# Brain Structure and Clinical Endpoints in Myotonic Dystrophy Type 2

> **NIH NIH K23** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2022 · $178,572

## Abstract

Project Summary
The overall goals of this K23 application are to evaluate the relationship between brain structure and function
on cognition and motor performance in myotonic dystrophy type 2 (DM2), and thereby contribute to the
Candidate’s preparation to independently lead future research elucidating the neurobiology of DM2. Although
muscle weakness is the key symptom in DM2, almost 70% of patients report that impaired cognition is among
the most disabling symptoms, and deeply affects their quality of life. DM2, a multifaceted genetic disorder,
results from a CCTG repeat expansion in the cellular nucleic acid binding protein (CNBP) gene, where the
RNA gain-of-function is the main disease mechanism. Although DM2 has several distinctions from myotonic
dystrophy type 1 (DM1), they share some genetic and clinical similarities, e.g. substantial cognitive symptoms
and muscle weakness. While studies of brain imaging in DM1 have increased over the past decade, relatively
little is known about how DM2 affects brain structure and function as brain imaging studies in DM2 are
extremely limited. Results of these studies have had conflicting results because of small sample sizes, lack of
quantitative analyses, and discrepancy between cognitive measures. However, most findings suggest that,
compared to controls, cerebral white matter (WM) is primarily affected in DM2, with reduced in WM volume and
abnormal WM integrity derived from diffusion tensor imaging (DTI). Emerging evidence has identified tau mis-
splicing and tangle pathology in DM2, which has prompted interest in elucidating the role of tau in DM2-related
cognitive impairment. This possibility is underscored by recent studies of relationships between WM integrity
and cortical tau deposition and cerebrospinal fluid (CSF) tau in Alzheimer’s Disease (AD) and Alzheimer’s
Disease Related Dementias (ADRD). Nevertheless, no study to date has evaluated the role of tau in DM2. In
sum, despite clear cognitive symptoms that suggest CNS involvement, no studies have meticulously evaluated
brain structure and fluid biomarkers of CNS pathology and their relationships to cognitive and motor measures
in DM2. In Aim 1, I will evaluate brain morphometry and DTI measures of white matter integrity, including
fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity between 40 adults with DM2 vs. 40 age-
and sex-matched control. In Aim 2, I will determine relationships of measures of white matter integrity (cerebral
FA and RD) with cognitive and motor endpoints. In Aim 3, I will conduct a pilot proof-of-concept study to
characterize tau profiles in the CSF and plasma of patients with DM2 and associate these findings with
measures of brain structure and cognitive endpoints. The proposed integrated research, mentorship, and
didactic training, combined with the outstanding research environment at Wake Forest University Health
Sciences, will foster my long-term career goals to become an independent investigato...

## Key facts

- **NIH application ID:** 10525819
- **Project number:** 1K23NS125110-01A1
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Araya Puwanant
- **Activity code:** K23 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $178,572
- **Award type:** 1
- **Project period:** 2022-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10525819

## Citation

> US National Institutes of Health, RePORTER application 10525819, Brain Structure and Clinical Endpoints in Myotonic Dystrophy Type 2 (1K23NS125110-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10525819. Licensed CC0.

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