Cerebral metabolism in fatal familial insomnia: Relation to duration, neuropathology, and distribution of protease-resistent prion protein

Abstract

We used [18F]-2-fluoro-2-deoxy-D-glucose (FDG) and PET to study regional cerebral glucose utilization in seven patients with fatal familial insomnia (FFI), an inherited prion disease with a mutation at codon 178 of the prion protein gene. Four patients were methionine/methionine homozygotes at codon 129 (symptom duration, 8.5 +/- 1 months) and three were methionine/valine (MET/VAL129) heterozygotes (symptom duration, 35 +/- 11 months). A severely reduced glucose utilization of the thalamus and a mild hypometabolism of the cingulate cortex were found in all FFI patients. In six subjects the brain hypometabolism also affected the basal and lateral frontal cortex, the caudate nucleus, and the middle and inferior temporal cortex. Comparison between homozygous or heterozygous patients at codon 129 showed that the hypometabolism was more widespread in the MET/VAL129 group, which had a significantly longer symptom duration at the time of [18F] FDG PET study. Comparison between neuropathologic and [18F] 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-resistant prion protein (PrPres). Our findings indicate that hypometabolism of the thalamus and cingulate cortex is the hallmark of FFI, while the involvement of other brain regions depends on the duration of symptoms and some unknown factors specific to each patient. The present data also support the notion that PrPres formation is the cause of neuronal dysfunction in prion diseases.

An in vivo 11C‐PK PET study of microglia activation in Fatal Familial Insomnia

“…In FFI, thalamus, midbrain, brainstem, and cerebellum bear the brunt of pathology8, 15 and here we showed focal and significant in vivo TSPO overexpression in the symptomatic patient. FFI patients with longest disease course have shown cortical pathology and dysfunction18, 24 and we here consistently detected TSPO overexpression in cortical regions in vivo.…”

“…At the cortical levels, previously reported FFI patients with longer disease durations (i.e., D178N‐129 M/V ) showed both marked in vivo 18 F‐FDG‐PET hypometabolism and significant postmortem spongiosis and gliosis, with a milder neuronal loss especially evident in frontal and cingulate regions 18, 24, 39…”

“…Limbic and cortical involvement is also supported by pathology studies showing a spread of PrP Sc deposition, neurodegeneration, and gliosis in these areas, depending on disease duration 8, 18…”

“…With regard to molecular Positron Emission Tomography (PET) imaging, several18F‐FDG‐PET studies revealed focal thalamic hypometabolism in FFI, variably reaching limbic and frontotemporal cortical regions possibly due to thalamic functional deafferentation 18, 21, 24, 25. Limbic and cortical involvement is also supported by pathology studies showing a spread of PrP Sc deposition, neurodegeneration, and gliosis in these areas, depending on disease duration 8, 18…”

“…Previous studies have reported only mild PrP Sc accumulation in FFI, particularly in patients with the shortest disease duration 16, 18. Significant microglia activation has been described in association with neuronal apoptosis in FFI, both in terms of topography and magnitude,17 but negative evidence also exists 19, 20…”