title: Anterior brain glucose hypometabolism predates dementia in progranulin mutation carriers.
abstract: OBJECTIVE
  In this prospective cohort study, we investigated cerebral glucose metabolism reductions on [(18)F]-fluorodeoxyglucose (FDG)-PET in progranulin (GRN) mutation carriers prior to frontotemporal dementia (FTD) onset.
  
  
  METHODS
  Nine mutation carriers (age 51.5 ± 13.5 years) and 11 noncarriers (age 52.7 ± 9.5 years) from 5 families with FTD due to GRN mutations underwent brain scanning with FDG-PET and MRI and clinical evaluation. Normalized FDG uptake values were calculated with reference to the pons. PET images were analyzed with regions of interest (ROI) and statistical parametric mapping (SPM) approaches.
  
  
  RESULTS
  Compared with noncarriers, GRN mutation carriers had a lowered anterior-to-posterior (AP) ratio of FDG uptake (0.86 ± 0.09 vs 0.92 ± 0.05) and less left-right asymmetry, consistent with an overall pattern of right anterior cerebral hypometabolism. This pattern was observed regardless of whether they were deemed clinically symptomatic no dementia or asymptomatic. Individual ROIs with lowered FDG uptake included right anterior cingulate, insula, and gyrus rectus. SPM analysis supported and extended these findings, demonstrating abnormalities in the right and left medial frontal regions, right insular cortex, right precentral and middle frontal gyri, and right cerebellum. Right AP ratio was correlated with cognitive and clinical scores (modified Mini-Mental State Examination r = 0.74; Functional Rating Scale r = -0.73) but not age and years to estimated onset in mutation carriers.
  
  
  CONCLUSIONS
  The frontotemporal lobar degenerative process associated with GRN mutations appears to begin many years prior to the average age at FTD onset (late 50s-early 60s). Right medial and ventral frontal cortex and insula may be affected in this process but the specific regional patterns associated with specific clinical variants remain to be elucidated.
authors.affiliation: From the Division of Neurology, Department of Medicine (C.J., G.-Y.R.H., I.T., H.L., P.S., P.B.-K., A.J.S., H.H.F.), Department of Physics and Astronomy (K.D., S.M., M.G., V.S.), and Department of Pathology and Laboratory Medicine (I.R.M.), University of British Columbia, Vancouver, Canada; and Department of Neuroscience (M.B., R.R.), Mayo Clinic, Jacksonville, FL.
authors.forename: Claudia
authors.initials: C
authors.lastname: Jacova
authors.forename: Ging-Yuek R
authors.initials: GY
authors.lastname: Hsiung
authors.forename: Itthipol
authors.initials: I
authors.lastname: Tawankanjanachot
authors.forename: Katie
authors.initials: K
authors.lastname: Dinelle
authors.forename: Siobhan
authors.initials: S
authors.lastname: McCormick
authors.forename: Marjorie
authors.initials: M
authors.lastname: Gonzalez
authors.forename: Hyunsoo
authors.initials: H
authors.lastname: Lee
authors.forename: Pheth
authors.initials: P
authors.lastname: Sengdy
authors.forename: Phoenix
authors.initials: P
authors.lastname: Bouchard-Kerr
authors.forename: Matthew
authors.initials: M
authors.lastname: Baker
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
authors.forename: Vesna
authors.initials: V
authors.lastname: Sossi
authors.forename: A Jon
authors.initials: AJ
authors.lastname: Stoessl
authors.forename: Howard H
authors.initials: HH
authors.lastname: Feldman
authors.forename: Ian R
authors.initials: IR
authors.lastname: Mackenzie
mesh_terms: D000328:Adult; D000368:Aged; D001931:Brain Mapping; D003704:Dementia / Q000150:complications / Q000235:genetics / Q000473:pathology; D018450:Disease Progression; D005260:Female; D019788:Fluorodeoxyglucose F18; D005625:Frontal Lobe / Q000000981:diagnostic imaging / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D049268:Positron-Emission Tomography; D000077153:Progranulins; D012189:Retrospective Studies
chemical_list: C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D019788:Fluorodeoxyglucose F18; D005947:Glucose