Brain Advance Access published online on March 24, 2009
Brain, doi:10.1093/brain/awp064
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Thalamo-striatal diffusion reductions precede disease onset in prion mutation carriers
1 Department of Psychiatry, Mount Sinai School of Medicine, New York, USA 2 Department of Neurology, Hadassah University Hospital, Jerusalem, Israel 3 Department of Neurology, Sheba Medical Center, Tel Hashomer, Israel 4 Department of Radiology, North Shore University Hospital, Manhasset, New York, USA 5 Department of Radiology, Sheba Medical Center, Tel Hashomer, Israel 6 Department of Neurology, Barzilai Medical Center, Ashkelon, Israel 7 Sieratzky Chair of Neurology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 8 Department of Radiology, Mount Sinai School of Medicine, New York, USA
Correspondence to:
Isak Prohovnik, MIRECC, Bronx VAMC, 130 W Kingsbridge Road, NY 10468, USA E-mail: isak.prohovnik{at}mssm.edu
Human prion diseases present substantial scientific and public health challenges. They are unique in being sporadic, infectious and inherited, and their pathogen is distinct from all other pathogens in lacking nucleic acids. Despite progress in understanding the molecular structure of prions, their initial cerebral pathophysiology and the loci of cerebral injury are poorly understood. As part of a large prospective study, we analysed early diffusion MRI scans of 14 patients with the E200K genetic form of Creutzfeldt–Jakob Disease, 20 healthy carriers of this mutation that causes the disease and 20 controls without the mutation from the same families. Cerebral diffusion was quantified by the Apparent Diffusion Coefficient, and analysed by voxel-wise statistical parametric mapping technique. Compared to the mutation-negative controls, diffusion was significantly reduced in a thalamic-striatal network, comprising the putamen and mediodorsal, ventrolateral and pulvinar thalamic nuclei, in both the patients and the healthy mutation carriers. With disease onset, these diffusion reductions intensified, but did not spread to other areas. The caudate nucleus was reduced only after symptomatic onset. These findings indicate that cerebral diffusion reductions can be detected early in the course of Creutzfeldt–Jakob Disease, and years before symptomatic onset in mutation carriers, in a distinct subcortical network. We suggest that this network is centrally involved in the pathogenesis of Creutzfeldt–Jakob Disease, and its anatomical connections are sufficient to account for the common symptoms of this disease. Further, we suggest that the abnormalities in healthy mutation-carrying subjects may reflect the accumulation of abnormal prion protein and/or associated vacuolation at this time, temporally close to disease onset.
Key Words: prion; MRI; Creutzfeldt–Jakob disease; E200K; diffusion
Abbreviations: ADC, apparent diffusion coefficient; BSE, bovine spongiform encephalopathy; CJD, Creutzfeldt–Jakob disease; DWI, diffusion weighted imaging; fCJD, familial CJD; sCJD, sporadic CJD; vCJD, variant CJD
Received November 4, 2008. Revised February 12, 2009. Accepted February 16, 2009.