Brain Structure and Clinical Endpoints in Myotonic Dystrophy Type 2-

Project Summary This administrative supplement application seeks funding to expand the research objectives for the current award, entitled “Brain Structure and Clinical Endpoint in Myotonic Dystrophy Type 2” (K23 NS125110). The parent K23 award aims to evaluate the relationship between brain structure and function on cognition and

motor performance in adults with myotonic dystrophy type 2 (DM2). The proposed supplement will support a DM2 biofluid repository initiative and collection of additional Alzheimer’s Disease (AD) biomarkers to sufficiently address potential confounders from age-related comorbidities. DM2, a multisystemic disorder, results from a

CCTG repeat expansion in the CNBP gene, where the RNA gain-of-function is the main disease mechanism. Although muscle weakness is the key feature in DM2, almost 70% of patients report that impaired cognition is one of the most disabling symptoms, adversely affecting their quality of life. A sparse literature describes

cognitive deficits in executive function, attention, verbal memory, and processing speed in those with DM2. Yet the mechanisms that lead to cognitive impairment in DM2 are poorly understood as brain imaging studies are very limited. Nevertheless, most studies suggest that, compared to controls, DM2 primarily affects white matter

(WM), with reduced cerebral WM volume and impaired WM integrity derived from diffusion tensor imaging (DTI). Emerging evidence has identified tau mis-splicing and tangle pathology in the brains of those with DM2, which has prompted interest in elucidating the role of tau in DM2-related cognitive impairment. One method of

investigating central nervous system (CNS) mechanisms is to evaluate fluid biomarkers that reflect brain pathology. But no studies to date have meticulously evaluated brain structure and their relationships to clinical endpoints and biomarkers of CNS pathology in DM2. In Aim 1, I will evaluate brain morphometry and DTI

measures of WM integrity, including fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD) in 40 adults with DM2 vs. 40 age and sex-matched control. In Aim 2, I will determine relationships between measures of WM integrity (FA and RD) and clinical (cognitive and motor) endpoints. In Aim 3, I will conduct a

pilot proof-of-concept study to characterize tau profiles in the plasma and CSF of DM2 and associate these findings with measures of brain structure and cognitive endpoints. The original study did not adequately address potential confounders from age-related comorbidities, i.e., preclinical AD. The requested funds will

enable me to examine plasma β-amyloid biomarkers (Aβ42, Aβ40) to help mitigate this concern. The supplement will also establish a DM2 biofluid repository at the Biospecimen Exchange for Neurological Disorders (BioSEND). By utilizing BioSEND’s infrastructure, this initiative will ensure the long-term preservation

of samples, foster collaborations, and facilitate access for the broader research community. Such samples will add neuromuscular disease to the BioSEND’s repository, and accelerate advancements in DM2 research.