Brain Advance Access originally published online on January 6, 2006
Brain 2006 129(3):668-675; doi:10.1093/brain/awl003
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Pre-symptomatic diagnosis in fatal familial insomnia: serial neurophysiological and 18FDG-PET studies
1 Department of Neuroscience, C.N.R.-I.B.F.M., Vita-Salute San Raffaele University, 2 C.N.R.-I.B.F.M., University of Milan-Bicocca, Scientific Institute H. S. Raffaele, Milan, 3 Department of Neurological Sciences, University of Bologna, 4 DISMR, Department of Motor Sciences, Center for Sleep Medicine, University of Genova, Italy and 5 Institute of Pathology, Case Western Reserve University, Cleveland, OH, USA
Correspondence to: Pietro Cortelli MD, PhD, Alma Mater Studiorum-Universita' di Bologna, Dipartimento di Scienze Neurologiche, Via Ugo Foscolo, 7, 40123 Bologna, Italy E-mail: pietro.cortelli{at}unibo.it
Knowing how and when the degenerative process starts is important in neurodegenerative diseases. We have addressed this issue in fatal familial insomnia (FFI) measuring the cerebral metabolic rate of glucose (CMRglc) with 2-[18F]fluoro-2-deoxy-D-glucose PET in parallel with detailed clinical, neuropsychological examinations and polysomnography with EEG spectral analyses. Nine asymptomatic carriers of the D178N mutation, 10 non-carriers belonging to the same family, and 19 age-matched controls were studied over several years. The CMRglc as well as clinical and electrophysiological examinations were normal in all cases at the beginning of the study. Four of the mutation carriers developed typical FFI during the study but CMRglc and the clinical and electrophysiological examinations remained normal 63, 56, 32 and 21 months, respectively before disease onset. The carrier whose tests were normal 32 months before disease onset was re-examined 13 months before the onset. At that time, selective hypometabolism was detected in the thalamus while spectral-EEG analysis disclosed an impaired thalamic sleep spindle formation. Following clinical disease onset, CRMglc was reduced in the thalamus in all 3 patients examined. Our data indicate that the neurodegenerative process associated with FFI begins in the thalamus between 13 and 21 months before the clinical presentation of the disease.
Key Words: fatal familial insomnia; 18FDG-PET; pre-symptomatic diagnosis; thalamus
Abbreviations: 18FDG-PET = 2-[18F]fluoro-2-deoxy-D-glucose PET; FFI = fatal familial insomnia; PrP = prion protein; rCMRglc = regional cerebral metabolic rate of glucose
Received September 7, 2005. Revised October 11, 2005. Accepted December 7, 2005.