Diffusion Tensor Imaging and Hyposmia as a Biomarker

Diffusion Tensor Imaging and Hyposmia as a Biomarker for Parkinson’s Disease in REM Sleep Behavior Disorder Phillip Setran MD, Matthew Brodsky MD, David Lahna BA, John Grinstead Ph. D, David Pettersson MD, and Jeffrey M. Pollock MD Departments of Neurology and Radiology, and The Advanced Imaging Research Center Oregon Health & Science University and Northwest PADRECC Control #429, Poster #EP-17

DISCLOSURES/ACKNOWLEDGEMENTS: This project was supported by a pilot grant from the OHSU Advanced Imaging Research Center. None of the authors have additional financial support or incentives to disclose.

PURPOSE • Parkinson's disease (PD) is characterized by a progressive neurodegenerative process that begins many years prior to the onset of specific signs and symptoms that are used to make the diagnosis. • Often, by the time a diagnosis is rendered, it is often too late to effectively intervene with a neuroprotective or neurorestorative treatment. • The purpose of this study was to evaluate the effectiveness of Fractional Anisotropic (FA) analysis and the University of Pennsylvania Smell Identification Test (UPSIT) in detecting early PD in non-symptomatic patients with REM sleep behavior disorder (RBD).

MATERIALS & METHODS • RBD subjects were recruited from community physicians. • PD subjects were recruited from the OHSU clinic. • Control subjects were recruited from the community. • RBD subjects had polysomnography to confirm their diagnosis using the International Classification of Sleep Disorders (ICSD) and were also administered the UPSIT. • All subjects were classified using the Unified Parkinson's Disease Rating Scale (UPDRS).

DEFINITIONS • Fractional Anisotropy (FA): a scalar value between zero and one used to describe the anisotropy of a diffusion process. A value of zero indicates that diffusion is isotropic i. e. it is unrestricted (or equally restricted) in all directions. A value of one indicates that diffusion occurs only along one axis (anisotropy) and is otherwise fully restricted. • REM sleep behavior disorder (RBD): a parasomnia (sleep disorder) in which the normal atonia (muscle paralysis) present during rapid eye movement (REM) sleep is lost and the patient is able to act out their dreams, sometimes resulting in injury to the patient and/or their sleeping partner.

DEFINITIONS • University of Pennsylvania Smell Identification Test (UPSIT): a test designed to quantify an individual’s ability to identify various smells as a marker for olfactory system function. It is considered the gold standard due to its reliability and practicality, and is often used as an aid in the diagnosis of neurologic disorders such as Parkinson’s and Alzheimer’s. • Unified Parkinson’s Disease Rating Scale (UPDRS): a five-part evaluation used to more objectively measure the longitudinal progression of Parkinson’s disease. In 2007, the Movement Disorder Society (MDS) released an updated version, aptly named the MDS-UPDRS, which better organized the various subscales used in the rating system.

MATERIALS & METHODS • A total of 3 PD subjects, 3 RBD subjects, and 3 controls were enrolled. • The average PD subject symptom onset was 9 – 26 months (UPDRS=22, range 12 -34; MDS-UPDRS=12, range 6 -19). • RBD subjects were without evidence of parkinsonism at the time of enrollment (UPDRS scores ranging 1 -3 and MDS-UPDRS scores ranging 0 -1).

MATERIALS & METHODS • A midbrain DTI sequence was performed on all subjects with a 3 T MRI (TR=9500 ms; TE=95 ms; slice thickness 2. 0 mm; number of slices=72; 20 directions; FOV 240 mm; phase partial Fourier=6/8; b-value=1, 000 s/mm 2). • Three regions of interest (ROI) were created by dividing the substantia nigra pars compacta (SNc) into thirds at the level just below the red nucleus by two blinded neuroradiologists (ROI 1=medial third; ROI 2=middle third; ROI 3=lateral third). FA mapping and analysis was performed by a blinded research assistant. ROI 1 ROI 2 ROI 3

RESULTS • The "ROI 2" (mid-portion of SNc) in PD subjects was significantly lower when compared to controls, as has been previously reported (1). • RBD subjects' mean changes in ROIs were not significant when compared to controls.

RESULTS • However, one RBD subject (#106) had significantly lower FA in all ROIs and significantly lower UPSIT (=11) versus controls. This subject developed signs and symptoms of PD at the 2 -year follow-up (UPDRS = 25, MDS-UPDRS = 13). RBD Subject 106 tensor ellipsoids texture diffusion map

CONCLUSIONS • This pilot study demonstrated changes in the mid-portion of the SNc in patients with early PD compared to age-matched controls based on fractional anisotropic analysis of diffusion tensor magnetic resonance imaging. • This may be consistent with degenerative changes in Nigrosome 1, the cabindin-poor region of the SNc situated in this same region where maximal cell loss has been reported in PD (2), and thus may be a potentially useful tool as an early imaging biomarker for PD. • Further, although mean changes in RBD subjects did not differ from controls, the one RBD subject with hyposmia and significantly reduced FA values on DTI phenoconverted to PD at a 2 year follow-up, thus demonstrating the potential utility of using these techniques for screening at-risk individuals for pre-motor Parkinson's disease.

REFERENCES 1. Vaillancourt et al Neurology 2009; 72: 1378 -84. 2. Damier et al, Brain 1999; 122: 1437 -1448.