CEREBRAL METABOLISM IN FATAL FAMILIAL INSOMNIA - RELATION TO DURATION, NEUROPATHOLOGY, AND DISTRIBUTION OF PROTEASE-RESISTANT PRION PROTEIN

We used [F-18]-2-fluoro-2-deoxy-D-glucose (FDG) and PET to study regio nal cerebral glucose utilization in seven patients with fatal familial insomnia (FFI), an inherited prion disease with a mutation at codon 1 78 of the prion protein gene. Four patients were methionine/methionine homozygotes at codon 129 (symptom duration, 8.5 +/- 1 months) and thr ee were methionine/valine (MET/VAL(129)) heterozygotes (symptom durati on, 35 +/- 11 months). A severely reduced glucose utilization of the t halamus and a mild hypometabolism of the cingulate cortex were found i n all FFI patients. In six subjects the brain hypometabolism also affe cted the basal and lateral frontal cortex, the caudate nucleus, and th e middle and inferior temporal cortex. Comparison between homozygous o r heterozygous patients at codon 129 showed that the hypometabolism wa s more widespread in the MET/VAL(129) group, which had a significantly longer symptom duration at the time of [F-18] FDG PET study. Comparis on between neuropathologic and [F-18] FDG PET findings in six patients showed that areas with neuronal loss were also hypometabolic. However , cerebral hypometabolism was more widespread than the histopathologic changes and significantly correlated with the presence of protease-re sistent prion protein (PrPres). Our findings indicate that hypometabol ism of the thalamus and cingulate cortex is the hallmark of FFI, while the involvement of other brain regions depends on the duration of sym ptoms and some unknown factors specific to each patient. The present d ata also support the notion that PrPres formation is the cause of neur onal dysfunction in prion diseases.