Clinical aspects of common genetic Creutzfeldt-Jakob disease

Schelzke, Gabi; Kretzschmar, Hans A.; Zerr, Inga

doi:10.1007/s10654-012-9660-3

Cited by 13 publications

(13 citation statements)

References 4 publications

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“…Surprisingly, our results using DTI and TBSS differ from a study on the TBSS findings in a cohort of patients with genetic CJD with the E200K mutation (Lee et al , 2012), which usually have several clinical and MRI features overlapping with sporadic CJD (Goldfarb et al , 1991; Parchi et al , 1999; Fulbright et al , 2006; Schelzke et al , 2012). In this interesting study on white matter magnetic resonance diffusion in 21 E200K subjects, they found average reduced fractional anisotropy in several white matter tracts (corticospinal tract, internal and external capsule, fornix, and posterior thalamic radiation) mainly due to increased radial diffusivity (with normal axial diffusivity), with a slightly increased mean diffusivity (Lee et al , 2012).…”

Section: Discussioncontrasting

confidence: 99%

White matter involvement in sporadic Creutzfeldt-Jakob disease

Caverzasi

Mandelli

DeArmond

et al. 2014

Brain

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Sporadic Creutzfeldt-Jakob disease is considered primarily a disease of grey matter, although the extent of white matter involvement has not been well described. We used diffusion tensor imaging to study the white matter in sporadic Creutzfeldt-Jakob disease compared to healthy control subjects and to correlated magnetic resonance imaging findings with histopathology. Twenty-six patients with sporadic Creutzfeldt-Jakob disease and nine age- and gender-matched healthy control subjects underwent volumetric T1-weighted and diffusion tensor imaging. Six patients had post-mortem brain analysis available for assessment of neuropathological findings associated with prion disease. Parcellation of the subcortical white matter was performed on 3D T1-weighted volumes using Freesurfer. Diffusion tensor imaging maps were calculated and transformed to the 3D-T1 space; the average value for each diffusion metric was calculated in the total white matter and in regional volumes of interest. Tract-based spatial statistics analysis was also performed to investigate the deeper white matter tracts. There was a significant reduction of mean (P = 0.002), axial (P = 0.0003) and radial (P = 0.0134) diffusivities in the total white matter in sporadic Creutzfeldt-Jakob disease. Mean diffusivity was significantly lower in most white matter volumes of interest (P < 0.05, corrected for multiple comparisons), with a generally symmetric pattern of involvement in sporadic Creutzfeldt-Jakob disease. Mean diffusivity reduction reflected concomitant decrease of both axial and radial diffusivity, without appreciable changes in white matter anisotropy. Tract-based spatial statistics analysis showed significant reductions of mean diffusivity within the white matter of patients with sporadic Creutzfeldt-Jakob disease, mainly in the left hemisphere, with a strong trend (P = 0.06) towards reduced mean diffusivity in most of the white matter bilaterally. In contrast, by visual assessment there was no white matter abnormality either on T2-weighted or diffusion-weighted images. Widespread reduction in white matter mean diffusivity, however, was apparent visibly on the quantitative attenuation coefficient maps compared to healthy control subjects. Neuropathological analysis showed diffuse astrocytic gliosis and activated microglia in the white matter, rare prion deposition and subtle subcortical microvacuolization, and patchy foci of demyelination with no evident white matter axonal degeneration. Decreased mean diffusivity on attenuation coefficient maps might be associated with astrocytic gliosis. We show for the first time significant global reduced mean diffusivity within the white matter in sporadic Creutzfeldt-Jakob disease, suggesting possible primary involvement of the white matter, rather than changes secondary to neuronal degeneration/loss.

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Section: Discussioncontrasting

confidence: 99%

White matter involvement in sporadic Creutzfeldt-Jakob disease

Caverzasi

Mandelli

DeArmond

et al. 2014

Brain

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“…[5][6][7] Disease penetrance in mutation heterozygotes appears to reach 80%-100% by age 80. 8,9 Reported estimates of the mean age of onset in individuals with this mutation range from 53 7 to 63, 10 and the mean survival after disease onset is 7 months. 11 Three reports 12,13 (see also Web Resources) have claimed statistical evidence that this genetic prion disease exhibits anticipation, a phenomenon in which successive generations exhibit progressively earlier disease onset or more severe presentation.…”

Section: Introductionmentioning

confidence: 99%

Ascertainment Bias Causes False Signal of Anticipation in Genetic Prion Disease

Minikel

Zerr

Collins

et al. 2014

The American Journal of Human Genetics

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Anticipation is the phenomenon whereby age of onset in genetic disease decreases in successive generations. Three independent reports have claimed anticipation in Creutzfeldt-Jakob disease (CJD) caused by the c.598G > A mutation in PRNP encoding a p.Glu200Lys (E200K) substitution in the prion protein. If confirmed, this finding would carry clear implications for genetic counseling. We analyzed pedigrees with this mutation from four prion centers worldwide (n = 217 individuals with the mutation) to analyze age of onset and death in affected and censored individuals. We show through simulation that selective ascertainment of individuals whose onset falls within the historical window since the mutation's 1989 discovery is sufficient to create robust false signals both of anticipation and of heritability of age of onset. In our data set, the number of years of anticipation observed depends upon how strictly the data are limited by the ascertainment window. Among individuals whose disease was directly observed at a study center, a 28-year difference between parent and child age of onset is observed (p = 0.002), but including individuals ascertained retrospectively through family history reduces this figure to 7 years (p = 0.005). Applying survival analysis to the most thoroughly ascertained subset of data eliminates the signal of anticipation. Moreover, even non-CJD deaths exhibit 16 years anticipation (p = 0.002), indicating that ascertainment bias can entirely explain observed anticipation. We suggest that reports of anticipation in genetic prion disease are driven entirely by ascertainment bias. Guidelines for future studies claiming statistical evidence for anticipation are suggested.

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“…9,10 The next most common mutation is V210I (isoleucine [I] in lieu of valine [V]), but this condition does not have a clear pattern. 10,11 To date, approximately 30 mutations associated with inherited prion disease have been identified in a diverse group of populations, and it is likely that, with increased awareness and improved molecular tools, more mutations will be observed. 6,10 …”

Section: What Are Some Forms Of Familial Cjd?mentioning

confidence: 99%

“…10,11 To date, approximately 30 mutations associated with inherited prion disease have been identified in a diverse group of populations, and it is likely that, with increased awareness and improved molecular tools, more mutations will be observed. 6,10 …”

Section: What Are Some Forms Of Familial Cjd?mentioning

confidence: 99%