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M Cruts

Publications and source records attributed to M Cruts.

At least 19 recordsLinked to original sources
PubMed2006

Increased risk of dementia following mild head injury for carriers but not for non-carriers of the APOE epsilon4 allele.

BACKGROUND: The epsilon4 allele of apolipoprotein E (APOE) and head injury are risk factors for dementia diseases, and may act synergistically to further increase the risk. The aim of this study was to examine the association between mild head injury, APOE and dementia. METHODS: Data were obtained from the Betula prospective population-based study of aging, memory, and health. The study included 543 participants in the age range 40-85 years, free of dementia at baseline, who were followed up within a 5-year interval. Dementia was classified using DSM-IV criteria. Information on previous head injury was obtained through screening of the participants' answers to health questionnaires at baseline and at follow-up. RESULTS: Subjects with head injury but without APOE epsilon4 had no increased risk of dementia. Subjects with APOE epsilon4 had an increased risk and those with both APOE epsilon4 and head injury had the highest risk of dementia (odds ratio = 5.2). CONCLUSIONS: APOE epsilon4 constitutes a risk factor for dementia, mild injury in isolation does not increase the risk, but head injury in combination with the APOE epsilon4 leads to increased risk of dementia.

Adult↗
PubMed2006

Altered brain white matter integrity in healthy carriers of the APOE epsilon4 allele: a risk for AD?

BACKGROUND: Previous research has shown that polymorphisms of apolipoprotein E (APOE) represent genetic risk factors for dementia and for cognitive impairment in the elderly. The neural mechanisms by which these genetic variations influence behavioral performance or clinical severity are not well understood. METHODS: The authors used diffusion tensor imaging to investigate ultrastructural properties in brain white matter to detect pathologic processes that modify tissue integrity. Sixty participants were included in the study of which 30 were homozygous for the APOE epsilon3 allele, 10 were homozygous for the APOE epsilon4 allele, and 20 had the APOE epsilon34 allele combination. All individuals were non-demented, and the groups were matched on demographic variables and cognitive performance. RESULTS: The results showed a decline in fractional anisotropy, a marker for white matter integrity, in the posterior corpus callosum of epsilon4 carriers compared to non-carriers. Additional sites of altered white matter integrity included the medial temporal lobe. CONCLUSIONS: Although the mechanism underlying vulnerability of white matter tracts in APOE epsilon4 carriers is still unknown, these findings suggest that increased genetic risk for developing Alzheimer disease is associated with changes in microscopic white matter integrity well before the onset of dementia.

Aged↗
PubMed2006

Alzheimer dementia caused by a novel mutation located in the APP C-terminal intracytosolic fragment.

Since the first report showing that Alzheimer disease (AD) might be caused by mutations in the amyloid precursor protein gene (APP), 20 different missense mutations have been reported. The majority of early-onset AD mutations alter processing of APP increasing relative levels of Abeta42 peptide, either by increasing Abeta42 or decreasing Abeta40 peptide levels or both. In a diagnostic setting using direct sequence analysis, we identified in one patient with familial early-onset AD a novel mutation in APP (c.2172G>C), predicting a K724N substitution in the intracytosolic fragment. The mutation is located downstream of the epsilon-cleavage site of APP and is the furthermost C-terminal mutation reported to date. In vitro expression of APP K724N cDNA showed an increase in Abeta42 and a decrease in Abeta40 levels resulting in a near three-fold increase of the Abeta42/Abeta40 ratio. Further, in vivo amyloid positron emission tomography (PET) imaging revealed significantly increased cortical amyloid deposits, supporting that in human this novel APP mutation is likely causing disease.

Aged↗
PubMed2004

Association of cyclin-dependent kinase 5 and neuronal activators p35 and p39 complex in early-onset Alzheimer's disease.

Malfunctioning of cyclin-dependent kinase 5 (CDK5) through aberrant proteolytic cleavage of its neuronal activators p35 and p39 is involved in neurodegeneration in Alzheimer's disease (AD) and other neurodegenerative brain diseases. By extensive genetic analysis of the genes encoding CDK5 (CDK5), p35 (CDK5R1) and p39 (CDK5R2), we excluded causal mutations in 70 familial early-onset AD patients. We performed an association study with five informative SNPs in CDK5 in two independent samples of early-onset AD patients and matched control individuals from The Netherlands and northern Sweden. Association was observed with g.149800G>C in intron 5 of CDK5, and a two times increased risk was observed in both patient samples for carriers of the C-allele. Our data are indicative for a role of the CDK5 molecular complex in the genetic etiology of early-onset AD, and suggest that a yet unknown functional variant in CDK5 or in a nearby gene might lead to increased susceptibility for early-onset AD.

Aged↗
PubMed2004

Possible association of nicastrin polymorphisms and Alzheimer disease in the Finnish population.

The authors previously reported that genetic variation in the gene coding for nicastrin (NCSTN) modified risk for familial early-onset Alzheimer disease (AD) in a Dutch population-based sample. Risk was highest in patients without an APOE epsilon4 allele. Here, they evaluated if NCSTN polymorphisms increased risk of AD in the eastern Finnish population. A significant difference in one haplotype was observed in AD patients without the APOE epsilon4 allele.

Aged↗
PubMed2004

APOE influences on neuropsychological function after mild head injury: within-person comparisons.

OBJECTIVE: To examine the relationship between neuropsychological outcome following mild head injury (MHI) and APOE genotype. METHODS: Data from a population-based longitudinal study (n = 3,500) were used to identify 34 adults who experienced MHI during the course of the study. Their pre- and postinjury performances on a battery of nine neuropsychological tests were compared within person, and the postinjury performance was compared with that of age- and gender-matched control subjects. RESULTS: The within-person comparisons showed that participants with at least one APOE epsilon4 allele (n = 11) had a significantly decreased postinjury performance on three of the tests, whereas the postinjury performance for APOE epsilon4-negative participants (n = 23) was unchanged. There was no significant difference in postinjury performance between participants with/without the epsilon4 allele, and neither group was impaired relative to controls. CONCLUSIONS: APOE genotype may influence the outcome following an MHI. Pre/postinjury within-person comparisons seem more sensitive than control group comparisons for detecting injury-related effects.

Adult↗
PubMed2004

Familial clustering and genetic risk for dementia in a genetically isolated Dutch population.

Despite advances in elucidating the genetic epidemiology of Alzheimer's disease and frontotemporal dementia, the aetiology for most patients with dementia remains unclear. We examined the genetic epidemiology of dementia in a recent genetically isolated Dutch population founded around 1750. The series of 191 patients ascertained comprised 122 probable Alzheimer's disease patients with late onset and 17 with early onset, and 22 with possible Alzheimer's disease. It further included 10 patients with vascular dementia, nine with Lewy body dementia and six with frontotemporal dementia. All patients, except those with vascular dementia, were more closely related than healthy individuals from the same area. Clustering was strongest for patients with early-onset Alzheimer's disease or Lewy body dementia. Although 14% of late-onset Alzheimer's disease patients had evidence of autosomal dominant disease, consanguinity was found in three late-onset Alzheimer's disease patients, suggesting a recessive or polygenic model underlying the trait. We found no clustering of vascular dementia, implying a difference in genetic risk for late-onset Alzheimer's disease and vascular dementia. Mutations in known genes could not explain the occurrence of dementia, but the population attributable proportion of apolipoprotein E gene (APOE*4) was high (45%) due to a high frequency of APOE*4 carriers. Earlier identified regions on chromosomes 10 and 12, nor the effect of the alpha-2-macroglobulin (A2M) I/D polymorphism on Alzheimer's disease could be confirmed in our study. We did find evidence for association between the A2M D-allele and Lewy body dementia. Our data showed a strong familial clustering of various forms of dementia in this isolated Dutch population. A high percentage of late-onset Alzheimer's disease could be explained by APOE*4, but 55% of its origin is still unknown.

Age of Onset↗
PubMed2004

The impact of APOE on myocardial infarction, stroke, and dementia: the Rotterdam Study.

It is unclear how the APOE genotype contributes to the incidence of vascular diseases and dementia. In a population-based sample (n = 6,852) with complete follow-up, APOE was weakly associated with myocardial infarction and not related with stroke. In the absence of epsilon4, the incidence of dementia would be 25.8% lower; in the absence of epsilon2/epsilon3, 2.8% higher. Risk estimates of dementia, specified for age, sex, and APOE, are provided for counseling. APOE is not strongly related to vascular diseases, but contributes substantially to dementia incidence.

Age Distribution↗
PubMed2004

The role of tau (MAPT) in frontotemporal dementia and related tauopathies.

Tau is a multifunctional protein that was originally identified as a microtubule-associated protein. In patients diagnosed with frontotemporal dementia and parkinsonism linked to chromosome 17, mutations in the gene encoding tau (MAPT) have been identified that disrupt the normal binding of tau to tubulin resulting in pathological deposits of hyperphosphorylated tau. Abnormal filamentous tau deposits have been reported as a pathological characteristic in several other neurodegenerative diseases, including frontotemporal dementia, Pick Disease, Alzheimer disease, argyrophilic grain disease, progressive supranuclear palsy, and corticobasal degeneration. In the last five years, extensive research has identified 34 different pathogenic MAPT mutations in 101 families worldwide. In vitro, cell-free and transfected cell studies have provided valuable information on tau dysfunction and transgenic mice carrying human MAPT mutations are being generated to study the influence of MAPT mutations in vivo. This mutation update describes the considerable differences in clinical and pathological presentation of patients with MAPT mutations and summarizes the effect of the different mutations on tau functioning. In addition, the role of tau as a genetic susceptibility factor is discussed, together with the genetic evidence for additional causal genes for tau-positive as well as tau-negative dementia.

Alzheimer Disease↗
PubMed2004

Octapeptide repeat insertions in the prion protein gene and early onset dementia.

OBJECTIVES: The most common familial early onset dementia mutations are found in the genes involved in Alzheimer's disease; the amyloid precursor protein (APP) and the presenilin 1 and 2 (PSEN1 and 2) genes; the prion protein gene (PRNP) may be involved. METHODS: Following identification of a two-octapeptide repeat insertion in PRNP, we conducted a meta-analysis to investigate the relation of number of PRNP octapeptide repeats with age at disease onset and duration of illness; identifying 55 patients with PRNP octapeptide repeat insertions. We used a linear mixed effects model to assess the relation of number of repeats with age at disease onset, and studied the effect of the number of inserted octapeptide repeats on disease duration with a Cox proportional hazards regression analysis. RESULTS: We found an increasing number of repeats associated with younger age at onset (p < 0.001). Duration of the disease decreased significantly with the length of the octapeptide repeat (p < 0.001) when adjusting for age at onset. CONCLUSIONS: Our findings show significant inverse associations of the length of the PRNP octapeptide repeat with age at disease onset and disease duration in the spongiform encephalopathies.

Age of Onset↗
PubMed2003

Prospective Belgian study of neurodegenerative and vascular dementia: APOE genotype effects.

OBJECTIVE: The authors conducted a prospective study of neurodegenerative and vascular dementia in Belgium. Strict diagnostic inclusion criteria were used to include well defined patients and controls. The results of apolipoprotein E (APOE) genotype effect on risk and clinical characteristics are presented. METHODS: APOE genotyping was performed in patients with probable Alzheimer's disease (AD) (n=504), frontotemporal dementia (FTD) (n=47), vascular dementia (VaD) (n=152), mixed dementia (n=132), mild cognitive impairment (MCI) (n=44), Parkinson's disease (PD) (n=30), dementia with Lewy bodies (DLB) (n=17), and multisystem atrophy (MSA)/progressive supranuclear palsy (PSP) (n=12). RESULTS: The APOE allele frequencies of this Belgian control population (epsilon 2: 6.9%; epsilon 3: 76.2%; epsilon 4: 16.9%) did not differ from those reported for other white populations. AD, MCI, and mixed dementia patients had higher APOE epsilon 4 (32.9%, 38.6%, and 28.4% respectively) and lower APOE epsilon 3 (62.2%, 53.4%, and 66.3%) frequencies compared with controls, whereas only AD and mixed dementia patients had lower APOE epsilon 2 frequencies (4.9% and 5.3%). Apart from a borderline significant different distribution of APOE allele frequencies in VaD patients compared with controls, no other differences were detected. The influence of APOE epsilon 4 on clinical features of dementia was limited to lower age at onset in AD patients and a less pronounced negative correlation between age at onset and number of epsilon 4 alleles in MCI and mixed dementia patients. CONCLUSIONS: This study confirmed the risk association between APOE epsilon 4 and AD. The observation that APOE epsilon 4 is associated with mixed dementia reflected the role of AD in the aetiopathogenesis of this condition. Although MCI is an aetiologically heterogeneous syndrome, the increased APOE epsilon 4 frequencies indicated that a large proportion of the MCI patients included in the study might be predisposed to develop AD.

Adult↗
PubMed2002

Effect of the APOE-491A/T promoter polymorphism on apolipoprotein E levels and risk of Alzheimer disease: The Rotterdam Study.

The apolipoprotein E (APOE) gene is involved in lipid transport. A common polymorphism in this gene with the APOE*2, APOE*3, and APOE*4 alleles influences plasma levels of apolipoprotein E and cholesterol. Besides its role in lipid transport, the APOE*4 allele is a genetic risk factor for Alzheimer disease (AD). Recently, a polymorphism in the APOE promoter region was found to be involved in plasma apolipoprotein E levels and was found associated with AD. We studied the effect of this -491A/T promoter polymorphism on plasma apolipoprotein E levels and risk for AD in a population-based case-control study. We found that there was a modest but statistically significant effect of the -491A/T polymorphism on plasma apolipoprotein E levels independent of the APOE genotype. The lowest plasma levels were measured for the AA genotype, highest levels for the TT genotype, and intermediate levels for the heterozygotes. There was a small effect of the -491 AA genotype on AD risk that disappeared after adjusting for APOE genotypes. Our data suggest that the -491A/T polymorphism has an APOE genotype-independent effect on plasma apolipoprotein E levels but no APOE-independent effect on AD risk.

Aged↗
PubMed2002

Tau negative frontal lobe dementia at 17q21: significant finemapping of the candidate region to a 4.8 cM interval.

We report the results of a genome-wide search in a four-generation pedigree with autosomal dominant early-onset dementia (mean onset age: 64.9 years, range 53-79 years). In this family we previously excluded the known Alzheimer's disease genes based on linkage analysis and mutation screening of the amyloid precursor protein gene (exons 16 and 17) and the presenilin 1 and 2 genes. In addition we excluded mutations in the prion protein gene and exons 9-13 of the microtubule associated protein tau (MAPT) gene. We obtained conclusive linkage with chromosome 17q21 markers with a maximum multi-point LOD score of 5.51 at D17S951 and identified a candidate region of 4.8 cM between D17S1787 and D17S958 containing MAPT. Recent clinical and neuropathological follow-up of the family showed that the phenotype most closely resembled frontotemporal dementia (FTD) characterized by dense ubiquitin-positive neuronal inclusions that were tau negative. Extensive mutation analysis of MAPT identified 38 sequence variations in exons, introns, untranslated regions and the 5' regulatory sequence, however none was comprised within the disease haplotype. Although our findings do not entirely exclude a mutation in a yet unanalyzed region of MAPT, the apparent absence of MAPT mutations combined with the lack of tau pathology is highly suggestive for another defective gene at 17q21 responsible for FTD in this family.

Aged↗
PubMed2001

The microtubule associated protein Tau gene and Alzheimer's disease--an association study and meta-analysis.

Several studies have suggested an association between polymorphisms and an extended haplotype of the microtubule associated protein tau gene and Alzheimer's disease (AD) in synergy with apolipoprotein E (APOE) epsilon 4 status. However these findings have not been consistently replicated. We investigated the role of the tau haplotype in AD by conducting an association study as well as a meta-analysis of all the studies conducted to date. We examined six polymorphisms known to be in the extended tau haplotypes, one in exon 7 and five in and around exon 9 in 200 late onset AD and 189 control samples. All the polymorphisms examined fell into the recognised tau haplotypes. There was no statistical significant association with any of the polymorphisms and late onset AD. Stratification of data by APOE epsilon 4 status also produced no strongly significant association. The meta-analysis showed no significant differences between AD cases and controls, however stratification of data by APOE epsilon 4 status showed a small significant decrease in the H1 haplotype in AD before correction for multiple testing.

Aged↗
PubMed2001

Amyloid beta secretase gene (BACE) is neither mutated in nor associated with early-onset Alzheimer's disease.

The beta-site of beta-amyloid precursor protein cleaving enzyme (BACE) cleaves the beta-amyloid (Abeta) precursor protein at the N-terminal end of Abeta, allowing for the production of Abeta by C-terminal gamma-secretase cleavage. We hypothesized that over-activity of BACE might lead to the overproduction of Abeta, hence causing Alzheimer's disease (AD). Molecular genetic analyses of BACE in 9 autosomal dominant AD families and a population-based sample of 101 presenile AD cases did not identify genetic linkage, pathogenic mutations or genetic association with BACE, suggesting that BACE is not genetically involved in the etiology of AD.

Age of Onset↗