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Marc Cruts

Publications and source records attributed to Marc Cruts.

25 records · Page 2Linked to original sources
PubMed2003

Genetics of early-onset Alzheimer dementia.

Alzheimer's dementia (AD) is the most common degenerative disorder of the central nervous system. Although the onset of dementia is above 65 years of age in the majority of the patients (late-onset AD, LOAD), a small subgroup of patients develops AD before 65 years of age (early-onset AD, EOAD). To date 3 genes responsible for EOAD have been identified: the amyloid precursor protein gene (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2). PSEN1 is the most frequently mutated EOAD gene with a mutation frequency of 18 to 50% in autosomal dominant EOAD. In addition, the epsilon4 allele of the gene encoding apolipoprotein E (APOE) was identified as a risk factor for both LOAD and EOAD. Many studies reported other susceptibility genes, but the APOEepsilon4 alelle has been the only risk factor that was consistently replicated in all AD populations. Extensive cell biology research in the past ten years led to the hypothesis that the 4 EOAD genes lead to AD through a common biological pathway resulting in abnormal APP processing by subtle different mechanisms. Now, transgenic mice are produced to study the influence of EOAD mutations in vivo, eventually leading to the development of novel therapeutic strategies.

Alzheimer Disease↗
PubMed2003

Alzheimer-associated C allele of the promoter polymorphism -22C>T causes a critical neuron-specific decrease of presenilin 1 expression.

We, amongst others, have shown that CC homozygosity at the -22C>T promoter polymorphism in presenilin 1 (PSEN1) is associated with increased risk for Alzheimer's disease (AD). Also, studies in AD brains suggested that CC homozygosity increased the risk for AD by increasing the Abeta load. We characterized the PSEN1 promoter by deletion mapping, and analysed the effect of the -22C and -22T alleles on the transcriptional activity of PSEN1 in a transient transfection system. We showed a neuron-specific 2-fold decrease in promoter activity for the -22C risk allele, which in homozygous individuals would lead to a critical decrease in PSEN1 expression. The deletion mapping suggested that the 13 bp region (-33/-20) spanning the -22C>T polymorphism harbours a binding site for a negative regulatory factor. This factor has a higher affinity for the -22C risk allele and is strongly dependent on downstream sequences for cell-type-specific expression differences. Together, these studies provide evidence that the increased risk for AD associated with PSEN1 may result from genetic variations in the regulatory region, leading to altered expression levels of PSEN1 in neurons.

Alleles↗
PubMed2003

PRNP Val129 homozygosity increases risk for early-onset Alzheimer's disease.

We analyzed the PRNP M129V polymorphism in a Dutch population-based early-onset Alzheimer's disease sample. We observed a significant association between early-onset Alzheimer's disease and homozygosity of M129V (odds ratio [OR], 1.9; 95% confidence interval [CI], 1.1-3.3; p = 0.02) with the highest risk for V homozygotes (OR, 3.2; 95% CI, 1.4-7.1; p < 0.01). In patients with a positive family history, these risks increased to 2.6 (95% CI, 1.3-5.3; p < 0.01) and 3.5 (95% CI, 1.3-9.3; p = 0.01), respectively.

Adult↗
PubMed2002

The gene encoding nicastrin, a major gamma-secretase component, modifies risk for familial early-onset Alzheimer disease in a Dutch population-based sample.

Nicastrin regulates gamma-secretase cleavage of the amyloid precursor protein by forming complexes with presenilins, in which most mutations causing familial early-onset Alzheimer disease (EOAD) have been found. The gene encoding nicastrin (NCSTN) maps to 1q23, a region that has been linked and associated with late-onset Alzheimer disease (LOAD) in various genome screens. In 78 familial EOAD cases, we found 14 NCSTN single-nucleotide polymorphisms (SNPs): 10 intronic SNPs, 3 silent mutations, and 1 missense mutation (N417Y). N417Y is unlikely to be pathogenic, since it did not alter amyloid beta secretion in an in vitro assay and its frequency was similar in case and control subjects. However, SNP haplotype estimation in two population-based series of Dutch patients with EOAD (n=116) and LOAD (n=240) indicated that the frequency of one SNP haplotype (HapB) was higher in the group with familial EOAD (7%), compared with the LOAD group (3%) and control group (3%). In patients with familial EOAD without the APOE epsilon4 allele, the HapB frequency further increased, to 14%, resulting in a fourfold increased risk (odds ratio = 4.1; 95% confidence interval 1.2-13.3; P=.01). These results are compatible with an important role of gamma-secretase dysfunction in the etiology of familial EOAD.

Age of Onset↗
PubMed2002

Diagnostic accuracy of the Preclinical AD Scale (PAS) in cognitively mildly impaired subjects.

The Preclinical AD Scale (PAS) is a newly developed scale for the diagnosis of preclinical Alzheimer's disease (AD). The PAS combines six markers of preclinical AD, namely age, MMSE score, functional impairment, cognitive test performance, medial temporal lobe atrophy, and the apolipoprotein E (APOE) genotype. The aim of the study was to investigate whether the PAS can accurately identify subjects with preclinical AD who become demented during a 2 or 5 year follow-up from among subjects with mild cognitive impairment for other reasons. We also investigated whether a step-wise scoring of the PAS could reduce the number of elaborate or expensive diagnostic procedures. The PAS was scored retrospectively in two independent samples of non-demented subjects with mild cognitive impairment older than 55 years (average age 65.6 years), who were selected from a memory clinic population. In the first sample, the follow-up was 5 years (5-year follow-up sample; n=69). In the second sample, the follow-up was 2 years (2-year follow-up sample; n=23). The PAS item medial temporal lobe atrophy was not scored in the 5-year follow-up sample. A PAS cut-off score of 4/5 could best identify subjects with AD-type dementia at follow-up (n=25) in the 5-year follow-up sample with a sensitivity of 80% and a positive predictive value of 77%. A PAS cut-off score of 5/6 could best identify subjects with AD-type dementia at follow-up (n=8) in the 2-year follow-up sample with a sensitivity of 88% and a positive predictive value of 70%. The positive predictive value could be increased to 94% in the 5-year follow-up sample and to 80% in the 2-year follow-up sample by using higher cut-off scores, but this reduced the sensitivity. Step-wise scoring of the PAS had the same diagnostic accuracy as the total PAS score and reduced the number of cognitive assessments by 22 to 38%, the number of assessments of medial temporal lobe atrophy by 57 to 74%, and the number of APOE genotypings by 74%. It is concluded that the PAS is a useful scale to identify subjects with preclinical AD who will become demented during the next 2 or 5 years. Step-wise scoring of the PAS can reduce the number of elaborate or expensive diagnostic procedures considerably.

Aged↗