Early Diagnosis of Human Prion Disease

Investigator: Michael Geschwind, MD, PhD
Sponsor: NIH National Institute on Aging

Location(s): United States


Human prion diseases, such as Jakob-Creutzfeldt disease (CJD), are difficult to diagnose and are of increasing public health concern due to the risk of transmission. Our dementia program is a major referral center for prion diseases in the United States with 952 potential CJD referrals over the past six years. We also are conducting the first ever US sporadic CJD (sCJD) treatment trial, sponsored by the NIH. Unfortunately, many cases of sCJD are misdiagnosed or are diagnosed too late in the course for any future potential treatment to be effective. We, and others, have shown that brain MRI has very high sensitivity and specificity for sCJD diagnosis. Unfortunately, the most widely used diagnostic criteria for sCJD, Revised 1998 WHO Criteria, are problematic for several reasons: 1. they require symptoms that often do not occur until late in the disease course; 2. they do not use MRI; 3. they use a surrogate biomarker in the spinal fluid, the 14-3-3 protein, which we have found lacks sensitivity and specificity; and 4. they rely on certain electroencephalography (EEG) findings that have low sensitivity, particularly earlier in the disease. We will prospectively evaluate 100 patients with sCJD, 20 patients with symptomatic gCJD, and 40 patients with asymptomatic (presymptomatic gCJD) and 80 with other forms of rapidly progressive dementia (RPDs) over five years. We will conduct comprehensive assessments, including clinical, behavioral, spinal fluid surrogate marker, EEG, and MRI analyses. We will evaluate our gCJD at an age close to their predicted age of onset which will help us to identify the earliest signs of prion disease. A major focus will be to identify specific regions and patterns of abnormality on FLAIR and DTI MRI that can differentiate sCJD from other RPDs. Through this prospectively acquired data, we will devise a state of the art diagnostic scheme, using contemporary statistical classification techniques and logistic regression, for early diagnosis of sCJD. PUBLIC HEALTH RELEVANCE: Prion diseases are uniformly fatal, transmissible neurodegenerative diseases. At least one form can be transmitted by blood transfusion, and prions have now been found in several other tissues outside of the nervous system, including muscle, lymphoreticular tissues, and olfactory epithelia. Through earlier diagnosis, patients may be spared unnecessary and time-consuming diagnostic procedures and have better chance of responding to potential treatments, and the risk of transmission can be greatly reduced.