Biomedical subjects

Julie Snowden

Publications and source records attributed to Julie Snowden.

5 recordsLinked to original sources

PubMed2006

Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17.

Frontotemporal dementia (FTD) is the second most common cause of dementia in people under the age of 65 years. A large proportion of FTD patients (35-50%) have a family history of dementia, consistent with a strong genetic component to the disease. In 1998, mutations in the gene encoding the microtubule-associated protein tau (MAPT) were shown to cause familial FTD with parkinsonism linked to chromosome 17q21 (FTDP-17). The neuropathology of patients with defined MAPT mutations is characterized by cytoplasmic neurofibrillary inclusions composed of hyperphosphorylated tau. However, in multiple FTD families with significant evidence for linkage to the same region on chromosome 17q21 (D17S1787-D17S806), mutations in MAPT have not been found and the patients consistently lack tau-immunoreactive inclusion pathology. In contrast, these patients have ubiquitin (ub)-immunoreactive neuronal cytoplasmic inclusions and characteristic lentiform ub-immunoreactive neuronal intranuclear inclusions. Here we demonstrate that in these families, FTD is caused by mutations in progranulin (PGRN) that are likely to create null alleles. PGRN is located 1.7 Mb centromeric of MAPT on chromosome 17q21.31 and encodes a 68.5-kDa secreted growth factor involved in the regulation of multiple processes including development, wound repair and inflammation. PGRN has also been strongly linked to tumorigenesis. Moreover, PGRN expression is increased in activated microglia in many neurodegenerative diseases including Creutzfeldt-Jakob disease, motor neuron disease and Alzheimer's disease. Our results identify mutations in PGRN as a cause of neurodegenerative disease and indicate the importance of PGRN function for neuronal survival.

Cell Survival↗

PubMed2006

CHMP2B mutations are not a common cause of frontotemporal lobar degeneration.

It was reported in 1995 that a large Danish family with familial frontotemporal dementia (FTD) was linked to the pericentromeric region of chromosome 3. It has since been claimed that a mutation in the splice acceptor site of exon 6 of CHMP2B is the pathogenic variant in this family. In order to determine whether CHMP2B mutations are a common cause of disease in patients with frontotemporal lobar degeneration (FTLD) we sequenced all exons and flanking regions of CHMP2B in 141 familial FTLD probands from the USA and UK. We failed to find a single pathogenic variant in any case. Polymorphisms were detected but were present in control samples. We conclude that mutations in CHMP2B are a rare cause of familial FTLD and may be specific to the Danish pedigree.

Dementia↗

PubMed2005

Frontotemporal dementia.

Frontotemporal dementia (FTD) is a focal clinical syndrome characterised by profound changes in personality and social conduct and associated with circumscribed degeneration of the prefrontal and anterior temporal cortex. Onset is typically in the middle years of life and survival is about 8 years. The presence of microtubule-associated-protein-tau-based pathological features in some patients and the discovery, in some familial cases, of mutations in the tau gene links FTD to other forms of tauopathy, such as progressive supranuclear palsy and corticobasal degeneration. However, more than half of all patients with FTD, including some with a strong family history, show no apparent abnormality in the tau gene or protein, indicating pathological and aetiological heterogeneity. FTD provides a challenge both for clinical management and for theoretical understanding of its neurobiological substrate.

Behavior↗

PubMed2004

Evidence of a founder effect in families with frontotemporal dementia that harbor the tau +16 splice mutation.

The +16 exon 10 splice mutation of the tau gene (microtubule-associated protein tau, MAPT) has been reported in numerous families with frontotemporal dementia (FTD). To date, the majority of these families are from England and Wales in the UK, although families with this mutation have been reported from Australia and the USA. Our own analysis has identified eight families with the +16 MAPT splice mutation from around the Manchester and North Wales areas of the UK. Given the proximity of the UK families to one another it is likely that they are related and represent a single extended pedigree. In order to investigate this possibility, and the possibility that the families with this mutation from London, the USA, and Australia are related, we genotyped 11 microsatellite markers around the tau locus. In most cases (20/25, 80%), a common haplotype, approximately 3 cM in size, was identified. In the remaining cases, this haplotype appears to have been varyingly reduced in size by recombination. We demonstrate that the +16 mutation is on the H1 tau haplotype and that H1 specific polymorphisms are also shared by these families. These data provide evidence that the MAPT +16 splice mutation cases from around the world analyzed in this study are indeed related and represent a single pedigree that probably originated in the North Wales area of the UK. Furthermore, this single large pedigree may be of use in the identification of disease modifying loci in FTD.

Australia↗

PubMedDate not supplied

Dilatation of the Virchow-Robin space is a sensitive indicator of cerebral microvascular disease: study in elderly patients with dementia.

BACKGROUND AND PURPOSE: Virchow-Robin spaces (VRSs) are CSF spaces that accompany blood vessels as they perforate the brain substance. Dilatation of VRS is associated with microangiopathy. Microvascular disease has a major etiologic and pathogenetic role in dementias. To our knowledge, no investigators have looked at the relationship between dilated VRS on MR imaging and cerebral microvascular disease. The aim of our study was to test the hypothesis that dilatation of VRS is associated with subcortical vascular dementia. METHODS: We recruited 75 patients with Alzheimer's disease (n = 35), ischemic vascular dementia (n = 24), or frontotemporal dementia (n = 16) and 35 healthy volunteers. We assessed deep white matter and periventricular hyperintensities and the severity of VRS dilatation, as scored on MR images. Statistical group comparisons and multiple regression analyses were performed to quantify the relationship between imaging features and diagnoses. RESULTS: White matter lesions were more common in patients with ischemic vascular dementia than in those with Alzheimer's disease or healthy volunteers (P < .01). VRS scores were significantly higher in patients with vascular dementia than in patients with AD (P < .001), patients with FTD (P < .01), or healthy volunteers (P < .001). VRS scores accounted for 29% of the variance in the regression model, and scores for periventricular hyperintensity accounted for 2%. CONCLUSION: VRS dilatation is common in diseases associated with microvascular abnormality and can be used as a diagnostic tool to differentiate vascular dementias from degenerative dementias.

Aged↗