Brain Structure and Clinical Endpoints in Myotonic Dystrophy Type 2 (BraCE-DM2)
Trial Snapshot
- Phase
- Not Applicable
- Status
- Enrolling By Invitation
- Enrollment
- 100
- Locations
- 1
- Primary Endpoint
- Measures of voxel-based brain morphometry
Study Overview
Brief Summary
Nearly two-third of patients with myotonic dystrophy type 2 (DM2) report that impaired cognition is among the most disabling symptoms and deeply affects their quality of life. Yet, relatively little is known about how DM2 affects brain structure and cognitive function as brain imaging studies in DM2 are extremely limited. This is a prospective, cross-sectional study of brain structure and function on cognitive and motor performance in patients with DM2 & DM1 compared to healthy controls. All participants will undergo magnetic resonance imaging (MRI) to evaluate brain structure and white matter integrity, a comprehensive battery of cognitive and motor measures, self-reported questionnaires, and blood collection for brain-based biomarker analysis. A subset of participants will undergo lumbar puncture for cerebrospinal fluid (CSF) collection for additional biomarker analysis and validation. This work is critical to inform the development of rigorous clinical trial designs and plan for a longitudinal study to evaluate MRI measures as imaging biomarkers of disease progression and therapeutic response in DM2 & DM1.
Detailed Description
Myotonic dystrophy type 2 (DM2), autosomal dominant muscular dystrophy, is characterized by late-onset proximal muscle weakness, myotonia, and multisystem features. Although muscle weakness is the key symptom, almost 70% of patients with DM2 report that impaired cognition is among the most disabling symptoms and affects their quality of life. This condition causes severe disability and impaired quality of life similar to those in myotonic dystrophy type 1 (DM1).Small literature describes cognitive deficits and cerebral white matter involvement in those with DM2, compared to controls. However, the mechanisms that lead to cognitive dysfunction are poorly understood.
As the momentum of therapeutic development is outpacing our understanding of the central nervous system (CNS) manifestations in myotonic dystrophy, there is an urgent need to identify measures of brain imaging, cognitive function, and biomarkers of CNS pathology that are disease-specific and clinically relevant, and establish relationships of these measures to inform future clinical trial designs in DM2. This study will carry out a comprehensive baseline characterization of 50 adults with DM2 and 50 age and gender-matched controls identified from clinical populations across the US and through the national myotonic dystrophy registry. A subset of DM1 cohort (n=20), aged over 40 years and without contraindications to MRI, will be invited to participate in the full study protocol similar to the DM2 group. All participants will undergo 3 Tesla (3T)-brain MRI to obtain voxel-based morphometry and diffusion tensor imaging (DTI) sequences, a comprehensive Clinical Assessment Battery (CAB) of cognitive and motor measures, patient-reported outcomes, and blood collection for analysis of CNS biomarkers at their baseline visits. A subset of 20 participants will undergo lumbar punctures to collect cerebrospinal fluid (CSF) specimens for additional biomarker analysis and validation. Measures of MRI, CAB, and fluid biomarkers will be compared between DM2, DM1 and controls.
Relationships between MRI measures, cognitive and motor endpoints, and biofluid (plasma and CSF) biomarkers will be analyzed within the DM2 & DM1 group. Validation of plasma and CSF biomarkers will also be determined.
Study Design
- Study Type
- Observational
- Observational Model
- Cohort
- Time Perspective
- Prospective
Eligibility Criteria
- Ages
- 30 Years to 65 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- •DM 2 Inclusion Criteria:
- •Age 30-65 years old
- •Diagnosis of DM1 or DM2 is based on genetic testing and/or clinical criteria. If the diagnosis is based on clinical criteria, positive DM2 genetic testing is required in first-degree relatives
- •Symptoms or clinical findings of proximal muscle weakness
- •Ambulate independently (a cane or walking stick is permitted)
- •Able to provide informed consent for participation in the study
- •DM1 Inclusion Criteria:
- •Only individuals who are 30-65 years old will be eligible to participate for the full study protocol
- •Diagnosis of adult-onset DM1 is based on genetic testing or clinical criteria. If the diagnosis is based on clinical criteria, positive DM1 genetic testing is required in first-degree relatives
- •The onset of first symptoms must be between the 2nd and 4th decades of life
- •Symptoms or clinical findings of distal muscle weakness and myotonia
- •Ambulate independently (a cane or walking stick is permitted)
- •Able to provide informed consent for participation in the study
Exclusion Criteria
- •Congenital or juvenile-onset DM1 (onset of first symptom < 20-year-old)
- •Individuals with a prior diagnosis of dementia, seizure, stroke, multiple sclerosis, Parkinson's Disease, or other neurodegenerative diseases
- •Individuals with active psychiatric illness or alcohol/substance abuse.
- •On medications with substantial sedative or cognitive side effects unless the doses have been stable for at least 3 months before the study visit.
- •Inability or unwillingness to give written informed consent.
- •DM 1 and 2 and Healthy Control (HC) Exclusion Criteria:
- •Individuals with a pacemaker, defibrillator, or metal implanted that is contraindicated for MRI
- •Individuals who are claustrophobic
- •Individuals with a prior diagnosis of dementia, seizure, stroke, multiple sclerosis, Parkinson's Disease, or other neurodegenerative diseases
- •Individuals with active psychiatric illness, alcohol or substance abuse, or dependence
- •Individuals with a pacemaker, defibrillator, or metal implanted that is contraindicated for MRI
- •Individuals who are claustrophobic
- •Major medical illness which would prevent safe testing of MRI or motor function.
- •On medications with substantial sedative or cognitive side effects unless the doses have been stable over the last 3 months before the study visit
- •pregnancy
- •Weight > 400 pounds as the participant could not be properly positioned on the MRI table
- •Inability or unwillingness to give written informed consent
- •For participants who undergo lumbar puncture procedure: Use of anti-platelet medications within 7 days, use of anticoagulants such as warfarin (Coumadin), history of a bleeding disorders, evidence of platelet count < 150,000 within the last 6 months, or have hardware (i.e., pins, screws, rods, etc.) in the lower back area
- •Healthy Control (HC) Inclusion Criteria:
- •Age 30-65 years
- •Ambulate independently
- •Able to provide informed consent for participation in the study
Arms & Interventions
Myotonic dystrophy types 1 and 2
Adults with myotonic dystrophy types 1 and 2 who meet all inclusion and exclusion criteria for the study.
To be assessed at the baseline visit: Medical history and a focused neurological examination, brain MRI, a comprehensive Clinical Assessment Battery (CAB) of cognitive and motor measures, self-reported questionnaires, strength and motor function evaluation, and blood drawn for biomarker analysis.
A subset of the participants who agree to have cerebrospinal fluid (CSF) collection for additional biomarker analysis will undergo lumbar puncture procedure.
Intervention: Non-interventional study (Other)
Controls
Healthy individuals who meet all inclusion and exclusion criteria for healthy controls.
To be assessed at the baseline visit: Medical history and a focused neurological examination, brain MRI, a comprehensive Clinical Assessment Battery (CAB) of cognitive and motor measures, self-reported questionnaires, strength and motor function evaluation, and blood drawn for biomarker analysis.
A subset of the participants who agree to have cerebrospinal fluid (CSF) collection for additional biomarker analysis will undergo lumbar puncture procedure.
Intervention: Non-interventional study (Other)
Outcomes
Primary Outcomes
Measures of voxel-based brain morphometry
Time Frame: Baseline
Measures of brain volume will be expressed as a ratio (0 to 1) to intracranial volume to create proportional values of brain volume.
Fractional Anisotropy (FA)
Time Frame: Baseline
FA is an index of non-uniform movement of water molecules ranging from 0 to 1. Higher values of FA indicate healthy, dense, and well-organized white matter fibers. Lower values of FA indicate less healthy white matter track.
Radial Diffusivity (RD)
Time Frame: Baseline
The value of apparent water diffusion coefficient in the direction perpendicular to the axonal fibers. The higher RD value indicates high dispersion of water and poorly-organized white matter fibers.
Axial Diffusivity (AD)
Time Frame: Baseline
The value of apparent water diffusion coefficient in the direction lying along with the axonal fibers. The higher AD value indicates greater extracellular water content consecutively to the impaired white-matter fibers health, and to alterations of axonal water content
Secondary Outcomes
- Trail Making Test Part B (TMT-B) for executive function domain(Baseline)
- NIH-TB: Processing Speed Domain Scores(Baseline)
- NIH-TB: Working Memory Domain Scores(Baseline)
- Patient-Reported Outcomes Measurement Information System (PROMIS) Global-10(Baseline)
- Short-Form Health Survey (SF-36) Scores(Baseline)
- Brief Pain Inventory (BPI) - Short Form Scores(Baseline)
- NIH-Toolbox (TB) Cognitive Measures: Executive Function Domain Scores(Baseline)
- NIH-TB: Episodic Memory Domain Scores(Baseline)
- Memory Domain Scores(Baseline)
- Beck Depression Inventory (BDI-II) Scores(Baseline)
- Checklist Individual Strength (CIS) - Fatigue Scores(Baseline)
- 10-meter walk test times (seconds)(Baseline)
- Nine-Hole Peg Test Times (9HPT)(Baseline)
- NIH-TB: Executive Function/Attention Domain Scores(Baseline)
- NIH-TB: Language Domain Scores(Baseline)
- Trail Making Test Part A (TMT-A) for processing speed.(Baseline)
- Controlled Oral Word Association (COWA)(Baseline)
- Verbal Fluency Animal Category(Baseline)
- Digit Span Scores for attention domain(Baseline)
- Pittsburgh Sleep Quality Index (PSQI) Scores(Baseline)
- Plasma Neurology 4-Plex E (N4PE)(Baseline)
- Plasma phosphorylated tau (P-tau) 181(Baseline)
- Short Physical Performance Battery (SPPB) Scores(Baseline)
- Grip and Pinch Strength (kg)(Baseline)
- Beck Anxiety Inventory (BAI) Scores(Baseline)
- Apathy Evaluation Scales (AES)(Baseline)
- CSF P-tau 181(Baseline)
- 6-minute walk test (6MWT) Times (minutes)(Baseline)
- Step Test - Number of Steps(Baseline)
- Cerebrospinal Fluid (CSF) Neurology 4-Plex E (N4PE)(Baseline)