Showing papers by "Harro Seelaar published in 2007"

TDP-43 pathology in familial frontotemporal dementia and motor neuron disease without Progranulin mutations

Abstract: Frontotemporal dementia is accompanied by motor neuron disease (FTD þMND) 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 þMND 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 þMND (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 þMND 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 þMND 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 þMND, which may be determined by other genetic or environmental factors. NII are also found in some cases of familial FTD þMND without Progranulin mutations. The observation of glial TDP- 43 positive inclusions in one brain is very interesting, although their pathophysiological significance is yet unknown.

Progranulin mutations in Dutch familial frontotemporal lobar degeneration

Abstract: 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.