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ABSTRACT: Neuropeptides are found throughout the entire nervous system where they can act as neurotransmitter, neuromodulator or neurohormone. In those functions, they play important roles in the regulation of cognition and behavior. In brain disorders like Alzheimer's disease (AD), where abnormal cognition and behavior are observed, the study of neuropeptides is particularly interesting since altered neuropeptides can function as biomarkers or as targets for new medication. In this article neuropeptides with relevance to AD are listed and their influence on cognitive and behavioral disturbances is discussed. Findings from human cerebrospinal fluid and brain tissue, and AD mouse models are described and related to the pathophysiology and symptomatology of the disease. In the past, clinical trials with neuropeptides have often failed due to insufficient delivery to the brain. Therefore, new strategies to target the brain with peptide drugs are also covered.
Current Alzheimer research 04/2013; · 4.97 Impact Factor
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ABSTRACT: OBJECTIVE: With a prevalence that varies between 20% and 65%, poststroke depression (PSD) is a frequent sequel of stroke. The aim of this study was to determine incidence and risk factors for PSD 18 months after stroke. METHODS: As part of the Middelheim Interdisciplinary Stroke Study, patients were followed up for 18 months in this prospective and longitudinal epidemiological study. Clinically significant signs and symptoms of PSD were quantified by means of the Cornell Scale for Depression (CSD) and the Montgomery and Åsberg Depression Rating Scale. Activities, including social activities, were measured with the Stroke Impact Scale (SIS). Relational problems since stroke onset were defined by a questionnaire. RESULTS: Data analysis was performed on 125 patients who completed follow-up assessments. Depression (CSD score ≥8) was diagnosed in 28% of the patients. Patients with PSD were more dependent for activities of daily living and displayed more physical and cognitive impairment than patients without PSD. The risk to become depressed decreased with 5% when the patient's activities increased with one unit on the SIS (odds ratio (OR) = 0.95; 95% confidence interval (CI) = 0.93-0.97). Patients with persistent relational problems since stroke onset had approximately four and a half times greater risk of becoming depressed than patients without (OR = 4.48; 95%CI = 1.17-16.87). CONCLUSIONS: Multiple regression models indicated that the most determining features for developing PSD at 18 months poststroke include reduced activity and relationship problems due to stroke. Further studies on risk factors for PSD are essential, including psychosocial aspects, given its negative impact on rehabilitation and quality of life. Copyright © 2013 John Wiley & Sons, Ltd.
International Journal of Geriatric Psychiatry 04/2013; · 2.42 Impact Factor
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ABSTRACT: Poststroke depression (PSD) is common. Early detection of depressive symptoms and identification of patients at risk for PSD are important as PSD negatively affects stroke outcome and costs of medical care. Therefore, the aim of this study was to determine incidence and risk factors for PSD at 3 months after stroke.
We conducted a prospective, longitudinal epidemiological study aiming to determine incidence and risk factors for PSD at 1, 3, 6, 12 and 18 months poststroke. The present data analysis covers the convalescent phase of 3 months poststroke. Participants in this study were inpatients, admitted to a stroke unit with first or recurrent stroke. Demographic data and vascular risk factors were collected and patients were evaluated at baseline and 3 months poststroke for functional and cognitive deficits, stroke characteristics, stroke severity and stroke outcome. Signs and symptoms of depression were quantified by means of the Cornell Scale for Depression (CSD) and Montgomery and Åsberg Depression Rating Scale (MADRS). Significantly associated variables from univariate analysis were analyzed by using multiple linear and logistic regression methods.
Data analysis was performed in 135 patients who completed follow-up assessments at 3 months poststroke. Depression (CSD score ≥8) was diagnosed in 28.1% of the patients. Patients with PSD were significantly more dependent with regard to activities of daily living (ADL) and displayed more severe physical and cognitive impairment than patients without PSD. A higher prevalence of speech and language dysfunction and apraxia were observed in patients with PSD (36.8 and 34.3%, respectively) compared to non-depressed stroke patients (19.6 and 12.4%; p = 0.036 and p = 0.004, respectively). Applying multiple linear regressions, cognitive impairment and reduced mobility as part of the Stroke Impact Scale were independently associated with PSD, as scored using CSD and MADRS (r(2) = 0.269 and r(2) = 0.474, respectively).
The risk of developing PSD is increased in patients with more functional and cognitive impairment, greater dependency with regard to ADL functions and with occurrence of speech and language dysfunctions and apraxia. Multiple regression models indicated that the most determining features for depression risk in the convalescent phase after stroke include reduced mobility and cognitive impairment. Further studies on risk factors for PSD are essential, given its negative impact on rehabilitation and quality of life. Identification of risk factors for PSD may allow more efficacious preventive measures and early implementation of adequate antidepressive treatment.
Cerebrovascular diseases extra. 01/2013; 3(1):1-13.
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ABSTRACT: To analyse the prevalence and incidence of dementia in a population of community-dwelling elderly (aged 75-80), living in socio-economically differing districts of Antwerp (Belgium), taking into account possible gender and educational differences.
A longitudinal cohort study (N=825) with a 3-year follow-up period (N=363). The Mini Mental State Examination (MMSE) was used as a primary screen of cognitive functioning. Scoring 21 or below led to a second phase examination by a neurologist, including the CAMDEX-R-N and a neurological examination, to provide a tentative aetiological diagnosis of dementia. These procedures were conducted annually during a 3-year follow-up period.
In accordance with international literature, the overall prevalence rate of dementia was 8.7%. The cumulative incidence rate (IR) of dementia was 36.60 per 1000Py with annual IRs ranging from 34.39 over 35.16 to 49.04 per 1000Py. Dementia of the Alzheimer type (DAT) was the most occurring prevalent and incident cause. Women appeared to be at higher risk and the occurrence of cognitive deterioration was more prominent in districts with lower socio-economic status, possibly related to a lower education level.
We demonstrate dementia is a considerable health problem in an urban Belgian population of community-dwelling elderly aged between 75 and 80 years old. In order to prepare health care and social security systems for the future management of dementia, proper epidemiological insight into the current and future magnitude of the burden of dementia, taking into account socio-economic differences, to which this study contributes, are required.
Clinical neurology and neurosurgery 08/2011; 113(9):736-45. · 1.30 Impact Factor
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N Brouwers,
C Van Cauwenberghe,
S Engelborghs,
J-C Lambert,
K Bettens,
N Le Bastard,
F Pasquier,
A Gil Montoya,
K Peeters,
M Mattheijssens,
R Vandenberghe, P P De Deyn,
M Cruts,
P Amouyel,
K Sleegers,
C Van Broeckhoven
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ABSTRACT: Two multicentre genome-wide association (GWA) studies provided substantial evidence, implicating the complement receptor 1 gene (CR1) in Alzheimer disease (AD) genetic etiology. CR1 encodes a large transmembrane receptor with a crucial role in the immune complement cascade. We performed a genetic follow-up of the GWA CR1 association in a Flanders-Belgian cohort (n=1883), and investigated the effect of single-nucleotide polymorphisms (SNPs) located in the CR1 locus on AD risk and cerebrospinal fluid (CSF) biomarker levels. We obtained significant association (P(adj)<0.03; odds ratio (OR)=1.24 (95% confidence interval (CI): 1.02-1.51)) for one CR1 risk haplotype, and haplotype association was strongest in individuals carrying apolipoprotein E (APOE) ɛ4 alleles (P(adj)<0.006; OR=1.50 (95% CI: 1.08-2.09)). Also, four SNPs correlated with increased CSF amyloid Aβ₁₋₄₂ levels, suggesting a role for the CR1 protein in Aβ metabolism. Moreover, we quantified a low-copy repeat (LCR)-associated copy number variation (CNV) in CR1, producing different CR1 isoforms, CR1-F and CR1-S, and obtained significant association in carriers of CR1-S. We replicated the CR1 CNV association finding in a French cohort (n=2003) and calculated in the combined cohorts, an OR of 1.32; 95% CI: 1.10-1.59 (P=0.0025). Our data showed that the common AD risk association may well be explained by the presence of CR1-S increasing the number of C3b/C4b and cofactor activity sites and AD risk with 30% in CR1-S carriers. How precisely the different functional role of CR1-S in the immune complement cascade contributes to AD pathogenesis will need additional functional studies.
Molecular psychiatry 03/2011; 17(2):223-33. · 15.05 Impact Factor
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ABSTRACT: A simple and fast HPLC method based on an isocratic, reversed-phased ion-pair with amperometric end-point detection for simultaneous measurement of noradrenergic (MHPG/NA and A), dopaminergic (DOPAC, HVA/DA) and serotonergic (5-HIAA/5-HT) compounds in mouse brain tissue was developed. In order to improve the chromatographic resolution (Rs) with an acceptable total analysis time, experimental designs for multivariate optimization of the experimental conditions were applied. The optimal conditions for the separation of the eight neurotransmitters and metabolites, as well as two internal standards, i.e., DHBA and 5-HMT, were obtained using a mixture of methanol-phosphate-citric buffer (pH 3.2, 50 mM) (9:91, v/v) containing 2 mM OSA as mobile phase at 32°C on a microbore ALF-115 column (150 mm × 1.0 mm, 3 μm particle size) filled with porous C(18) silica stationary phase. In this study, a two-level fractional factorial experimental design (½ 2(K)) was employed to optimize the separation and capacity factor (k') of each molecule, leading to a good separation of all biogenic amines and their metabolites in brain tissue. A simple method for the preparation of different bio-analytical samples in phosphate-citric buffer was also developed. Results show that all molecules of interest were stabilized for at least 24 h in the matrix conditions without any antioxidants. The method was fully validated according to the requirements of SFSTP (Société Française des Sciences et Techniques Pharmaceutiques). The acceptance limits were set at ±15% of the nominal concentration. The method was found accurate over a concentration range of 4-2000 ng/ml for MHPG, 1-450 ng/ml for NA, 1-700 ng/ml for A, 1-300 ng/ml for DOPAC, 1-300 ng/ml for 5-HIAA, 1-700 ng/ml for DA, 4-2800 ng/ml for HVA and 1-350 ng/ml for 5-HT. The assay limits of detection for MHPG, NA, A, DOPAC, 5-HIAA, DA, HVA and 5-HT were 2.6, 2.8, 4.1, 0.7, 0.6, 0.8, 4.2 and 1.4 pg, respectively. It was found that the mean inter- and intra-assay relative standard deviations (RSDs) over the range of standard curve were less than 3%, the absolute and the relative recoveries were around 100%, demonstrating the high precision and accuracy, and reliability of the analytical method described to apply in routine analysis of biogenic amines and their metabolites in brain tissue.
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 09/2010; 878(29):3003-14. · 2.78 Impact Factor
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T Van Langenhove,
J van der Zee,
K Sleegers,
S Engelborghs,
R Vandenberghe,
I Gijselinck,
M Van den Broeck,
M Mattheijssens,
K Peeters, P P De Deyn,
M Cruts,
C Van Broeckhoven
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ABSTRACT: Recently, the FUS gene was identified as a new causal gene for amyotrophic lateral sclerosis (ALS) in approximately 4% of patients with familial ALS. Since ALS and frontotemporal lobar degeneration (FTLD) are part of a clinical, pathologic, and genetic disease spectrum, we investigated a potential role of FUS in FTLD.
We performed mutational analysis of FUS in 122 patients with FTLD and 15 patients with FTLD-ALS, as well as in 47 patients with ALS. Mutation screening was performed by sequencing of PCR amplicons of the 15 FUS exons.
We identified 1 patient with FTLD with a novel missense mutation, M254V, that was absent in 638 control individuals. In silico analysis predicted this amino acid substitution to be pathogenic. The patient did not have a proven family history of neurodegenerative brain disease. Further, we observed the known R521H mutation in 1 patient with ALS. No FUS mutations were detected in the patients with FTLD-ALS. While insertions/deletions of 2 glycines (G) were suggested to be pathogenic in the initial FUS reports, we observed an identical GG-deletion in 2 healthy individuals and similar G-insertions/deletions in 4 other control individuals, suggesting that G-insertions/deletions within this G-rich region may be tolerated.
In a first analysis of FUS in patients with frontotemporal lobar degeneration (FTLD), we identified a novel FUS missense mutation, M254V, in 1 patient with pure FTLD. At this point, the biologic relevance of this mutation remains elusive. Screening of additional FTLD patient cohorts will be needed to further elucidate the contribution of FUS mutations to FTLD pathogenesis.
Neurology 02/2010; 74(5):366-71. · 8.31 Impact Factor
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ABSTRACT: Procarboxypeptidase U (proCPU, TAFI) concentration in plasma is potentially related to thrombotic tendency, and elevated proCPU levels have been reported in ischemic stroke patients. Improved insight into the role of proCPU in acute ischemic stroke is essential for the development of more adequate therapeutics that may include carboxypeptidase inhibitors. In this study we investigated whether the plasma concentration of proCPU and the proCPU kinetic profile in acute ischemic stroke are related to initial stroke severity, stroke evolution in the subacute phase and long-term stroke outcome.
Plasma concentration of proCPU was assessed in 136 stroke patients at admission (7.5 h after stroke onset), at 24 h, at 72 h and at day 7 after stroke onset. We evaluated the relation between change in proCPU concentrations and (a) stroke severity (patients with TIA vs. stroke patients, NIHSS score at admission), (b) stroke evolution (stroke progression, infarct volume at 72 h), and (c) stroke outcome (mRS score at month 3).
ProCPU concentration decreased significantly in the first 72 h after stroke onset and thereafter returned to baseline. This biphasic time course, with its nadir at 72 h, was more pronounced in patients with severe stroke, unfavourable stroke evolution in the first 72 h and poor long-term outcome.
The decrease in proCPU concentration in the first 72 h after stroke onset correlates with more severe stroke, unfavourable stroke evolution, and poor long-term stroke outcome.
Journal of Thrombosis and Haemostasis 10/2009; 8(1):75-80. · 5.73 Impact Factor
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J van der Zee,
D Pirici,
T Van Langenhove,
S Engelborghs,
R Vandenberghe,
M Hoffmann,
G Pusswald,
M Van den Broeck,
K Peeters,
M Mattheijssens,
J-J Martin, P P De Deyn,
M Cruts,
D Haubenberger,
S Kumar-Singh,
A Zimprich,
C Van Broeckhoven
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ABSTRACT: Families associated with missense mutations in the valosin-containing protein (VCP) present with a rare autosomal dominant multisystem disorder of frontotemporal lobar degeneration (FTLD), inclusion body myopathy (IBM), and Paget disease of bone (PDB), referred to as IBMPFD.
We used exon-based genomic DNA sequencing to test for VCP mutations in 123 unrelated Belgian patients with FTLD and their relatives, and the absence of such mutations in 157 control individuals. We analyzed haplotype sharing among mutation carriers by genotyping 8 microsatellite markers in the VCP locus. We obtained family history and clinical and pathologic data using established diagnostic instruments.
Mutation analysis of VCP identified 2 Belgian patients with FTLD carrying the p.Arg159His mutation, which segregated in their families. In one family, patients presented with FTLD only, whereas in the other family, patients developed FTLD, PDB, or both without signs of IBM for any of the mutation carriers. We had previously identified p.Arg159His in an Austrian family with patients exhibiting both IBM and PDB. Haplotype sharing analysis indicated that the 3 p.Arg159His families are unrelated. Clinical follow-up of the Austrian family identified dementia symptoms in 1 patient. Autopsy data of 3 patients of the 2 Belgian families revealed FTLD pathology with numerous ubiquitin-immunoreactive, intranuclear inclusions and dystrophic neurites staining positive for TDP-43 protein.
In 3 unrelated families with IBMPFD segregating VCP p.Arg159His, we observed a high degree of clinical heterogeneity and variable penetrance of the 3 cardinal clinical phenotypes: inclusion body myopathy, Paget disease of bone, and frontotemporal lobar degeneration. In contrast, the neuropathologic phenotype was consistent with FTLD-TDP type 4.
Neurology 09/2009; 73(8):626-32. · 8.31 Impact Factor
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ABSTRACT: There is an urgent need for improved diagnostics and therapeutics for acute ischemic stroke. This is the focus of numerous research projects involving in vitro studies, animal models and clinical trials, all of which are based on current knowledge of disease mechanisms underlying acute focal cerebral ischemia. Insight in the chain of events occurring during acute ischemic injury is essential for understanding current and future diagnostic and therapeutic approaches. In this review, we summarize the actual knowledge on the pathophysiology of acute ischemic stroke. We focus on the ischemic cascade, which is a complex series of neurochemical processes that are unleashed by transient or permanent focal cerebral ischemia and involves cellular bioenergetic failure, excitotoxicity, oxidative stress, blood-brain barrier dysfunction, microvascular injury, hemostatic activation, post-ischemic inflammation and finally cell death of neurons, glial and endothelial cells.
Clinical neurology and neurosurgery 06/2009; 111(6):483-95. · 1.30 Impact Factor
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D. Harold,
R. Abraham,
P. Hollingworth,
R. Sims,
A. Gerrish,
M. L. Hamshere,
J. S. Pahwa,
V. Moskvina,
K. Dowzell,
A. Williams, [......],
K. H. Jockel,
N. Klopp,
H. E. Wichmann,
M. M. Carrasquillo,
V. S. Pankratz,
S. G. Younkin,
P. A. Holmans,
M. O'Donovan,
M. J. Owen,
J. Williams
Nat Genet. 01/2009; 41(10):1156.
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K Nuytemans,
P Pals,
K Sleegers,
S Engelborghs,
E Corsmit,
K Peeters,
B Pickut,
M Mattheijssens,
P Cras, P P De Deyn,
J Theuns,
C Van Broeckhoven
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ABSTRACT: Different loss-of-function mutations were identified underlying PGRN haploinsufficiency in patients with frontotemporal lobar degeneration. PGRN mutations were also identified in other neurodegenerative brain diseases such as amyotrophic lateral sclerosis and Alzheimer disease, though their biologic contribution to these diseases remains elusive. Because of its apparent role in neuronal survival, we argued that PGRN might also contribute to Parkinson disease (PD) pathogenesis.
We screened PGRN exons for mutations in 255 patients with PD and 459 control individuals by direct genomic sequencing. Genetic association of PGRN with risk for PD was assessed using single nucleotide polymorphisms (SNPs) across the gene.
In patients we identified four missense mutations of which p.Asp33Glu and p.Arg514Met were absent in control individuals. Single SNP and haplotype analyses did not detect significant associations with PD.
Our results do not support a major role for PGRN in the genetic etiology of Parkinson disease (PD). At this stage and in the absence of functional data, it remains unclear whether p.Asp33Glu and p.Arg514Met are biologically relevant to PD pathogenesis in the mutation carriers.
Neurology 11/2008; 71(15):1147-51. · 8.31 Impact Factor
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Nederlands tijdschrift voor geneeskunde 10/2008; 152(37):2043.
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ABSTRACT: This study aimed to investigate the use of actigraphy (accelerometry) to measure disuse of the impaired arm in acute stroke patients. We correlated the National Institute of Health Stroke Scale (NIHSS) and the Fugl-Meyer Assessment arm section (FMA) findings with actigraphic data as a measure of validity.
Thirty-nine acute ischemic stroke patients were included within 1 week after stroke onset. At inclusion, motor deficits were assessed by the NIHSS, FMA and 48-hour actigraphic recordings of both wrists were performed.
Moderate but highly significant correlations (Spearman's rho) between actigraphic recordings and total NIHSS (ratio r = -0.59 and activity of impaired arm r = -0.75; p < 0.001) and FMA (ratio r = 0.54 and activity of impaired arm r = 0.69; p < 0.001) scores were found. Based on actigraphic motor activity scores, ROC curves were calculated following dichotomization of the population based on NIHSS = 7 and FMA = 45, showing good sensitivity and specificity, with negative predictive value of 100% and positive predictive value of 91% for the ratio variable.
Moderate but highly significant correlations were found between actigraphy and the stroke scales NIHSS and FMA. Actigraphy was able to reliably discriminate less impaired from more impaired stroke patients with excellent sensitivity and specificity values. Actigraphy is a simple, valid, objective and reliable clinical research tool that can be used to determine motor impairment of the upper limb in stroke patients.
Cerebrovascular Diseases 10/2008; 26(5):533-40. · 2.72 Impact Factor
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N Brouwers,
K Sleegers,
S Engelborghs,
S Maurer-Stroh,
I Gijselinck,
J van der Zee,
B A Pickut,
M Van den Broeck,
M Mattheijssens,
K Peeters,
J Schymkowitz,
F Rousseau,
J-J Martin,
M Cruts, P P De Deyn,
C Van Broeckhoven
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ABSTRACT: Loss-of-function mutations in the progranulin gene (PGRN) were identified in frontotemporal lobar degeneration (FTLD) with ubiquitin-immunoreactive neuronal inclusions (FTLD-U). We assessed whether PGRN also contributes to genetic risk for Alzheimer disease (AD) in an extended Belgian AD patient group (n = 779, onset age 74.7 +/- 8.7 years).
A mutation analysis of the PGRN coding region was performed. The effect of missense mutations was assessed using in silico predictions and protein modeling. Risk effects of common genetic variants were estimated by logistic regression analysis and gene-based haplotype association analysis.
We observed seven missense mutations in eight patients (1.3%). Convincing pathogenic evidence was obtained for two missense mutations, p.Cys139Arg and p.Pro451Leu, affecting PGRN protein folding and leading to loss of PGRN by degradation of the misfolded protein. In addition, we showed that PGRN haplotypes were associated with increased risk for AD.
Our data support a role for PGRN in patients with clinically diagnosed Alzheimer disease (AD). Further, we hypothesize that at least some PGRN missense mutations might lead to loss of functional protein. Whether the underlying pathology in our cases proves to be AD, frontotemporal lobar degeneration, or a combination of the two must await further investigations.
Neurology 07/2008; 71(9):656-64. · 8.31 Impact Factor
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ABSTRACT: The APP23 model is a transgenic mouse model for Alzheimer’s disease. Cognitive performance in the APP23-model was assessed by Morris water maze (MWM) and passive avoidance learning, but the latter failed to show any difference between the genotypes. A 10 % cell loss in pyramidal neurons of the CA1 hippocampal region was found at the age of 14-18 months. Given the fact that the hippocampus may also be involved in non-spatial memory a non-spatial alternative for assessment of hippocampus-dependent memory would be useful. We evaluated an odour paired-associate test, which is based on learning an association between two sets of odours. The possibility of a progressive development of hyposmia was excluded by means of a novel odour test at the age of 75 weeks. The protocol of the odour paired-associate test includes a shaping phase, in which the animals learn to dig up a reward, a preliminary training phase and a training phase, where the actual association is learned. Subsequently, mice are tested for transitive inference and subjected to a symmetry test. Impairment was seen in the APP23 mice, in comparison with wild type mice, in training; however, both groups failed the transitivity and symmetry test. Possible explanations for this discrepancy with earlier published results are the advanced age of the mice or the C57Bl/6J background, in which the model was established. An advantage of this test is the fact that the mice do not need to swim. Provided the animals can dig, motor impairment will not influence the results. Moreover, the results are not biased by anxiety, since the test is based on natural scavenging habits, in contrast to the Morris Water Maze paradigm. In addition, the paired associate task can form a solution for the assessment of memory in transgenic mice with impaired vision.
Dutch Endo Neuro Psycho Meeting, Doorwerth (The Netherlands); 06/2008
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Nederlands tijdschrift voor geneeskunde 05/2008; 152(14):843; author reply 844.
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ABSTRACT: The paced auditory serial addition test (PASAT) is increasingly used in multiple sclerosis (MS) studies. Since these studies rely on repeated assessments with relatively short inter-test intervals, practice effects can be a confounding factor. We examined intra-session PASAT practice effects in 70 relapsing remitting (RR) and 40 secondary progressive (SP) patients. The average number of correct answers increased from 39.6+/-11.7 in the first PASAT run to 43.8+/-11.4 in the second run for the RR group, and from 39.1+/-11.6 to 41.8+/-13.3 in the SP group. PASAT scores showed a consistent decrease when comparing the second half of each test to the first half for both patient groups, and for both runs. Items for which the answer was a number greater than 9 had the same discrimination ability as other test items, but were significantly more difficult. A simulation of ;single-button' responses supported the use of the simplified scoring method which is currently used in fMRI studies. Our results demonstrate a within-session PASAT practice effect in MS, as well as a fatigability effect for both patient groups.
Multiple Sclerosis 02/2008; 14(1):106-11. · 4.26 Impact Factor
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I Gijselinck,
J van der Zee,
S Engelborghs,
D Goossens,
K Peeters,
M Mattheijssens,
E Corsmit,
J Del-Favero, P P De Deyn,
C Van Broeckhoven,
M Cruts
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ABSTRACT: Ubiquitin-positive, tau-negative, frontotemporal dementia (FTD) is caused by null mutations in progranulin (PGRN; HUGO gene symbol GRN), suggesting a haploinsufficiency mechanism. Since whole gene deletions also lead to the loss of a functional allele, we performed systematic quantitative analyses of PGRN in a series of 103 Belgian FTD patients. We identified in one patient (1%) a genomic deletion that was absent in 267 control individuals. The deleted segment was between 54 and 69 kb in length and comprised PGRN and two centromeric neighboring genes RPIP8 (HUGO gene symbol RUNDC3A) and SLC25A39. The patient presented clinically with typical FTD without additional symptoms, consistent with haploinsufficiency of PGRN being the only gene contributing to the disease phenotype. This study demonstrates that reduced PGRN in absence of mutant protein is sufficient to cause neurodegeneration and that previously reported PGRN mutation frequencies are underestimated.
Human Mutation 02/2008; 29(1):53-8. · 5.69 Impact Factor
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P J Visser,
F R J Verhey,
M Boada,
R Bullock, P P De Deyn,
G B Frisoni,
L Frolich,
H Hampel,
J Jolles,
R Jones, [......],
A-S Rigaud,
P Scheltens,
H Soininen,
L Spiru,
J Touchon,
M Tsolaki,
B Vellas,
L-O Wahlund,
G Wilcock,
B Winblad
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ABSTRACT: There is an urgent need to identify subjects with Alzheimer's disease (AD) in the predementia phase, but validated diagnostic approaches are currently lacking. In this paper, we present the background, design and methods of a study, which aims to develop clinical criteria for predementia AD. We also present baseline characteristics of the subjects included. The study was part of the multicentre DESCRIPA project, which is being conducted within the network of the European Alzheimer's Disease Consortium.
Clinical criteria will be based on a prospective cohort study of non-demented subjects older than 55 years and referred to a memory clinic. At baseline, a number of markers and risk factors for AD were collected, including demographic variables, measures of performance in activities of daily living, cognitive, neuroimaging and genetic markers, and serum and cerebrospinal fluid markers. Subjects will be reassessed annually for 2-3 years, and we will evaluate which combination of variables best predicts AD-type dementia at follow-up.
Between 2003 and 2005, 881 subjects were included from 20 memory clinics. Subjects were on average 70.3 years old, and had 10.4 years of education. The average score on the Mini-Mental State Examination was 27.4.
Neuroepidemiology 02/2008; 30(4):254-65. · 2.31 Impact Factor
