The long-term goal of this project is to establish non-invasive magnetic resonance spectroscopy (MRS) biomarkers that are sensitive to progressive neurodegeneration and its reversal. To accomplish this with high sensitivity and specificity, high field scanners (3 tesla and higher) are utilized. The focus of the application in this first cycle is hereditary spinocerebellar ataxias (SCAs), which provide the ideal neurodegenerative disease model because their diagnoses can be genetically confirmed, the patient populations are well characterized and they offer transgenic mouse models that faithfully reproduce the pathology and phenotype of the human disease enabling translation of findings between pre-clinical and clinical trials. Furthermore, various treatments are currently entering the pipeline for SCAs and their testing in clinical trials may benefit immensely from objective surrogate markers. In this respect, a recently established SCA Consortium will provide the opportunity to utilize the technology in clinical trials because high field scanners are available at each participating site. Recent work demonstrated that 1) high fields enable acquisition of cerebellar neurochemical profiles from patients with SCAs and transgenic mouse models of SCA type 1 (SCA1) with excellent reproducibility;2) SCA1, SCA2 and SCA6 can be distinguished by neurochemical signatures;3) alterations in MRS biomarkers correlate cross-sectionally with disease severity in patients with SCA1 and longitudinally with pathology in SCA1 mice and 4) alterations in MRS biomarkers are partially-to-completely reversed in a conditional SCA1 mouse model upon suppression of transgene expression. Studies are proposed to further validate proton MRS (1H MRS) as an outcome measure in pre-clinical and clinical trials.
The specific aims are:
Aim # 1) To determine if disease progression can be monitored by 1H MRS by measuring cerebellar and brainstem neurochemical profiles longitudinally over 5 years in early- moderate stage patients with SCA1.
Aim # 2) To identify the 1H MRS biomarkers that reflect disease severity in patients with SCA2, SCA3 and SCA6 and to determine if MRS biomarkers are disease specific by a cross- sectional comparison of neurochemical differences in early-moderate stage patients with SCA1, SCA2, SCA3 and SCA6 relative to healthy controls.
Aim # 3) To determine if neurochemical levels measured by 1H MRS accurately reflect the extent of recovery from neurodegeneration following complete and partial suppression of transgene expression by evaluating neurochemical levels, mRNA levels of ataxin-1 and pathology simultaneously in the cerebella of conditional SCA1 mice.

Public Health Relevance

This work intends to establish non-invasive, quantitative imaging measures of biochemical and cellular alterations in neurodegenerative diseases. Such measures can eventually be used in the clinic for early disease detection, which will facilitate application of treatments to delay the onset of these diseases, and for monitoring disease progression and treatment response. Successful application of such treatments is expected to reduce the burden caused by these diseases on individuals, their families and society.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS070815-03
Application #
8324308
Study Section
Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Gwinn, Katrina
Project Start
2010-09-15
Project End
2015-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
3
Fiscal Year
2012
Total Cost
$324,146
Indirect Cost
$104,843
Name
University of Minnesota Twin Cities
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Deelchand, Dinesh K; Adanyeguh, Isaac M; Emir, Uzay E et al. (2015) Two-site reproducibility of cerebellar and brainstem neurochemical profiles with short-echo, single-voxel MRS at 3T. Magn Reson Med 73:1718-25
Oz, Gulin; Tkac, Ivan; Ugurbil, Kamil (2013) Animal models and high field imaging and spectroscopy. Dialogues Clin Neurosci 15:263-78