The overall goal of this project is to map the distribution of PrPCJD in the human brain in 20 cases of sporadic Creutzfeldt-Jakob disease (CJD) and 20 cases of familial CJD. The great majority, if not all, of the familial CJD cases will be from the Libyan Jew population in which a prion protein gene codon 200 mutation has been genetically linked to dominantly inherited CJD. The histoblot technique will be adapted to large coronal sections of brain to generate comprehensive and detailed maps of the location of PrPCJD deposition and to estimate its regional brain concentration. The extraordinarily high sensitivity and specificity of the histoblot method has proven invaluable for studies of PrPSc infectious scrapie of rodents. New testable hypotheses regarding both the etiology and pathogenesis prion diseases have emerged. The two most relevant and important are: 1) That the pattern of PrPsc accumulation in the brain is the most fundamental characteristic which defines the different cliniconeuropathological syndromes of scrapie arguing that each prion isolate (""""""""strain"""""""") targets different neuron populations for he synthesis of PrPsc and raises the possibility that the information encoded in PrPsc, which determines the characteristics of each prion isolated, are determined by neurons. 2) The neuropathological changes in scrapie colocalize with PrPsc in support of the hypothesis that PrPsc deposition in the brain causes the clinically relevant neuropathology. Because of the great success of histoblot analysis to understanding scrapie, we now want to apply the technique to cases of CJD because there are many issues of human prion diseases which cannot be resolved by studying infectious scrapie in animals. Human CJD is more complex because most of the cases are classified as sporadic, because there are multiple mutations of the prion protein gene linked to different familial prion syndromes and because proven infectious forms are rare. Both the clinical course and severity of neuropathological features of CJD are quite variable. Some objectives of this study are to test whether PrPCJD is only found in prion diseases, whether PrPCJK and neuropathology colocalize, whether their is a diversity of cliniconeuropathological CJD subtypes, and to test whether the neuroanatomic pattern of PrPCJD deposition distinguishes CJD subtypes better than clinical features or the distribution of neuropathology.
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