Thalamo-striatal diffusion reductions precede disease onset in prion mutation carriers

Area of Science:

• Neuroscience
• Genetics
• Radiology

Background:

• Human prion diseases, including genetic Creutzfeldt-Jakob Disease (CJD), pose significant public health challenges.
• The pathophysiology and early cerebral injury in CJD remain poorly understood.
• Prions are unique infectious agents lacking nucleic acids.

Purpose of the Study:

• To investigate early cerebral pathophysiology in the E200K genetic form of CJD using diffusion MRI.
• To identify specific brain regions affected by diffusion changes in mutation carriers before and after symptomatic onset.

Main Methods:

• Analysis of early diffusion MRI scans from 14 E200K CJD patients, 20 healthy mutation carriers, and 20 controls.
• Quantification of cerebral diffusion using the Apparent Diffusion Coefficient (ADC).
• Voxel-wise statistical parametric mapping to analyze diffusion changes.

Main Results:

• Significantly reduced diffusion was observed in a thalamic-striatal network (putamen, mediodorsal, ventrolateral, and pulvinar thalamic nuclei) in both CJD patients and healthy carriers compared to controls.
• Diffusion reductions intensified with disease onset but did not spread to other areas.
• The caudate nucleus showed reduced diffusion only after symptomatic onset.

Conclusions:

• Cerebral diffusion reductions are detectable years before symptomatic onset in E200K CJD mutation carriers.
• The identified thalamic-striatal network is likely central to CJD pathogenesis.
• Early diffusion abnormalities may reflect prion protein accumulation or vacuolation near disease onset.