Pre-symptomatic diagnosis in fatal familial insomnia: serial neurophysiological and 18FDG-PET studies

Abstract

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.

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

“…Considering that FFI has been shown to harbor almost complete penetrance,7 with risk of clinical onset peaking around 50–55 years of age,41 our cohort was studied about 6–11 years before the expected clinical onset. These negative 11 C‐(R)‐PK11195‐PET findings are in accordance with a previous 18 F‐FDG‐PET study in FFI presymptomatic mutation carriers, showing the only dysfunctional marker being significant thalamic hypometabolism 42. More specifically, the latter was evident only shortly before the clinical onset (about 13–21 months)42 and was considered related to underlying fast and abrupt pathology processes.…”

“…These negative 11 C‐(R)‐PK11195‐PET findings are in accordance with a previous 18 F‐FDG‐PET study in FFI presymptomatic mutation carriers, showing the only dysfunctional marker being significant thalamic hypometabolism 42. More specifically, the latter was evident only shortly before the clinical onset (about 13–21 months)42 and was considered related to underlying fast and abrupt pathology processes. Four out of eight presymptomatic carriers showed spatially consistent and significant 11 C‐(R)‐PK11195 BP increases in the limbic structures, such as anterior/middle/posterior cingulate cortices and insula; with two of them showing an additional involvement of basal ganglia.…”

Fatal familial insomnia: Clinical features and early identification

“…However, it has been proposed that thalamic and cingular involvement correlates with an early disease stage, whereas involvement of further regions depends on disease duration. 9 The MM2 thalamic type of sCJD was found to correspond with sporadic fatal insomnia. Sporadic fatal insomnia phenotypically matches FFI and has clinical features such as insomnia and restlessness accompanied by ataxia and dementia, and should be considered in patients with a negative family history and negative genetic test results.…”

Sporadic Fatal Insomnia in an Adolescent

“…7,8 Polysomnography typically shows reduction of sleep-related EEG activities, such as K-complexes and spindles, 9 and positron emission tomography scans may show focal thalamic hypometabolism. 10 Neuropathologic studies demonstrate prominent lesions in the thalamus relative to other brain regions. 7,11 In April 2012, the US National Prion Disease Pathology Surveillance Center (NPDPSC) confirmed a prion disease based on the autopsy findings of a deceased boy with illness onset at 13 years of age.…”