Research Julie van der Zee

Abstract

This grant finances the coordination activities of the European Early-Onset Dementia (EU EOD) consortium. The EU EOD consortium was founded in 2011 by the P.I. to promote and facilitate translational genetic and clinical research of early-onset dementia (EOD) at the European level. The aim of the consortium is to capitalize on the genetic power of EOD patients combined with the novel –omics technologies that have become available. The consortium unites partners from dementia expert centers covering the fields of neurology, neuropathological, clinical research (biomarkers, neuroimaging) and treatment trials, medical genetics and molecular genetics. The FWO ICA fund supports the coordination and activities of the consortium such as organizing regular meetings between the partners either in conjunction with international conferences or of formal EU EOD consortium annual meetings.

Researcher(s)

• Promoter: Van Broeckhoven Christine
• Co-promoter: van der Zee Julie

Research team(s)

Project type(s)

• Research Project

Abstract

There is a current paucity of effective prophylactic treatments for neurodegenerative dementia disorders and as such they represent one of the major classes of widespread diseases with increasing mortality rates in the developed world. Drug development programs have faced numerous problems. The clinical and biological complexity of dementia has long been underestimated. Evidence increases that patients with the same clinical symptoms develop disease through different biological processes. This implicates that intervention trials should be directed towards subgroups of patients that share the same molecular signature of disease biology. The proposed PhD project aims to further elucidate the genetic etiology and molecular signatures of dementia through the identification of novel genes and genetic disease modifiers. A better understanding of the molecular complexity of dementia will improve classification of patients based on their molecular disease signatures rather than on clinico-pathological symptomatology, which is expected to drastically improve development of effective diagnostic tools, biomarkers and targeted therapies. We will apply advanced genetic profiling strategies for novel gene discovery, including whole exome and gene panel sequencing focusing on the subgroup of early-onset dementia (EOD) patients. Because EOD patients suffer from a disease of the aging brain at a relatively young age, they have an extreme presentation of the disease and as such are expected to have a strong genetic heritage. Study of this subgroup of dementia patients will therefore more likely lead to identification of novel genes and molecular pathways. The research will build on an impressive collection of >4000 patients ascertained within the European Early-Onset Dementia consortium. Making use of these powerful genomic approaches in selected patient cohorts with strong genetic heritage, we aim to identify novel key genes and proteins and enhance our knowledge of the molecular signatures of neurodegenerative dementia. These signatures will be instrumental in pinpointing diagnostic biomarkers and drug targets for therapy development, will allow more accurate stratification of patient cohorts for follow-up translational research and clinical trials, and ultimately offer better perspectives for patients and families affected by dementia.

Researcher(s)

• Promoter: van der Zee Julie
• Fellow: Baradaran Heravi Yalda

Research team(s)

Project type(s)

• Research Project

Abstract

Frontotemporal lobar degeneration (FTLD) is the second most common early-onset dementia, after Alzheimer's disease (AD). Given that FTLD indeed mostly affects middle-aged individuals, this debilitating disease has a dramatic effect on the patients' personal as well as professional life. The differential diagnosis of dementia based on a clinical diagnosis and with the help of AD biomarkers in cerebrospinal fluid is still suboptimal. Unfortunately, well-characterized and validated diagnostic markers for FTLD do not yet exist. With the discovery of TAR DNA-binding protein of 43 kDa (TDP-43) as the major disease protein in 50-60% of this clinically and genetically heterogeneous group of FTLD patients, a potential diagnostic marker for FTLD-TDP was identified. The current project aims to (1) generate new TDP-43 antibodies and characterize TDP-43; (2) develop an immunoassay to quantify TDP-43 in biological samples and (3) assess its diagnostic potential, for which samples from confirmed FTLD-TDP and AD patients will be used. If successful, this project will provide new tools (well-characterized TDP-43 antibodies and an immunoassay) for researchers to unravel the TDP-43 pathogenesis, leading to new research hypotheses and possible therapeutic ventures. By applying the TDP-43 immunoassay as a tool to identify FTLD-TDP patients, we hope to improve (differential) dementia diagnostics as well as contribute to progress within the field of other TDP-pathologies.

Researcher(s)

• Promoter: Engelborghs Sebastiaan
• Co-promoter: van der Zee Julie
• Fellow: Goossens Joery

Research team(s)

Project type(s)

• Research Project

Abstract

This project finances the coordination activities of the European Early-Onset Dementia (EU EOD) consortium. The EU EOD consortium was founded in 2011 by the P.I. to promote and facilitate translational genetic and clinical research of early-onset dementia (EOD) at the European level. The aim of the consortium is to capitalize on the genetic power of EOD patients combined with the novel –omics technologies that have become available. The consortium consists of 29 partners from 14 EU countries. These are dementia expert centers covering the fields of neurology, neuropathological, clinical research (biomarkers, neuroimaging) and treatment trials, medical genetics and molecular genetics. Amongst the participating centers, collections includes > 5000 EOD patients with an expected yearly growth of 500 patients. The FWO ICA fund supports the coordination and activities of the consortium such as organizing regular meetings between the partners either in conjunction with international conferences or of formal EU EOD consortium annual meetings.

Researcher(s)

• Promoter: Van Broeckhoven Christine
• Co-promoter: van der Zee Julie

Research team(s)

Project type(s)

• Research Project

Abstract

This project represents a formal research agreement between UA and on the other SAO. UA provides SAO research results mentioned in the title of the project under the conditions as stipulated in this contract. We propose an integrated approach for high-profile translational genetic research of early-onset dementia. Our research builds on two major research strategies: early-onset dementia genetic research and translational biobanking. In our early-onset dementia (EOD) research, we aim to contribute to the elucidation of the missing heritability of dementia by focusing on extreme-phenotype patients in terms of early onset or high familial load. Study of these high-genetic load patients combined with the latest next-generation sequencing and -omics technologies will lead to the discovery of new genetic factors for dementia. With translational biobanking, we build upon our existing biobank for neurodegenerative brain disease. We will further invest in the systematic collection of wide ranges of human samples from thoroughly characterized EOD patients through national and international collaborations. This will ensure that genetic findings can be translated to patient-derived material, such as e.g. body fluids for biomarker studies and brain material for expression or epigenetic studies. Through this integrated approach, we aim to facilitate the translation of genetic breakthroughs into biologically and clinically relevant approaches towards improved diagnostics, genetic counseling, and therapy of both early- and late-onset dementia. Specifically, we will build a patient registry and biobank for EOD. The registry will hold standardized patient information (clinical, demographic, and biological data) together with information on available biomaterials (DNA, serum, plasma, fibroblasts, CSF, EBV-transformed lymphoblasts, frozen and formalin-fixed brain). We have recently developed a high-throughput and cost-effective diagnostic screening tool for the genetic screening of all known dementia genes into one single assay. This NGS-based resequencing assay of all genes associated with neurodegenerative brain diseases (NBD), referred to as the NBD MASTR assay, will be used for the deep genetic profiling of EOD patients that are submitted to the EOD registry. The budget of this Pilot Grant will be allocated to a pilot project for the genetic profiling of 250 EOD patients using the NBD MASTR assay. This will provide epidemiological data on mutation frequencies across the NBD spectrum and reveal novel genotype-phenotype correlations. E.g. mutations in AD patients could be revealed in genes that are usually associated with other dementia types, yet unknown exon or whole-gene deletions could be detected that would otherwise be missed by classical Sanger sequencing. Patients that are negative for known genetic causes of dementia can subsequently be enrolled in whole-genome sequencing gene-discovery projects.

Researcher(s)

• Promoter: van der Zee Julie

Research team(s)

Project type(s)

• Research Project

Abstract

We aim to establish an integrated network to identify genes and proteins involved in neurodegenerative disorders, determine their biological functions, establish their role in the pathophysiological processes, identify modifiers of the function by genetic screens, The network meets the prerequisites for such a project: frontline research in functional genomics related to human health, creating synergies with and between research efforts, teaming up with clinical groups through translational research for providing novel avenues for diagnosis, prevention, treatment and providing training and mobility to improve the skills of our young researchers.

Researcher(s)

• Promoter: Van Broeckhoven Christine
• Co-promoter: Cruts Marc
• Co-promoter: Sleegers Kristel
• Co-promoter: Theuns Jessie
• Co-promoter: van der Zee Julie

Research team(s)

Project type(s)

• Research Project

Abstract

In the past decade remarkable advances have been made in understanding the origin of frontotemporal lobar degeneration (FTLD), after Alzheimer's disease one of the leading causes of dementia. In sharp contrast however, is the absence of any therapeutic strategy based on these novel discoveries and the fact that a significant portion of patients remains in which the source of the disease is still unknown. This research project proposes an integrated approach to further uncover the genetic etiology of FTLD. This includes the establishment of a centralized repository of tissues and biofluids from medically and molecularly thoroughly characterized, extended collections of FTLD patients and unaffected individuals (biobank). This powerful biobank will allow the set-up of state of the art genetic studies of FTLD. We will participate to international large scale genome-wide association studies aiming to discover genetic risk factors for FTLD. We will further investigate these findings in our population of Flanders- Belgian FTLD patients to examine population-specific risk profiles. Moreover, the biobank will facilitate translation of knowledge obtained from these basic molecular research studies into clinical applications for improved diagnosis and treatment of future patients.

Researcher(s)

• Promoter: Van Broeckhoven Christine
• Fellow: van der Zee Julie

Research team(s)

Project type(s)

• Research Project

Abstract

Frontotemporal lobar degeneration (FTLD) is a fatal neurodegenerative disease and one of the leading causes of dementia affecting the younger population. In Belgium 10.000 people are estimated to be affected, and over 1 million people world-wide. Disease onset generally occurs between 45 to 65 years but can also touch younger and older age groups. Although a lot of progress was made in recent years identifying causal genes and underlying brain pathology, as yet the disease is not fully understood and no effective treatment is available. Frontotemporal lobar degeneration has a strong genetic component with up to 40% of patients having another family member with a similar disease. The four known genes to date can explain 10 to 20% of all patients, leaving a significant fraction unresolved. Based on this observation molecular genetic studies are now focusing on the identification of more common genetic factors that increase the risk for frontotemporal lobar degeneration. In the present study we seek to investigate the role of TMEM160B in frontotemporal lobar degeneration and its impact on disease susceptibility in a powerful, well-documented, homogenous Flanders-Belgian study population.

Researcher(s)

• Promoter: van der Zee Julie

Research team(s)

Project type(s)

• Research Project

Abstract

In the past decade a lot of progress was made in elucidating the genetic and pathologic make-up of frontotemporal lobar degeneration (FTLD), one of the leading causes of dementia. The genes known to date however are implicated in the autosomal dominant forms of the disease and leave a significant fraction (about 80%) of patients as yet unresolved. Therefore the first genome-wide association (GWA) studies were initiated in search for more common genetic variants influencing risk for FTLD. An essential step in the identification of novel genetic risk factors for complex diseases is the replication and confirmation of GWA association signals in independent study populations. The aim of this research project is to provide these invaluable replication studies using a powerful, well-documented, homogenous Flanders-Belgian study population. We recently participated in a GWA of FTLD with TDP43 pathology, the major pathological subtype of FTLD. The study uncovered common genetic variation in the gene TMEM106B as a putative risk factor for FTLD-TDP. Samples to set-up a second large scale international GWA study of patients with a clinical diagnosis of FTLD, to which we contributed 256 patients, have now been collected and results of the genome-wide genotyping are expected by the end of 2010. For this research project we plan to perform in depth follow-up studies of these two GWA studies of FTLD. Hereto we will test association of the GWA top single nucleotide polymorphisms (SNPs) in our Flanders-Belgian FTLD sample; sequence candidate genes within the associated regions, saturate the loci with SNPs and define the minimal associated risk haplotype blocks by allelic, genotypic and haplotype-based association analysis; and ultimately tend to isolate the genetic variants responsible for the risk modifying effect by genomic sequencing of the minimal associated loci. A better understanding of the genes and proteins involved in the pathogenic cascade leading to FTLD will be instrumental for the development of targeted therapeutic strategies to alleviate the suffering of these patients.

Researcher(s)

• Promoter: van der Zee Julie

Research team(s)

Project type(s)

• Research Project

Abstract

Frontotemporal lobar degeneration (FTLD) is a heterogeneous group of irreversible clinical conditions that are characterized by progressive neuronal loss in the frontal and/or temporal cortices. Motor neuron disease (MND) and parkinsonism complicate the disease in up to 15% of patients, and overlap with symptoms of Alzheimer disease (AD), corticobasal syndrome (CBS), and progressive supranuclear palsy (PSP) is not uncommon. In the age group below 65 years, FTLD is the second most common type of neurodegenerative dementia after AD. There are currently no preventive or curative treatments available. To develop effective therapies our understanding of the pathological mechanisms leading to the neurodegenerative processes in the patients' brains is essential. Molecular genetic studies provide a gateway to uncover such mechanisms for further cell biological studies. FTLD has a strong genetic component: in up to 50% of patients, familial aggregation has been observed suggesting highly penetrant genetic factors. Mutations in four genes have been demonstrated to cause autosomal dominant forms of FTLD and common variants affecting expression of TMEM106B were suggested to confer genetic risk for FTLD. Further genetic heterogeneity does exist including a major disease locus at chromosome 9p. Using state-of-the-art molecular genetic and genomic strategies, we aim to further expand our understanding of the biochemical pathways that contribute to the etiology of FTLD. Familial FTLD patients that are not explained by mutations in the known genes will be studied to identify additional FTLD genes including the chromosome 9p gene. In addition we will identify novel risk and disease modifier genes in an extended population of FTLD patients. As a direct result of these molecular genetic studies, improved molecular diagnostics can be offered to the patients and their families, dramatically improving delay times towards correct diagnosis and treatment. Further, results obtained in this project will be the basis for subsequent cell biology studies of the functions and dysfunctions of pathways contributing to neurodegeneration in FTLD.

Researcher(s)

• Promoter: Cruts Marc
• Co-promoter: Gijselinck Ilse
• Co-promoter: van der Zee Julie

Research team(s)

Project type(s)

• Research Project

Abstract

Recently we demonstrated that mutations in PGRN explain a significant fraction of the genetic etiology of frontotemporal lobar degeneration (FTLD) and a follow-up study identified serum PGRN as a potential biomarker for FTLD with underlying PGRN pathology. In the frame of this project we wish to confirm and expand these initial findings by measuring serum PGRN levels trough ELISA in a large sample of Belgian FTLD patients.

Researcher(s)

• Promoter: van der Zee Julie

Research team(s)

Project type(s)

• Research Project

Abstract

The aim of this research project is to assemble an extended, well-documented collection of biologic material from patients with frontotemporal lobar degeneration (FTLD) in Belgium. FTLD is after Alzheimer's disease an important form of dementia. In the frame of this project we will collect biologic material including DNA, serum, plasma, brain material from a large group of Belgian FTLD patients together with extended clinical and pathologic information of these patients. In order to be able to compare genetic findings from patients with the healthy population, neurologically normal aged individuals are assembled from the same geographical region. This project will allow us to compare genetic changes across the entire genome between FTLD patients and neurologically normal individuals to study if some of these changes are more frequent in patients than in normal individuals. This approach is called genome-wide association (GWA) studies. The extended clinical, pathological and biologic information we will collect, combined with whole-genome information obtained from GWA studies will increase our understanding of the disease mechanisms leading to FTLD. These insights will lay the groundwork for a better and early diagnosis, prevention and therapy of this deadly disease.

Researcher(s)

• Promoter: van der Zee Julie

Research team(s)

Project type(s)

• Research Project

Abstract

Aging of the global population has caused dementia to become one of the leading causes of morbidity and mortality. Notwithstanding there is still no therapy available that can cure or prevent dementia. For this research project our focus is on frontotemporal lobar degeneration (FTLD). FTLD is after Alzheimer's disease one of the major causes of dementia, accounting for 5 to 10% of all dementia patients and up to 20% of patients younger than 65 years. Up to up to 40% of FTLD patients have a positive family history of dementia. In the last few years major progress has been made in dissecting the genetic etiology of FTLD. Four genes have already been identified for autosomal dominant FTLD ¿ MAPT, PGRN, CHMP2B, VCP ¿ explaining about 20% of patients. Despite these efforts the majority of FTLD patients still remain unexplained. It is expected that in these patients the cause of the disease is complex in nature, i.e. the result of interplay between genetic and environmental factors. The aim of this research project is to identify such genetic factors that contribute to the risk of developing FTLD in a significant fraction of patients trough a genome-wide association approach. To this extent we will invest in the assembly of an extended, well-documented collection of biomaterials ¿ DNA/RNA, plasma/serum, EBV cell lines, fibroblasts, CSF, brain material ¿ from FTLD patients, families, and control individuals to create a powerful tool to undertake genome-wide association studies. This project will allow extended clinical, pathological, and biologic information to be combined with whole-genome information which will in turn offer the potential to increase our understanding of the pathogenesis of FTLD and provide targets for early diagnosis, prevention and therapy.

Researcher(s)

• Promoter: Van Broeckhoven Christine
• Fellow: van der Zee Julie

Research team(s)

Project type(s)

• Research Project

Abstract

Frontotemporal dementia (FTD) is the second most common cause of neurodegenerative dementia in people younger than 65 years. Clinically FTD is characterized by profound disturbances in behavior, personality and language and may be associated with parkinsonism or motor neuron disease. Up to 50% of FTD patients have a positive family history for dementia and in the majority of these families the disease is inherited in an autosomal dominant fashion. FTD has proven to be genetically heterogeneous with the identification of mutations in the microtubule associated protein tau gene (MAPT) on chromosome 17q21, in the charged multivesicular body protein 2B or chromatin modifying protein 2B gene (CHMP2B) located in the pericentromeric region of chromosome 3, and in the valosin containing protein gene (VCP) on chromosome 9p13-p12. Also, evidence has accumulated for a second gene at the 17q21 region that is associated with non-tauopathy FTD characterized by ubiquitine-immunoreactive neuronal inclusions of unknown nature (FTDU-17). The aim of this research project is the identification of the genetic causes of tau-negative FTD on chromosome 17, chromosome 3, and chromosome 9.

Researcher(s)

• Promoter: Van Broeckhoven Christine
• Fellow: van der Zee Julie

Research team(s)

Project type(s)

• Research Project

Abstract

Frontotemporal dementia (FTD) is the second most common cause of neurodegenerative dementia in people younger than 65 years. Clinically FTD is characterized by profound disturbances in behavior, personality and language and may be associated with parkinsonism or motor neuron disease. Up to 50% of FTD patients have a positive family history for dementia and in the majority of these families the disease is inherited in an autosomal dominant fashion. So far only mutations in the microtubule associated protein tau gene (MAPT) on chromosome 17q21 have been identified for FTD linked to chromosome 17, with a frequency of 10 tot 43% in familial FTD. In a number of autosomal dominant FTD families linked to 17q21 mutation analysis failed to identify any MAPT mutations (FTDU-17). With this research project we aim to investigate the genetic causes of FTDU-17 trough positional cloning strategy in autosomal dominant FTD families.

Researcher(s)

• Promoter: Van Broeckhoven Christine
• Co-promoter: Cruts Marc
• Fellow: van der Zee Julie

Research team(s)

Project type(s)

• Research Project