Biomedical subjects

John C van Swieten

Publications and source records attributed to John C van Swieten.

At least 19 recordsLinked to original sources

PubMed2025

Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer's disease.

BACKGROUND: Protein truncating variants (PTVs) in SORL1 are observed almost exclusively in Alzheimer’s Disease (AD) cases, but the effect of rare SORL1 missense variants is unclear. METHODS: To identify high-priority missense variants (HPVs), we applied ‘domain mapping of disease mutations’ for the 637 unique coding SORL1 variants detected in 18,959 AD-cases and 21,893 non-demented controls. RESULTS: In this sample, PTVs and HPVs associated with respectively a 35- and 10-fold increased risk of early onset AD and 17- and 6-fold increased risk of overall AD. The median age at onset (AAO) of PTV- and HPV-carriers was 62 and 64 years, and APOE-genotype contributed to AAO-variability. The median AAO of PTV- and HPV-carriers is ~8–10 years earlier than wild-type SORL1 carriers, matched for APOE-genotype. Specific HPVs are highly penetrant and lead to earlier AAOs than PTVs, suggesting possible dominant negative effects. CONCLUSION: Our results justify a debate on whether HPV carriers should be considered for clinical counseling.

Humans↗

PubMed2025

Proteomic analysis reveals distinct cerebrospinal fluid signatures across genetic frontotemporal dementia subtypes.

We used an untargeted mass spectrometric approach, tandem mass tag proteomics, for the identification of proteomic signatures in genetic frontotemporal dementia (FTD). A total of 238 cerebrospinal fluid (CSF) samples from the Genetic FTD Initiative were analyzed, including samples from 107 presymptomatic (44 C9orf72, 38 GRN, and 25 MAPT) and 55 symptomatic (27 C9orf72, 17 GRN, and 11 MAPT) mutation carriers as well as 76 mutation-negative controls ("noncarriers"). We found shared and distinct proteomic alterations in each genetic form of FTD. Among the proteins significantly altered in symptomatic mutation carriers compared with noncarriers, we found that a set of proteins including neuronal pentraxin 2 and fatty acid binding protein 3 changed across all three genetic forms of FTD and patients with Alzheimer's disease from previously published datasets. We observed differential changes in lysosomal proteins among symptomatic mutation carriers with marked abundance decreases in MAPT carriers but not other carriers. Further, we identified mutation-associated proteomic changes already evident in presymptomatic mutation carriers. Weighted gene coexpression network analysis combined with gene ontology annotation revealed clusters of proteins enriched in neurodegeneration and glial responses as well as synapse- or lysosome-related proteins indicating that these are the central biological processes affected in genetic FTD. These clusters correlated with measures of disease severity and were associated with cognitive decline. This study revealed distinct proteomic changes in the CSF of patients with genetic FTD, providing insights into the pathological processes involved in the disease. In addition, we identified proteins that warrant further exploration as diagnostic and prognostic biomarker candidates.

Humans↗

PubMed2007

Progranulin mutations in Dutch familial frontotemporal lobar degeneration.

Mutations in the progranulin (PGRN) gene have recently been identified in frontotemporal lobar degeneration with ubiquitin inclusions linked to chromosome 17q21. We report here the finding of two novel frameshift mutations and three possible pathogenic missense mutations in the PGRN gene. Furthermore, we determined the frequency of PGRN mutations in familial cases recruited from a large population-based study of frontotemporal lobar degeneration carried out in The Netherlands.

Aged↗

PubMed2007

The DeltaK280 mutation in MAP tau favors exon 10 skipping in vivo.

Tau mutations in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) are associated with changes in alternative splicing of exon 10. The DeltaK280 mutation in exon 10 is exceptional because in vitro observations suggest a dramatic effect on microtubule binding, enhanced self-aggregation, as well as a decrease of the 4R/3R ratio by the ablation of an exon splicing enhancer element. Using immunohistochemistry, Western blotting, and electron microscopy on brain material with the DeltaK280 mutation, we investigated which of these effects is most dominant in vivo. The brain showed abundant Pick bodies in several brain regions, which stained positive with 3-repeat-specific but not with 4-repeat-specific tau antibodies. Western blots of sarkosyl-insoluble tau showed exclusively three repeat (3R0N and 3R1N) tau in most regions, although some 4R1N could be detected in the frontal cortex. In addition, the sarkosyl-soluble tau fraction showed a significantly higher amount of 3-repeat tau. Because quantitative analysis of 4R and 3R mRNA transcripts showed a 4R/3R ratio of only 0.3, association between increased transcription and protein expression was observed. These observations confirm the postulated hypothesis that the DeltaK280 mutation abolishes a splice enhancer element, which overrules the decreased microtubule binding and enhanced self-aggregation.

Alzheimer Disease↗

PubMed2006

CHMP2B mutations are not a cause of dementia in Dutch patients with familial and sporadic frontotemporal dementia.

Mutations in the CHMP2B gene have been recently identified in a large Danish pedigree with autosomal dominant frontotemporal dementia (FTD) linked to chromosome 3 (FTD3). We report the frequency of CHMP2B mutations in 162 FTD patients recruited from a large population-based study of FTD carried out in The Netherlands. Our results suggest that mutations in CHMP2B are a rare cause of FTD as compared to MAPT mutations.

DNA Mutational Analysis↗

PubMed2006

Impact of behavioural problems on spousal caregivers: a comparison between Alzheimer's disease and frontotemporal dementia.

BACKGROUND: Behavioural changes are a key factor in distinguishing frontotemporal dementia (FTD) from Alzheimer's disease (AD), however, little is known about the impact of these changes on caregivers. The aim of this study was to compare caregivers' distress related to behavioural symptoms of AD and FTD. METHODS: 47 spouse caregivers of consecutively referred patients with AD and 27 spouse caregivers of patients with FTD participated in this study. Behavioural disturbances in the patient and caregivers' emotional reactions were measured with the Neuropsychiatric Inventory. RESULTS: Patients with FTD had significantly higher levels of agitation, apathy, disinhibition and aberrant motor behaviour than did patients with AD. High distress scores were found for disinhibition, depression and apathy in caregivers of FTD patients whereas caregivers of AD patients reported patient apathy, depression and anxiety as being severely distressing. Higher mean distress scores were found for disinhibition in the FTD group. Furthermore, caregivers of FTD patients reported higher levels of general burden, and felt less competent than AD caregivers. CONCLUSIONS: Caregivers of FTD patients were overall more distressed by the behaviour of their partners than were the caregivers of AD patients. Findings from this study underscore the importance of differentiating between diagnostic groups and specific behavioural domains when focusing on caregiver reactions to problem behaviour.

Aged↗

PubMed2006

Spinocerebellar ataxia associated with a mutation in the fibroblast growth factor 14 gene (SCA27): A new phenotype.

Autosomal dominant cerebellar ataxias (ADCAs) are genetically classified into spinocerebellar ataxias (SCAs). We describe 14 patients of a Dutch pedigree displaying a distinct SCA-phenotype (SCA27) associated with a F145S mutation in the fibroblast growth factor 14 (FGF14) gene on chromosome 13q34. The patients showed a childhood-onset postural tremor and a slowly progressive ataxia evolving from young adulthood. Dyskinesia was often present, suggesting basal ganglia involvement, which was supported by functional imaging in 1 patient. Magnetic resonance imaging (MRI) of the brain showed only moderate cerebellar atrophy in the 2 eldest patients. Neuropsychological testing indicated low IQ and deficits in memory and executive functioning. Behavioral problems were also observed. Further investigations will have to determine the role of FGF14 in the pathogenesis of neurodegeneration and the frequency of this FGF14 mutation in SCA. (c) 2005 Movement Disorder Society.

Adult↗

PubMed2005

Evidence for novel loci for late-onset Parkinson's disease in a genetic isolate from the Netherlands.

We studied patients with idiopathic Parkinson's disease (PD) from an isolated population in the Netherlands aiming to map gene(s) involved in PD susceptibility. A total of 109 parkinsonism patients were independently ascertained, of whom 62 presented late-onset, idiopathic PD. Genealogical research showed that 45 index cases with idiopathic PD were linked to a common ancestor, indicating familiar clustering among the patients. This strong familial clustering was highly significant (P = 0.005) when compared to random controls from the same population. We performed a genome wide scan using 382 polymorphic markers in 44 distantly related PD patients plus 112 unaffected first-degree relatives and spouses. Our genome wide association analysis (DISLAMB) revealed evidence of association at a nominal P-value < 0.01 for markers D2S2333, D4S405, D9S158, D13S153. Other regions on chromosomes 3p, 4q, 14q, 17p and 17q were found at a significance level of P < 0.05. In a follow-up study, we investigated all the positive regions using a denser marker set and a larger sample (total of 630 individuals including all late-onset PD patients). The strongest evidence for association remained for the 9q and 14q region. A significant association was found for marker D9S1838 (OR = 2.0, 95% CI 1.1-3.5, P = 0.014) and D14S65 (OR = 3.2, 95% CI 1.7-6.1, P < 0.001). Moreover, a common haplotype with excess of sharing among late-onset PD cases was observed on both regions. Our results suggest the existence of two loci influencing PD susceptibility on chromosome 9q and 14q.

Age of Onset↗

PubMed2005

Cerebral hypoperfusion and clinical onset of dementia: the Rotterdam Study.

Cerebral blood flow (CBF) velocity is decreased in patients with Alzheimer's disease. It is being debated whether this reflects diminished demand because of advanced neurodegeneration or that cerebral hypoperfusion contributes to dementia. We examined the relation of CBF velocity as measured with transcranial Doppler with dementia and markers of incipient dementia (ie, cognitive decline and hippocampal and amygdalar atrophy on magnetic resonance imaging) in 1,730 participants of the Rotterdam Study aged 55 years and older. Cognitive decline in the 6.5 years preceding CBF velocity measurement was assessed with repeated Mini-Mental State Examinations in nondemented subjects (n = 1,716). Hippocampal and amygdalar volumes were assessed in a subset of 170 nondemented subjects. Subjects with greater CBF velocity were less likely to have dementia. Furthermore, in nondemented subjects, greater CBF velocity was related to significantly less cognitive decline over the preceding period (odds ratio per standard deviation increase in mean CBF 0.74 [95% confidence interval, 0.58-0.98]) and larger hippocampal and amygdalar volumes. A low CBF is associated with dementia, but also with markers of incipient dementia. Although we cannot exclude that this is caused by preclinical neurodegeneration leading to hypoperfusion, it does suggest that cerebral hypoperfusion precedes and possibly contributes to onset of clinical dementia.

Aged↗

PubMed2004

Plasma levels of antioxidants are not associated with Alzheimer's disease or cognitive decline.

Antioxidants prevent oxidative stress that possibly causes neuronal loss in Alzheimer's disease (AD). We examined whether high plasma levels of the antioxidant vitamins A and E were associated with lower prevalence of AD or cognitive decline (CD). We performed a cross-sectional study within the Rotterdam Study. In an univariate model, higher levels of vitamins A and E were significantly associated with lower prevalence of AD. However, when additional adjustments were made for important confounders, such as age, gender and total cholesterol, the relation substantially weakened -- odds ratios per standard deviation increase were 0.87 (95% CI 0.64-1.19) for vitamin A and 0.94 (95% CI 0.60-1.48) for vitamin E. Antioxidants were not related to CD in non-demented subjects. Our findings suggest no association between plasma levels of vitamin A and E and AD or CD.

Aged↗

PubMed2004

A deletion in DJ-1 and the risk of dementia--a population-based survey.

The DJ-1 gene is associated with autosomal recessive early-onset Parkinsonism, most likely through its role in defense against oxidative stress. Oxidative stress is not only involved in Parkinson's disease, but also in other neurodegenerative disorders, such as dementia. We assessed the presence of a 14 kb DJ-1 deletion in 191 patients with dementia, ascertained from the genetically isolated population where the first kindred with DJ-1 related Parkinsonism was originally identified. The control group consisted of 129 non-demented subjects. We found the deletion in two patients and one control. There was no evidence for an increased risk of dementia in carriers. All subjects were heterozygous for the deletion and related to a common ancestor within eight generations. Our results suggest it is unlikely that haploinsufficiency in the DJ-1 gene imparts an increased risk for dementia.

Aged↗

PubMed2004

Inflammatory proteins in plasma and the risk of dementia: the rotterdam study.

BACKGROUND: Increased levels of inflammatory proteins have been found in the brains and plasma samples of patients with dementia. Whether the levels of inflammatory proteins in plasma samples are elevated before clinical onset of dementia is unclear. OBJECTIVE: To determine whether high levels of inflammatory proteins in plasma samples are associated with an increased risk of dementia. DESIGN AND SETTING: A case-cohort study within the Rotterdam Study, a population-based prospective cohort study in the Netherlands. PARTICIPANTS: The source population comprises 6713 subjects who, at baseline (1990-1993), were free of dementia and underwent venipuncture. From these, we selected both a random subcohort of 727 subjects and 188 cases who had developed dementia at follow-up. MAIN OUTCOME MEASURES: The associations between plasma levels of alpha1-antichymotrypsin, C-reactive protein, interleukin 6, the soluble forms of intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 and the risk of dementia were examined using the Cox proportional hazards regression models. RESULTS: High levels of alpha1-antichymotrypsin, interleukin 6, and, to a lesser extent, C-reactive protein were associated with an increased risk of dementia; rate ratios per standard deviation increase were 1.49 (95% confidence interval, 1.23-1.81), 1.28 (95% confidence interval, 1.06-1.55), and 1.12 (95% confidence interval, 0.99-1.25), respectively. Similar associations were observed for Alzheimer disease, whereas rate ratios of vascular dementia were higher for alpha1-antichymotrypsin and C-reactive protein. Soluble forms of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 were not associated with dementia. CONCLUSION: Plasma levels of inflammatory proteins are increased before clinical onset of dementia, Alzheimer disease, and vascular dementia.

Aged↗

PubMed2004

Phenotypic variation in frontotemporal dementia and parkinsonism linked to chromosome 17.

Hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) caused by mutations in the tau gene shows a wide range in age at onset, several distinct clinical presentations, and a spectrum of tau pathology. Although the clinical and pathological phenotype often correlate with the location of the mutation, there also exists considerable interfamilial and intrafamilial phenotypical variation. Not all families with FTDP-17 do have mutations and deposition of hyperphosphorylated tau in the brain, but show ubiquitin-positive, tau-negative inclusions. Future research should focus on the role of other genetic and environmental factors in this form of FTDP-17, whereas the responsible gene defect(s) has still to be identified for hereditary FTD without tau mutations.

Chromosomes, Human, Pair 17↗

PubMed2003

Mutations in the hemochromatosis gene (HFE), Parkinson's disease and parkinsonism.

Iron overload increases oxidative stress and may lead to neurodegenerative disease like Parkinson's disease (PD). We studied the role of mutations in the hemochromatosis gene HFE in PD and other parkinsonism (non-PD PS) in two population-based series. The first series consisted of 137 patients with PD and 47 with non-PD PS, and the second of 60 patients with PD and 25 with non-PD PS. In the first series, PD patients were significantly more often homozygous for the C282Y mutation than controls (P=0.03). Patients with non-PD PS in both series were more often carriers for the C282Y mutation than controls (P=0.009, P=0.006, respectively). Our data are hampered by small numbers, yet suggest that the C282Y mutation increases the risk of PD and non-PD PS. The rarity of this genotype requires a large series of patients to prove our hypothesis.

Aged↗

PubMed2003

Frontotemporal dementia in The Netherlands: patient characteristics and prevalence estimates from a population-based study.

Since 1994, a population-based study of frontotemporal dementia (FTD) in The Netherlands has aimed to ascertain all patients with FTD, and first prevalence estimates based on 74 patients were reported in 1998. Here, we present new prevalence estimates after expansion of our FTD population to 245 patients, with emphasis on the prevalence in the province Zuid-Holland where the main study centre is located. All neurologists and physicians in nursing homes received a yearly postal enquiry about suspected FTD cases. FTD was diagnosed in 245 patients according to the Lund-Manchester criteria, supported by neuroimaging and neuropsychology. tau mutation analysis was performed in a subgroup of 154 patients (63%), and 40 out of 98 patients (41%) who died during follow-up were autopsied during the course of the study. The prevalence of FTD in the province Zuid-Holland was 3.6 per 100,000 at age 50-59 years, 9.4 per 100,000 at age 60-69 years and 3.8 per 100,000 at age 70-79 years. The median age at onset of the 245 patients (51% female) was 58.0 years (range 33-80 years). Dementia in one or more first-degree family members was found in 43% of patients and mutation analysis of the tau gene showed mutations in 34 patients (19 P301L, five L315R, four G272V, four R406W, one Delta K280 and one S320F), all with a positive family history for dementia (14% of the total population, 32% of patients with a positive family history). Pathological findings in the 40 autopsied patients consisted of dementia lacking distinctive histology in 22%, FTD with ubiquitin-positive inclusions in 33%, Pick's disease in 15% and tauopathy in the remaining 30% of patients, with tau mutations identified in more than half of the latter patients. We conclude that the prevalence of FTD in The Netherlands is higher than previously reported, confirming that FTD is more common than was previously thought. The finding of tau mutations in 32% of patients with a positive family history for dementia justifies mutation screening in FTD patients with a positive family history, while tau mutations in non-familiar cases are rare.

Adult↗

PubMed2003

Total tau and phosphorylated tau 181 levels in the cerebrospinal fluid of patients with frontotemporal dementia due to P301L and G272V tau mutations.

BACKGROUND: Frontotemporal dementia (FTD) is a pathologically heterogeneous group of presenile neurodegenerative disorders, with or without the deposition of hyperphosphorylated tau protein in affected brain regions. Mutations in the tau gene have been found in the familial form of FTD, linked to chromosome 17q21-22, showing a spectrum of tauopathy. OBJECTIVE: To evaluate levels of total tau, phosphorylated tau 181 (Ptau-181), and amyloid-beta1-42 in the cerebrospinal fluid (CSF) of patients with FTD, with special emphasis on FTD due to tau mutations. DESIGN: Case-control study. SETTING: Outpatient neurology clinics at 2 university medical centers, in Rotterdam and Amsterdam (the Netherlands). PATIENTS: Twenty-six patients with FTD (9 with tau mutations 7 P301L and 2 G272V), 18 patients with Alzheimer disease (AD), and 13 nondemented controls. METHODS: Total tau, Ptau-181, and amyloid-beta1-42 levels in CSF, obtained by lumbar puncture, were determined by sandwich enzyme-linked immunosorbent assay. Patients were diagnosed after clinical examination, neuropsychologic evaluation, and neuroimaging. Differences between patient groups were statistically evaluated using nonparametric tests. RESULTS: Although CSF levels of total tau were mildly increased in FTD patients compared with nondemented controls (P =.05), median CSF total tau levels were low in the subgroup with tau mutations compared with AD patients. Furthermore, CSF levels of Ptau-181 and amyloid-beta1-42 were not different in FTD patients, including the patients with tau mutations, compared with nondemented controls. CONCLUSIONS: The tauopathy in P301L and G272V does not appear to be associated with an evident increase in CSF levels of Ptau-181 in FTD patients with these tau mutations, in contrast with findings in patients with AD.

Aged↗

PubMed2003

Endogenous estradiol and risk of dementia in women and men: the Rotterdam Study.

We determined whether higher endogenous estradiol levels were associated with lower risk of dementia in older men and women not using hormonal replacement therapy, using a case-cohort design within the Rotterdam Study, a population-based follow-up study on chronic diseases, including dementia, in 7983 subjects aged 55 years or older, and ongoing since 1990. The analyses were based on a random subcohort of 508 women and 438 men, and on 76 women and 53 men with incident dementia. Cox proportional hazards models with robustly estimated standard errors showed that in women higher levels of total estradiol were associated with higher risk of dementia (age-adjusted hazard ratio per standard deviation increase 1.38; 95% CI 1.04-1.84). Age-adjusted HR's of Alzheimer's disease and vascular dementia associated with higher levels of total estradiol (per SD increase) were 1.24 (95% CI 0.87-1.76) and 2.19 (95% CI 1.22-3.92), respectively. Similar results were observed for bioavailable estradiol. Additional adjustments for potential confounders did not change the results substantially. In men, no clear association was observed between estradiol levels and risk of dementia or its subtypes. The findings do not support the hypothesis that higher levels of endogenous estradiol reduce risk of dementia, neither in women nor in men.

Aged↗

PubMed2003

Variable phenotypic expression and extensive tau pathology in two families with the novel tau mutation L315R.

Mutations in the tau gene cause familial frontotemporal dementia and parkinsonism linked to chromosome 17. Here, we describe two Dutch families with familial frontotemporal dementia associated with the novel missense mutation L315R in exon 11 of tau. The age at onset of disease showed a large variation within each family, ranging from 25 to 64 years. Incomplete penetrance was established in an 82-year-old mutation carrier with no signs of dementia and appeared probable in two additional subjects. The brains of two affected subjects were studied and showed extensive tau pathology in neurons (Pick-like inclusions) and astroglial cells, particularly in the frontotemporal cortex and the hippocampal formation. Sarkosyl-insoluble tau extracted from the cerebral cortex showed the presence of straight and twisted tau filaments and a pattern of pathological tau bands similar to that of Pick's disease. Upon dephosphorylation, only five of the six brain tau isoforms were observed, with the shortest isoform being undetectable. All six tau isoforms were present in soluble brain tau. Recombinant tau proteins with the L315R mutation showed a reduced ability to promote microtubule assembly.

Adult↗