Michael David Geschwind - US grants

DESCRIPTION (provided by applicant): Creutzfeldt-Jakob disease (CJD)is a rapidly progressive, universally fatal, and transmissible neurodegenerative disease that imposes a terrible burden on patients and their families. The recent discovery that quinacrine may be a potential therapy for CJD could have enormous implications for patients. Unfortunately, patients are usually diagnosed in advanced stages of the disease - a time when available treatments may be ineffective. This delayed diagnosis is in part because current clinical criteria for sporadic CJD (sCJD) are based on a constellation of symptoms that often occur only late in a patient's course. Recently, neuroimaging has shown potential to improve the diagnosis of sCJD. Additionally, an elevated level of the protein 14-3-3 in the cerebrospinal fluid (CSF) has been touted as a sensitive and specific biomarker for sCJD and has recently been added to the diagnostic criteria for sCJD. Yet, no systematic study has been undertaken to identify the sensitivity and specificity of these two types of biomarkers in pathologically proven sCJD versus non-prion rapidly progressive dementias. The research goals of this proposal focus on identifying better ways for early diagnosis of CJD through a systematic analysis of clinical and imaging findings. The specific aims of this research will be as follows: 1 . To determine the sensitivity and specificity of diffusion-weighted imaging (DWI) sequence abnormalities in sporadic CJD, and 2. To determine the sensitivity and specificity of the CSF 14-3-3 protein as a marker for sporadic CJD. This research should provide new information on the early features of sCJD and thus facilitate diagnosis. In addition, this proposal will combine didactic teaching, mentoring, and clinical research experience to build upon Dr. Geschwind's training in behavioral neurology and neuroscience, thereby helping him to design and implement future clinical treatment studies for human prion disease and other dementias.

[unreadable] DESCRIPTION (provided by applicant): 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. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Human prion diseases, such as Jakob-Creutzfeldt disease (CJD) are devastating neurodegenerative diseases that currently are untreatable. As treatment trials are underway and planned, we need to have improved methods for predicting the course of progression of an individual with CJD. Our CJD and rapidly progressive dementia (RPD) clinical research program is a major referral center for prion diseases in the United States with about 750 RPD/CJD referrals over the past four years. Through our past R01, Early diagnosis of human prion disease, we acquired data that led to improved diagnosis of CJD. We had several important clinical findings regarding CJD, including: 1) the most widely used biomarker for sCJD diagnosis, CSF 14-3-3 protein, has relatively low sensitivity and specificity, despite being in several diagnostic criteria; 2) DWI brain MRI, showing restricted diffusion in gray matter, is the single best diagnostic test for sCJD, although CSF biomarkers, such as total tau and neuron-specific enolase, sometimes are useful; 3) Diffusion does not continually become increasingly restricted in gray matter during the disease course, but eventually becomes less restricted; thus, diffusion is linearly downward in the earlier part of disease, but then moving upward (less restricted) in later stages, thus giving a U or even J shaped curve: this makes following restricted diffusion as an outcome marker problematic in treatment trials; 4) Certain areas of gray matter appear to be preferentially involved on MRI in sCJD, and they overlap with various functional connectivity networks identified by fMRI. It is not clear if prion disease spreads in the brain via functional and structural networks or through transmission to adjacent brain regions; 5) Although not previously reported, we found diffuse restricted diffusion in the white matter in sCJD and 6) the presence of certain clinical signs/symptoms in patients, such as cerebellar or visual symptoms, predict shorter survival. Most of these findings were based on cross-sectional assessment. For this current project, we will be following approximately 120 patients with CJD longitudinally, studying patients for at serial visits, between about 1-4 months after their initial visit. At each serial visit we will conduct a detailed assessment (neurological exam, neuropsychological testing, functional scores, various brain MRI metrics (discussed above), and CSF biomarkers). Through this prospectively acquired data of longitudinal assessment of CJD, we will develop an algorithm for disease staging (predicting the survival) and predicting progression of individual patients. This information will not only be helpful for prognosticating for patients and families, but also for development of treatment trials

Project Summary/Abstract The main goal of this project is to identify and develop biomarkers for treatment trials in presymptomatic genetic prion disease (PreSx gPrD). Most PrDs are potentially transmissible and rapidly progressive; all are fatal. As has been shown in a related disorder, Alzheimer?s disease, it is critical to develop early detection methods and biomarkers so that potential treatments can be given in early pre-presymptomatic (pre-clinical) phases when they have the best chance of working. Approximately 15% of human prion diseases (PrDs) are genetic, caused by mutations in the prion protein gene, PRNP. Because a simple genetic blood test can identify PRNP mutation carriers from families with gPrD, we can identify those with mutations prior to their developing symptoms (presymptomatic; PreSx); this group is an ideal target for therapeutic trials, to delay or even prevent, clinical onset. Similar methods are being used in autosomal dominant forms of genetic Alzheimer?s disease, such as with the Alzheimer?s Disease Prevention Initiative (API) and the Dominantly Inherited Alzheimer?s Disease Network (DIAN) studies. Therapies for PrD are currently under development, but to prepare for these trials it is necessary to identify markers sensitive to biological changes in pre-clinical stages, when symptoms have not yet developed. Our preliminary data suggest that such biological changes (biomarkers) can be measured in PreSx gPrDs and include brain volume, MRI mean diffusivity, cognitive & quantified motor assessments, retinal layer thickness and possibly CSF and plasma proteins. Over five years, we will recruit ~80 PreSx gPrD mutation carriers and ~40 age & gender-matched controls without PRNP mutations (non-carriers) from gPrD families. Subjects will have serial annual visits, for at least three years, that include: neurological exam, neuropsychological testing, functional scores, blood and CSF collection, olfactory mucosal swabbings, skin biopsies, brain MRI, and optical coherence tomography. We will establish rates of change of various biomarkers in PreSx mutation carriers vs. controls, to determine the best outcome measures for PreSx gPrD treatment trials. Our aims are: Aim 1. Characterize the rates of biomarker change in PreSx Slow-gPrD. We hypothesize that, compared with controls, PreSx Slow-gPrD will show greater rates of: A) cortical MD elevation, B) decline on quantitative motor testing, & C) decline in processing speed. Aim 2. Characterize the rates of biomarker change in PreSx Fast-gPrD. We hypothesize that, compared with controls, PreSx Fast-gPrD will show great rates of: A) deep nuclei (putaminal) MD reduction, B) Greater rates of decline on quantified motor testing, & C) decline in processing speed Exploratory Aims. A) We hypothesize that subjects with positive RT-QuIC assays will have more rapid imaging and clinical changes than RT-QuIC negative subjects. B) Fast and Slow PreSx gPrD will have greater rates of 1. elevation of certain CSF & serum biomarkers, 2. cognitive & motor decline, and 3. cortical volume loss, whereas only PreSx Slow gPrD will have a greater rate of decline in INL thickness, than controls.