Longitudinal clinical, neuropsychological, and neuroimaging characterization of a kindred with a 12-octapeptide repeat insertion in PRNP: the next generation

Abstract

Background: Highly penetrant inherited mutations in the prion protein gene (PRNP) offer a window to study the pathobiology of prion disorders.

Method: Clinical, neuropsychological, and neuroimaging characterization of a kindred.

Results: Three of four mutation carriers have progressed to a frontotemporal dementia phenotype. Declines in neuropsychological function coincided with changes in FDG-PET at the identified onset of cognitive impairment.

Conclusions and relevance: Gene silencing treatments are on the horizon and when they become available, early detection will be crucial. Longitudinal studies involving familial mutation kindreds can offer important insights into the initial neuropsychological and neuroimaging changes necessary for early detection.

Keywords: FDG-PET; Genetic prion; neuroimaging; neuropsychological; octapeptide repeat insertion.

Figure 1:

Genetic pedigree of three affected generations. Participant III-3 has an MRI abnormality, but FDG-PET is normal and clinical symptoms do not indicate clear onset at last evaluation. Two unaffected individuals in the third generation had normal findings on neuropsychological examination, brain MRI, and FDG-PET. C – current age; O – symptom onset; D – age of death. *Ages of generation III participants range from the late thirties to early forties but exact ages have been removed for confidentiality purposes.

Figure 2:

Participant III-1 with evolving mild cognitive impairment by visit 5 and behavioral variant frontotemporal dementia by visit 7. (A) Neuropsychological domain z-scores (y-axis range: −3.5 to 3.5) across 7 visits are shown. Grey area represents the average range. Of note, this participant was unable to complete any neuropsychological testing at visit 8 due to global aphasia. (B) MRI MP-RAGE sequences demonstrated cerebellar and midline atrophy on sagittal view, frontal and parietal atrophy on axial view, and L > R temporal and frontal lobe atrophy on coronal view. (C) FDG-PET (using Cortex ID, GE Healthcare with z-score from 0 to −7 on the left side) went from normal at visit 4 to abnormal by visit 6 with worsening hypometabolism in the L>R frontal, parietal, temporal, precuneus regions by visit 7.

Figure 3:

Participant III-2 with evolving mild dementia by visit 9. (A) Neuropsychological domain z-scores (y-axis range: −3.5 to 3.5) across visits 1–10 are shown. Grey area represents the average range. (B) MRI MP-RAGE sequences demonstrated mild cerebellar atrophy and brainstem sag on sagittal view and minimal cortical atrophy on axial and coronal views. (C) FDG-PET (using Cortex ID, GE Healthcare with z-score from 0 to −7 on the left side) became most abnormal by visit 9. There was thalamus, caudate, anterior cingulate and mild posterior cingulate hypometabolism along with patchy hypometabolism throughout the cortex.

Figure 4:

Participant III-3 with variable degrees of memory and judgment problems through all 12 visits. (A) Neuropsychological domain z-scores (y-axis range: −3.5 to 3.5) across visits 1–12 are shown. Grey area represents the average range. (B) MRI MP-RAGE sequences demonstrated mild to moderate cerebellar atrophy on sagittal view and minimal cortical atrophy on axial and coronal views. (C) FDG-PET (using Cortex ID, GE Healthcare with z-score from 0 to −7 on the left side) was normal across all time points.

Figure 5:

Participant III-4 (who had moderately low baseline functioning) with evolving behavioral variant frontotemporal dementia diagnosed at visit 8. (A) Neuropsychological domain z-scores (y-axis range: −3.5 to 3.5) across 11 visits are shown. Grey area represents the average range. (B) MRI MP-RAGE sequences demonstrated moderate cerebellar and midline atrophy on sagittal view, frontal and parietal atrophy on axial view, and temporal atrophy on coronal view. (C) FDG-PET (using Cortex ID, GE Healthcare with z-score from 0 to −7 on the left side) had abnormalities from the first scan which progressed to involve more L > R frontal lobe by visit 9 and then further progression of L > R frontal, medial frontal, superior parietal, and precuneus regions by visit 11.