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.

CONCLUSION:

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: Claudia Jacova, Ging-Yuek R Hsiung, Itthipol Tawankanjanachot, Katie Dinelle, Siobhan McCormick, Marjorie Gonzalez, Hyunsoo Lee, Pheth Sengdy, Phoenix Bouchard-Kerr, Matthew Baker, Rosa Rademakers, Vesna Sossi, A Jon Stoessl, Howard H Feldman, Ian R Mackenzie
• Journal: Neurology (Neurology) Vol. 81 Issue 15 Pg. 1322-31 (Oct 08 2013) ISSN: 1526-632X [Electronic] United States
• PMID: 24005336 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• GRN protein, human
• Intercellular Signaling Peptides and Proteins
• Progranulins
• Fluorodeoxyglucose F18
• Glucose

Topics

• Adult
• Aged
• Brain Mapping
• Dementia (complications, genetics, pathology)
• Disease Progression
• Female
• Fluorodeoxyglucose F18
• Frontal Lobe (diagnostic imaging, metabolism)
• Glucose (metabolism)
• Humans
• Intercellular Signaling Peptides and Proteins (genetics)
• Magnetic Resonance Imaging
• Male
• Middle Aged
• Mutation (genetics)
• Positron-Emission Tomography
• Progranulins
• Retrospective Studies