<h3>Objective:</h3> Myotonic dystrophies (DM) are neuromuscular conditions that cause widespread effects throughout the body. New therapeutics are being developed that attack the RNA mechanism underlying DM. Here, we address the urgent need of identifying DM neuroimaging biomarkers that can be used in trials. <h3>Background:</h3> DTI shows decreased white matter connectivity in DM patients and MRI reveals decreased parietal, frontal, and temporal resting state metabolism. Additionally, DTI studies of DM have shown that the white matter abnormalities are diffuse as opposed to multi-focal. <h3>Design/Methods:</h3> Extracting important features from neuroimaging data is challenging due to the high feature dimension and low sample-size problem. This work utilizes a sparse matrix decomposition method and a manifold regularization approach to identify the most discriminative features and improves spatial and temporal resolutions of neuroimaging data. To this end, neuroimaging data of 46 DM1, 17 DM2 patients and 92 healthy controls were analyzed using a ten-fold-cross-validation technique. In addition to neuroimaging data, additional clinical assessments including Quebec Muscular Impairment Rating Scale and Quebec Daytime Sleepiness Scale were calculated for DM patients. Wavelet approximation and detailed coefficients were calculated to consider both long term and short-term fluctuations caused by the disease process. <h3>Results:</h3> Normalized sub-band energy calculated based on wavelet coefficients can characterize DM1 and DM2. Patients with DM1 have widespread white matter volume reductions that are correlated with distal to proximal progression of the muscular involvement in DM1. A significant difference can be seen between DM1 and healthy controls in terms of executive function, motor speed, processing speed, and memory. <h3>Conclusions:</h3> The proposed method can potentially be used to develop and validate key predictors of DM type, severity, and progression of DM central nervous system abnormalities using brain morphometry. Identified features can also potentially provide multidisciplinary biomarkers that help unravel our understanding of fatigue, sleepiness, and attention. <b>Disclosure:</b> Ms. Kamali has nothing to disclose. Dr. Day has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Affinia Therapeutics. Dr. Day has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis Gene Therapy. Dr. Day has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Day has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche/Genentech. Dr. Day has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sarepta. Dr. Day has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Scholar Rock. Dr. Day has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Avidity. Dr. Day has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Muscular Dystrophy Association. The institution of Dr. Day has received research support from Audentes. The institution of Dr. Day has received research support from Novartis Gene Therapy. The institution of Dr. Day has received research support from Biogen. The institution of Dr. Day has received research support from Cytokinetics. The institution of Dr. Day has received research support from Roche/Genentech. The institution of Dr. Day has received research support from Sanofi/Genzyme. The institution of Dr. Day has received research support from Sarepta. The institution of Dr. Day has received research support from Scholar Rock. Dr. Day has received intellectual property interests from a discovery or technology relating to health care. Dr. Sampson has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Dyne Therapeutics. Dr. Sampson has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Expansion Therapeutics. Dr. Sampson has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Viking Therapeutics. Dr. Sampson has received research support from Marigold Foundation. Dr. Sampson has a non-compensated relationship as a Scientific Advisory Committee with Myotonic Dystrophy Foundation that is relevant to AAN interests or activities. Dr. Murad has received personal compensation for serving as an employee of UCB. Dr. Murad has received personal compensation for serving as an employee of Skyhawk Therapeutics. Dr. Murad has stock in Forma Therapeutics. Dr. Murad has stock in Skyhawk Therapeutics. Mr. Chaufty has received personal compensation for serving as an employee of UCB. Mr. Chaufty has stock in UCB. Mr. Chaufty has received intellectual property interests from a discovery or technology relating to health care.