http://repub.eur.nl/res/aut/5555/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/27583/ 2010-04-01T00:00:00Z Objective To compare survival and to identify prognostic predictors for progressive supranuclear palsy and frontotemporal dementia. Background Progressive supranuclear palsy (PSP) and frontotemporal dementia (FTD) are related disorders. Homozygosity for H1 haplotype is associated with PSP, whereas several MAPT mutations have been identified in FTLD-s. Survival duration probably reflects underlying pathophysiology or disease. Methods Patients with PSP and FTD were recruited by nationwide referral. Survival of 354 FTD patients was compared with that of 197 PSP patients. Cox regression analysis was performed to identify prognostic predictors. FTLD-s was defined as Pick disease and FTDP-17 with MAPT mutations. Semiquantitative evaluation of s-positive pathology was performed on all pathologically proven cases. Results The median survival of PSP patients (8.0 years; 95% CI 7.3 to 8.7) was significantly shorter than that of FTD patients (9.9 years; 95% CI 9.2 to 10.6). Corrected for demographic differences, PSP patients were still significantly more at risk of dying than FTD patients. In PSP, male gender, older onset-age and higher PSP Rating Scale score were identified as independent predictors for shorter survival, whereas in FTD a positive family history and an older onset-age were associated with a poor prognosis. The difference in hazard rate was even more pronounced when comparing pathologically proven cases of PSP with FTLD-s. Conclusion Survival of PSP patients is shorter than that of FTD patients, and probably reflects a more aggressive disease process in PSP. Independent predictors of shorter survival in PSP were male gender, older onsetage and higher PSP rating scale score, whereas in FTD a positive family history and higher onset-age were predictors for worse prognosis. http://repub.eur.nl/res/pub/18471/ 2009-02-12T00:00:00Z Patients with frontotemporal dementia (FTD) need complete care in the final stages of the disease. Some informal caregivers continue the in-home care whereas others institutionalize. This study identifies differences between in-home FTD patients and their caregivers (FTDH) and institutionalized FTD patients (FTDN) and their caregivers. Twelve in-home and 24 institutionalized FTD patients in the final stages of the disease, and their spousal caregivers, were observed. Neuropsychiatric function disorders, dementia duration and severity, burden, mental and physical health, quality of the current and premorbid relationship and caregiver motivation were analysed. The majority of FTDH patients had dementia of shorter duration and showed residual independence. In FTDH patients, neuropsychiatric symptoms were more often present whereas apathy and disinhibition were more intense in FTDN patients. FTDH caregivers felt more emotionally burdened but had better mental health. Caregiver motivations were similarly present in FTDH and FTDN caregivers, while the love-motivated caregivers had worse physical and mental health. Our data suggest that all FTD caregivers could benefit from psychological support. Motivation for caregiving has intervention potential. http://repub.eur.nl/res/pub/30372/ 2008-11-01T00:00:00Z Background/Aims: The current study examined the change of caregiver burden and the development of the quality of the partner relation in frontotemporal dementia (FTD). Methods: During a 2-year period, deterioration, behavioural problems, caregiver burden, general psychopathology, quality of life, social support, coping strategies and relationship quality were inspected in 63 FTD caregiver-care recipient dyads. Results: After 2 years patients reached maximum dementia severity with stable Neuropsychiatric Inventory levels. Contrary to expectations, caregiver burden decreased and psychological well-being remained stable. Coping style and social support changed unfavourably. Relationship closeness and getting along were preserved, whereas communication and sharing viewpoint on life were dramatically reduced. Conclusions: FTD caregivers need support in coping with the increasingly hopeless situation of their patients. Future research methods into caregiver burden should address response shift as a means for psychological adjustment. Copyright http://repub.eur.nl/res/pub/15126/ 2008-10-14T00:00:00Z BACKGROUND: Frontotemporal dementia (FTD) is the second most common type of presenile dementia and can be distinguished into various clinical variants. The identification of MAPT and GRN defects and the discovery of the TDP-43 protein in FTD have led to the classification of pathologic and genetic subtypes. In addition to these genetic subtypes, there exist familial forms of FTD with unknown genetic defects. METHODS: We investigated the frequency, demographic, and clinical data of patients with FTD with a positive family history in our prospective cohort of 364 patients. Genetic analysis of genes associated with FTD was performed on all patients with a positive family history. Immunohistochemical studies were carried out with a panel of antibodies (tau, ubiquitin, TDP-43) in brains collected at autopsy. RESULTS: In the total cohort of 364 patients, 27% had a positive family history suggestive for an autosomal mode of inheritance, including MAPT (11%) and GRN (6%) mutations. We identified a new Gln300X GRN mutation in a patient with a sporadic FTD. The mean age at onset in GRN patients (61.8 +/- 9.9 years) was higher than MAPT patients (52.4 +/- 5.9 years). In the remaining 10% of patients with suggestive autosomal dominant inheritance, the genetic defect has yet to be identified. Neuropathologically, this group can be distinguished into familial FTLD+MND and familial FTLD-U with hippocampal sclerosis. CONCLUSION: Future genetic studies need to identify genetic defects in at least two distinct familial forms of frontotemporal dementia (FTD) with unknown genetic defects: frontotemporal lobe degeneration with ubiquitin-positive inclusions with hippocampal sclerosis and frontotemporal lobe degeneration with motor neuron disease. http://repub.eur.nl/res/pub/35465/ 2007-05-01T00:00:00Z Frontotemporal dementia is accompanied by motor neuron disease (FTD + MND) in ∼10% of cases. There is accumulating evidence for a clinicopathological overlap between FTD and MND based on observations of familial aggregation and neuropathological findings of ubiquitin-positive neuronal cytoplasmatic inclusions (NCI) in lower motor neurons, hippocampus and neocortex in both conditions. Several familial forms exist with different genetic loci and defects. We investigated the familial aggregation and clinical presentation of FTD + MND cases in a large cohort of 368 FTD patients in the Netherlands. Immunohistochemistry of available brain tissue of deceased patients was investigated using a panel of antibodies including ubiquitin, p62 and TAR DNA-binding protein of 43kDa antibodies. A total of eight patients coming from six families had a family history positive for FTD + MND (mean age at onset 53.2 ± 8.4 years). Five patients presented with behavioural changes and cognitive changes followed by motor neuron disease, whereas symptoms of motor neuron disease were the presenting features in the remaining three patients. Other affected relatives in these families showed dementia/FTD, MND or FTD + MND reflecting the clinical interfamilial variation. No mutations were identified in any of the candidate genes, including Superoxide Dismutase 1, dynactin, angiogenin, Microtubule-Associated Protein Tau, valosin-containing protein and progranulin. Available brain tissue of five patients with familial FTD + MND showed NCI in hippocampus, neocortex and spinal cord in all, and neuronal intranuclear inclusions (NII) in two brains. TDP-43 antibody showed robust staining of neuronal inclusions similar in distribution and morphology to NCI and NII. Additionally, TDP-43 antibody also stained ubiquitin-negative glial inclusions in the basal striatum of one case. In conclusion, there exists considerable clinical variation within families with FTD + MND, which may be determined by other genetic or environmental factors. NII are also found in some cases of familial FTD + MND without Progranulin mutations. The observation of glial TDP-43 positive inclusions in one brain is very interesting, although their pathophysiological significance is yet unknown. http://repub.eur.nl/res/pub/36698/ 2007-03-01T00:00:00Z 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. http://repub.eur.nl/res/pub/13187/ 2003-09-01T00:00:00Z 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. http://repub.eur.nl/res/pub/13201/ 2003-09-01T00:00:00Z 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. http://repub.eur.nl/res/pub/8426/ 2003-01-01T00:00:00Z A retrospective case-control study was carried out on 80 patients with sporadic frontotemporal dementia and 124 age, sex, and surrogate informant matched controls with respect to various medical and environmental risk factors. Head trauma was associated with an odds ratio of 3.3 (95% confidence interval (CI), 1.3 to 8.1). Although recall bias may play a role, the frontal lobes are known to be especially vulnerable to even mild head trauma. Thyroid disease was associated with a 2.5 times increased risk of frontotemporal dementia (95% CI, 0.9 to 7.9), which was not statistically significant (p = 0.09) owing to limited power. As altered thyroid hormone status has been observed before in frontotemporal dementia, future studies will be important to confirm this observation. http://repub.eur.nl/res/pub/5888/ 2002-06-05T00:00:00Z http://repub.eur.nl/res/pub/8427/ 2002-01-01T00:00:00Z http://repub.eur.nl/res/pub/9764/ 2001-01-01T00:00:00Z Hereditary frontotemporal dementia (FTD) is an autosomal dominant neurodegenerative disorder that is associated with mutations in the tau gene and with the pathological accumulation of hyperphosphorylated tau protein in affected brain cells in about a quarter of cases. However, most FTD families have no demonstrable tau mutations. Here we describe the clinical and neuropathological features of a large family with hereditary FTD. Genetic analysis showed strong evidence for linkage to chromosome 17q21-22 (maximum lod score 3.46, theta = 0 for marker D17S950), but mutations in the tau gene were not found. Clinical symptoms, neuropsychological deficits and neuroimaging findings of affected family members were similar to sporadic and tau-related FTD. The mean age at onset was 61.2 years, with loss of initiative and decreased spontaneous speech as the most prominent presenting symptoms. Pathological examination of the brains of two affected family members showed non-specific neuronal degeneration with dense cytoplasmic ubiquitin-positive inclusions in neurones of the second layer of the frontotemporal cortex and dentate gyrus of the hippocampus. In a number of neurones these inclusions appeared to be located inside the nucleus, although due to the small number of these inclusions this localization could not be confirmed by electron microscopy. The inclusions were not stained by tau, alpha-synuclein or polyglutamine antibodies. Biochemical analysis of soluble tau did not reveal abnormalities in tau isoform distribution and analysis of mRNA showed the presence of both three- and four-repeat transcripts. This is the first report of ubiquitin-positive, tau-negative inclusions in an FTD family with significant linkage to chromosome 17q21-22. Further characterization of the ubiquitin-positive inclusions may clarify the neurodegenerative pathways involved in this subtype of FTD.