e13950.
Background
Late Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes.
Methodology
We applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset.
Principal Findings
We found a significant overrepresentation of association signals in pathways related to cholesterol metabolism and the immune response in both of the two largest genome-wide association studies for LOAD.
Significance
Processes related to cholesterol metabolism and the innate immune response have previously been implicated by pathological and epidemiological studies of Alzheimer's disease, but it has been unclear whether those findings reflected primary aetiological events or consequences of the disease process. Our independent evidence from two large studies now demonstrates that these processes are aetiologically relevant, and suggests that they may be suitable targets for novel and existing therapeutic approaches.
doi:10.1371/journal.pone.0013950
PMCID: PMC2981526  PMID: 21085570
21.  Retrieval of the Alzheimer's amyloid precursor protein from the endosome to the TGN is S655 phosphorylation state-dependent and retromer-mediated 
Background
Retrograde transport of several transmembrane proteins from endosomes to the trans-Golgi network (TGN) occurs via Rab 5-containing endosomes, mediated by clathrin and the recently characterized retromer complex. This complex and one of its putative sorting receptor components, SorLA, were reported to be associated to late onset Alzheimer's disease (AD). The pathogenesis of this neurodegenerative disorder is still elusive, although accumulation of amyloidogenic Abeta is a hallmark. This peptide is generated from the sucessive β- and γ- secretase proteolysis of the Alzheimer's amyloid precursor protein (APP), events which are associated with endocytic pathway compartments. Therefore, APP targeting and time of residence in endosomes would be predicted to modulate Abeta levels. However, the formation of an APP- and retromer-containing protein complex with potential functions in retrieval of APP from the endosome to the TGN had, to date, not been demonstrated directly. Further, the motif(s) in APP that regulate its sorting to the TGN have not been characterized.
Results
Through the use of APP-GFP constructs, we show that APP containing endocytic vesicles targeted for the TGN, are also immunoreactive for clathrin-, Rab 5- and VPS35. Further, they frequently generate protruding tubules near the TGN, supporting an association with a retromer-mediated pathway. Importantly, we show for the first time, that mimicking APP phosphorylation at S655, within the APP 653YTSI656 basolateral motif, enhances APP retrieval via a retromer-mediated process. The phosphomimetic APP S655E displays decreased APP lysosomal targeting, enhanced mature half-life, and decreased tendency towards Abeta production. VPS35 downregulation impairs the phosphorylation dependent APP retrieval to the TGN, and decreases APP half-life.
Conclusions
We reported for the first time the importance of APP phosphorylation on S655 in regulating its retromer-mediated sorting to the TGN or lysosomes. Significantly, the data are consistent with known interactions involving the retromer, SorLA and APP. Further, these findings add to our understanding of APP targeting and potentially contribute to our knowledge of sporadic AD pathogenesis representing putative new targets for AD therapeutic strategies.
doi:10.1186/1750-1326-5-40
PMCID: PMC2994555  PMID: 20937087
22.  Phagocytosis and LPS alter the maturation state of β-amyloid precursor protein and induce different Aβ peptide release signatures in human mononuclear phagocytes 
Background
The classic neuritic β-amyloid plaque of Alzheimer's disease (AD) is typically associated with activated microglia and neuroinflammation. Similarly, cerebrovascular β-amyloid (Aβ) deposits are surrounded by perivascular macrophages. Both observations indicate a contribution of the mononuclear phagocyte system to the development of β-amyloid.
Methods
Human CD14-positive mononuclear phagocytes were isolated from EDTA-anticoagulated blood by magnetic activated cell sorting. After a cultivation period of 72 hours in serum-free medium we assessed the protein levels of amyloid precursor protein (APP) as well as the patterns and the amounts of released Aβ peptides by ELISA or one-dimensional and two-dimensional urea-based SDS-PAGE followed by western immunoblotting.
Results
We observed strong and significant increases in Aβ peptide release upon phagocytosis of acetylated low density lipoprotein (acLDL) or polystyrene beads and also after activation of the CD14/TLR4 pathway by stimulation with LPS. The proportion of released N-terminally truncated Aβ variants was increased after stimulation with polystyrene beads and acLDL but not after stimulation with LPS. Furthermore, strong shifts in the proportions of single Aβ1-40 and Aβ2-40 variants were detected resulting in a stimulus-specific Aβ signature. The increased release of Aβ peptides was accompanied by elevated levels of full length APP in the cells. The maturation state of APP was correlated with the release of N-terminally truncated Aβ peptides.
Conclusions
These findings indicate that mononuclear phagocytes potentially contribute to the various N-truncated Aβ variants found in AD β-amyloid plaques, especially under neuroinflammatory conditions.
doi:10.1186/1742-2094-7-59
PMCID: PMC2958903  PMID: 20929546
23.  cNEUPRO: Novel Biomarkers for Neurodegenerative Diseases 
“clinical NEUroPROteomics of neurodegenerative diseases” (cNEUPRO) is a Specific Targeted Research Project (STREP) within the sixth framework program of the European Commission dedicated to the search for novel biomarker candidates for Alzheimer's disease and other neurodegenerative diseases. The ultimate goal of cNEUPRO is to identify one or more valid biomarker(s) in blood and CSF applicable to support the early and differential diagnosis of dementia disorders. The consortium covers all steps required for the discovery of novel biomarker candidates such as acquisition of high quality CSF and blood samples from relevant patient groups and controls, analysis of body fluids by various methods, and finally assay development and assay validation. Here we report the standardized procedures for diagnosis and preanalytical sample-handling within the project, as well as the status of the ongoing research activities and some first results.
doi:10.4061/2010/548145
PMCID: PMC2945639  PMID: 20886057
24.  Combined Analysis of CSF Tau, Aβ42, Aβ1–42% and Aβ1–40ox% in Alzheimer's Disease, Dementia with Lewy Bodies and Parkinson's Disease Dementia 
We studied the diagnostic value of CSF Aβ42/tau versus low Aβ1–42% and high Aβ1–40ox% levels for differential diagnosis of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), respectively. CSF of 45 patients with AD, 15 with DLB, 21 with Parkinson's disease dementia (PDD), and 40 nondemented disease controls (NDC) was analyzed by Aβ-SDS-PAGE/immunoblot and ELISAs (Aβ42 and tau). Aβ42/tau lacked specificity in discriminating AD from DLB and PDD. Best discriminating biomarkers were Aβ1–42% and Aβ1–40ox% for AD and DLB, respectively. AD and DLB could be differentiated by both Aβ1–42% and Aβ1–40ox% with an accuracy of 80% at minimum. Thus, we consider Aβ1–42% and Aβ1–40ox% to be useful biomarkers for AD and DLB, respectively. We propose further studies on the integration of Aβ1–42% and Aβ1–40ox% into conventional assay formats. Moreover, future studies should investigate the combination of Aβ1–40ox% and CSF alpha-synuclein for the diagnosis of DLB.
doi:10.4061/2010/761571
PMCID: PMC2938459  PMID: 20862375
25.  Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease, and shows evidence for additional susceptibility genes 
Harold, Denise | Abraham, Richard | Hollingworth, Paul | Sims, Rebecca | Gerrish, Amy | Hamshere, Marian | Singh Pahwa, Jaspreet | Moskvina, Valentina | Dowzell, Kimberley | Williams, Amy | Jones, Nicola | Thomas, Charlene | Stretton, Alexandra | Morgan, Angharad | Lovestone, Simon | Powell, John | Proitsi, Petroula | Lupton, Michelle K | Brayne, Carol | Rubinsztein, David C. | Gill, Michael | Lawlor, Brian | Lynch, Aoibhinn | Morgan, Kevin | Brown, Kristelle | Passmore, Peter | Craig, David | McGuinness, Bernadette | Todd, Stephen | Holmes, Clive | Mann, David | Smith, A. David | Love, Seth | Kehoe, Patrick G. | Hardy, John | Mead, Simon | Fox, Nick | Rossor, Martin | Collinge, John | Maier, Wolfgang | Jessen, Frank | Schürmann, Britta | van den Bussche, Hendrik | Heuser, Isabella | Kornhuber, Johannes | Wiltfang, Jens | Dichgans, Martin | Frölich, Lutz | Hampel, Harald | Hüll, Michael | Rujescu, Dan | Goate, Alison | Kauwe, John S.K. | Cruchaga, Carlos | Nowotny, Petra | Morris, John C. | Mayo, Kevin | Sleegers, Kristel | Bettens, Karolien | Engelborghs, Sebastiaan | De Deyn, Peter | van Broeckhoven, Christine | Livingston, Gill | Bass, Nicholas J. | Gurling, Hugh | McQuillin, Andrew | Gwilliam, Rhian | Deloukas, Panagiotis | Al-Chalabi, Ammar | Shaw, Christopher E. | Tsolaki, Magda | Singleton, Andrew | Guerreiro, Rita | Mühleisen, Thomas W. | Nöthen, Markus M. | Moebus, Susanne | Jöckel, Karl-Heinz | Klopp, Norman | Wichmann, H-Erich | Carrasquillo, Minerva M. | Pankratz, V. Shane | Younkin, Steven G. | Holmans, Peter | O'Donovan, Michael | Owen, Michael J. | Williams, Julie
Nature genetics  2009;41(10):1088-1093.
We undertook a two-stage genome-wide association study of Alzheimer's disease involving over 16,000 individuals. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the APOE locus (most significant SNP: rs2075650, p= 1.8×10−157) and observed genome-wide significant association with SNPs at two novel loci: rs11136000 in the CLU or APOJ gene (p= 1.4×10−9) and rs3851179, a SNP 5′ to the PICALM gene (p= 1.9×10−8). Both novel associations were supported in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with AD in the combined dataset (rs11136000: p= 8.5×10−10, odds ratio= 0.86; rs3851179: p= 1.3×10−9, odds ratio= 0.86). We also observed more variants associated at p< 1×10−5 than expected by chance (p=7.5×10−6), including polymorphisms at the BIN1, DAB1 and CR1 loci.
doi:10.1038/ng.440
PMCID: PMC2845877  PMID: 19734902

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