Petersen, R.C.

Mutations in protein N-arginine methyltransferases are not the cause of FTLD-FUS (Article)

2013-04-29T00:00:00Z

The nuclear protein fused in sarcoma (FUS) is found in cytoplasmic inclusions in a subset of patients with the neurodegenerative disorder frontotemporal lobar degeneration (FTLD-FUS). FUS contains a methylated arginine-glycine-glycine domain that is required for transport into the nucleus. Recent findings have shown that this domain is hypomethylated in patients with FTLD-FUS. To determine whether the cause of hypomethylation is the result of mutations in protein N-arginine methyltransferases (PRMTs), we selected 3 candidate genes (PRMT1, PRMT3, and PRMT8) and performed complete sequencing analysis and real-time polymerase chain reaction mRNA expression analysis in 20 FTLD-FUS cases. No mutations or statistically significant changes in expression were observed in our patient samples, suggesting that defects in PRMTs are not the cause of FTLD-FUS.

FUS pathology defines the majority of tau-and TDP-43-negative frontotemporal lobar degeneration (Article)

2010-07-01T00:00:00Z

Through an international consortium, we have collected 37 tau-and TAR DNA-binding protein 43 (TDP-43)-negative frontotemporal lobar degeneration (FTLD) cases, and present here the first comprehensive analysis of these cases in terms of neuropathology, genetics, demographics and clinical data. 92% (34/37) had fused in sarcoma (FUS) protein pathology, indicating that FTLD-FUS is an important FTLD subtype. This FTLD-FUS collection specifically focussed on aFTLD-U cases, one of three recently defined subtypes of FTLD-FUS. The aFTLD-U subtype of FTLD-FUS is characterised clinically by behavioural variant frontotemporal dementia (bvFTD) and has a particularly young age of onset with a mean of 41 years. Further, this subtype had a high prevalence of psychotic symptoms (36% of cases) and low prevalence of motor symptoms (3% of cases). We did not find FUS mutations in any aFTLD-U case. To date, the only subtype of cases reported to have ubiquitin-positive but tau-, TDP-43-and FUS-negative pathology, termed FTLD-UPS, is the result of charged multivesicular body protein 2B gene (CHMP2B) mutation. We identified three FTLD-UPS cases, which are negative for CHMP2B mutation, suggesting that the full complement of FTLD pathologies is yet to be elucidated.

Survival profiles of patients with frontotemporal dementia and motor neuron disease (Article)

2009-11-01T00:00:00Z

Background: Frontotemporal dementia and amyotrophic lateral sclerosis are neurodegenerative diseases associated with TAR DNA-binding protein 43- and ubiquitin-immunoreactive pathologic lesions. Objective: To determine whether survival is influenced by symptom of onset in patients with frontotemporal dementia and amyotrophic lateral sclerosis. Design, Setting, and Patients: Retrospective review of patients with both cognitive impairment and motor neuron disease consecutively evaluated at 4 academic medical centers in 2 countries. Main Outcome Measures: Clinical phenotypes and survival patterns of patients. Results: A total of 87 patients were identified, including 60 who developed cognitive symptoms first, 19 who developed motor symptoms first, and 8 who had simultaneous onset of cognitive and motor symptoms. Among the 59 deceased patients, we identified 2 distinct subgroups of patients according to survival. Long-term survivors had cognitive onset and delayed emergence of motor symptoms after a long monosymptomatic phase and had significantly longer survival than the typical survivors (mean, 67.5 months vs 28.2 months, respectively; P<.001). Typical survivors can have simultaneous or discrete onset of cognitive and motor symptoms, and the simultaneous-onset patients had shorter survival (mean, 19.2 months) than those with distinct cognitive or motor onset (mean, 28.6 months) (P=.005). Conclusions: Distinct patterns of survival profiles exist in patients with frontotemporal dementia and motor neuron disease, and overall survival may depend on the relative timing of the emergence of secondary symptoms.

Creating a transatlantic research enterprise for preventing Alzheimer's disease (Article)

2009-07-01T00:00:00Z

In recognition of the global problem posed by Alzheimer's disease and other dementias, an international think-tank meeting was convened by Biocat, the Pasqual Maragall Foundation, and the Lou Ruvo Brain Institute in February 2009. The meeting initiated the planning of a European Union-North American collaborative research enterprise to expedite the delay and ultimate prevention of dementing disorders. The key aim is to build parallel and complementary research infrastructure that will support international standardization and inter-operability among researchers in both continents. The meeting identified major challenges, opportunities for research resources and support, integration with ongoing efforts, and identification of key domains to influence the design and administration of the enterprise.

Apolipoprotein E genotype does not affect the age of onset of dementia in families with define tau mutations (Article)

1999-02-05T00:00:00Z

We have assessed whether apolipoprotein E (ApoE) genotype influences the age of onset of dementia in a series of families with frontal temporal dementia with defined mutations in the tau gene. In contrast to the situation in Alzheimer's disease (AD), we could find no evidence that the age of onset of disease was influenced by the ApoE genotype.