Brain Advance Access published online on January 21, 2009
Brain, doi:10.1093/brain/awn352
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Plasma progranulin levels predict progranulin mutation status in frontotemporal dementia patients and asymptomatic family members
1 Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA 2 Department of Neurology, Mayo Clinic, Rochester, MN, USA 3 Inserm U614, Faculty of Medicine and Pharmacy, Rouen, France 4 University and Memory Clinic, University Hospital, Lille, France 5 Department of Neurology, Mayo Clinic, Jacksonville, FL, USA
Correspondence to:
Dr Rosa Rademakers, Mayo Clinic, Department of Neuroscience, 4500 San Pablo Road, Jacksonville, FL 32224, USA E-mail: rademakers.rosa{at}mayo.edu and Dr Neill R Graff-Radford, Mayo Clinic, Department of Neurology, 4500 San Pablo Road, Jacksonville, FL 32224, USA E-mail: graffradford.neil{at}mayo.edu
Mutations in the progranulin gene (GRN) are an important cause of frontotemporal lobar degeneration (FTLD) with ubiquitin and TAR DNA-binding protein 43 (TDP43)-positive pathology. The clinical presentation associated with GRN mutations is heterogeneous and may include clinical probable Alzheimer's disease. All GRN mutations identified thus far cause disease through a uniform disease mechanism, i.e. the loss of functional GRN or haploinsufficiency. To determine if expression of GRN in plasma could predict GRN mutation status and could be used as a biological marker, we optimized a GRN ELISA and studied plasma samples of a consecutive clinical FTLD series of 219 patients, 70 control individuals, 72 early-onset probable Alzheimer's disease patients and nine symptomatic and 18 asymptomatic relatives of GRN mutation families. All FTLD patients with GRN loss-of-function mutations showed significantly reduced levels of GRN in plasma to about one third of the levels observed in non-GRN carriers and control individuals (P < 0.001). No overlap in distributions of GRN levels was observed between the eight GRN loss-of-function mutation carriers (range: 53–94 ng/ml) and 191 non-GRN mutation carriers (range: 115–386 ng/ml). Similar low levels of GRN were identified in asymptomatic GRN mutation carriers. Importantly, ELISA analyses also identified one probable Alzheimer's disease patient (1.4%) carrying a loss-of-function mutation in GRN. Biochemical analyses further showed that the GRN ELISA only detects full-length GRN, no intermediate granulin fragments. This study demonstrates that using a GRN ELISA in plasma, pathogenic GRN mutations can be accurately detected in symptomatic and asymptomatic carriers. The 
75% reduction in full-length GRN, suggests an unbalanced GRN metabolism in loss-of-function mutation carriers whereby more GRN is processed into granulins. We propose that plasma GRN levels could be used as a reliable and inexpensive tool to identify all GRN mutation carriers in early-onset dementia populations and asymptomatic at-risk individuals.
Key Words: Progranulin; ELISA; frontotemporal lobar degeneration; Alzheimer's disease
Abbreviations: bvFTD, behavioural variant frontotemporal dementia; FTLD, frontotemporal lobar degeneration; PNFA, progressive non-fluent aphasia; SD, semantic dementia; SPECT, single photon emission tomography
Received October 10, 2008. Revised November 12, 2008. Accepted November 30, 2008.