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

Public Health Relevance

Prion diseases, such as CJD, are uniformly fatal, transmissible brain diseases;although rare, recent data has shown that other brain diseases, such as Alzheimer's disease, Parkinson's disease and Frontotemporal dementia, might spread in the brain through a similar prion-like mechanism. This project will follow patients with CJD over time to determine factors that assess where a patient is in the course of their illness as wel as predict their survival. This data is essential for proper development of treatment trials for CJD, and possibly other conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
2R01AG031189-06
Application #
8579837
Study Section
Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Mackiewicz, Miroslaw
Project Start
2007-12-01
Project End
2018-06-30
Budget Start
2013-08-01
Budget End
2014-06-30
Support Year
6
Fiscal Year
2013
Total Cost
$627,594
Indirect Cost
$217,595
Name
University of California San Francisco
Department
Neurology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Graus, Francesc; Titulaer, Maarten J; Balu, Ramani et al. (2016) A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 15:391-404
Geschwind, Michael D (2016) Rapidly Progressive Dementia. Continuum (Minneap Minn) 22:510-37
Coulthart, Michael B; Geschwind, Michael D; Qureshi, Shireen et al. (2016) A case cluster of variant Creutzfeldt-Jakob disease linked to the Kingdom of Saudi Arabia. Brain 139:2609-2616
Savard, Martin; Irani, Sarosh R; Guillemette, Annie et al. (2016) Creutzfeldt-Jakob Disease-Like Periodic Sharp Wave Complexes in Voltage-Gated Potassium Channel-Complex Antibodies Encephalitis: A Case Report. J Clin Neurophysiol 33:e1-4
Geschwind, Michael D; Paras, Nick (2016) Deutetrabenazine for Treatment of Chorea in Huntington Disease. JAMA 316:33-5
Kim, Mee-Ohk; Geschwind, Michael D (2015) Clinical update of Jakob-Creutzfeldt disease. Curr Opin Neurol 28:302-10
Geschwind, Michael D (2015) Prion Diseases. Continuum (Minneap Minn) 21:1612-38
Ng, Adeline S L; Kramer, Joel; Centurion, Alejandro et al. (2015) Clinico-pathological correlation in adenylate kinase 5 autoimmune limbic encephalitis. J Neuroimmunol 287:31-5
Rosenbloom, Michael H; Tartaglia, M Carmela; Forner, Sven A et al. (2015) Metabolic disorders with clinical and radiologic features of sporadic Creutzfeldt-Jakob disease. Neurol Clin Pract 5:108-115
Forner, Sven A; Takada, Leonel T; Bettcher, Brianne M et al. (2015) Comparing CSF biomarkers and brain MRI in the diagnosis of sporadic Creutzfeldt-Jakob disease. Neurol Clin Pract 5:116-125

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