Tracking the Brain in Myotonic Dystrophies: a 5-year Longitudinal Follow-up Study

The natural history of brain affection in myotonic dystrophy types 1 and 2 is still unknown. The investigators designed a 5-year longitudinal neuropsychological and neuroimaging follow-up study to address this issue. Myotonic dystrophy type 1, myotonic dystrophy type 2 patients, and healthy controls were enrolled. All participants undergo clinical-neurological examinations, neuropsychological analyses according to a 13-item neuropsychological test battery, and 3T-brain MRI including voxel-based morphometry and diffusion tensor imaging at baseline and at follow-up using identical examination protocols.

Study Overview

• Status: Completed
• Conditions: Myotonic Dystrophy 1; Myotonic Dystrophy 2
• Intervention / Treatment: Other: medical history; Other: neurological clinical examination; Other: neuropsychological testing; Other: brain MRI

Detailed Description

It is unknown whether brain affection in myotonic dystrophy types 1 and 2 is due to neurodevelopmental defects, neurodegeneration, or both. An exact definition of the nature and dynamic of brain affection is of urgent need for the identification of clinical trial outcome parameters and the design of therapy compounds. The investigators planned a 5-year longitudinal study to examine the natural history of functional and structural brain affection. Myotonic dystrophy type 1, myotonic dystrophy type 2 patients, and healthy controls were enrolled. All participants undergo clinical-neurological examinations, neuropsychological analyses according to a 13-item neuropsychological test battery, and 3T-brain MRI at baseline and at follow-up using identical examination protocols. The intended time span between baseline and follow-up examinations is 5 years minimum. To investigate gray and white matter affection, voxel-based morphometry and diffusion tensor imaging are performed, and data are statistically analyzed including (i) group comparisons between patients and controls at baseline and follow-up, and (ii) group comparisons using difference maps to focus on isolated disease-related effects over time.

• Study Type: Observational
• Enrollment (Actual): 49

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients with genetically proven myotonic dystrophy type 1 and myotonic dystrophy type 2 and healthy controls

Description

Inclusion criteria for healthy controls:

• written informed consent
• normal neurological examination without any acute or former neurological or severe psychiatric disease, no medical history of traumatic brain injury

Inclusion criteria for patients:

• written informed consent
• diagnosis confirmed by genetic testing
• no other neurological or severe psychiatric disease, no medical history of traumatic brain injury

Exclusion criteria for healthy controls and patients:

• use of psychoactive substances including alcohol (except nicotine), formerly or currently; treatment with modafinil
• severe psychiatric disorders, serious physical illnesses, particularly cardiovascular diseases, formerly or currently
• non-removable ferromagnetic metallic implants, sensors, stimulators, prostheses, pacemaker, large tattoos
• claustrophobia
• age under 18 years

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Myotonic dystrophy type 1 patients; Patients with myotonic dystrophy type 1 (diagnosis confirmed by genetic testing) who meet all inclusion and exclusion criteria for patients. To be assessed at baseline and follow-up: medical history, neurological clinical examination, neuropsychological testing, brain MRI	Other: medical history; The complete medical history (including cardiovascular risk factors and medication) will be assessed at baseline and follow-up.; Other: neurological clinical examination; Neurological examination will be performed at baseline and follow-up.; Other: neuropsychological testing; Neuropsychological testing using a 13 item test battery will be performed at baseline and follow-up.; Other: brain MRI; Brain MRI ( 3.0 T) will be performed using the same hard- and software at baseline and follow-up.
Myotonic dystrophy type 2 patients; Patients with myotonic dystrophy type 2 (diagnosis confirmed by genetic testing) who meet all inclusion and exclusion criteria for patients. To be assessed at baseline and follow-up: medical history, neurological clinical examination, neuropsychological testing, brain MRI	Other: medical history; The complete medical history (including cardiovascular risk factors and medication) will be assessed at baseline and follow-up.; Other: neurological clinical examination; Neurological examination will be performed at baseline and follow-up.; Other: neuropsychological testing; Neuropsychological testing using a 13 item test battery will be performed at baseline and follow-up.; Other: brain MRI; Brain MRI ( 3.0 T) will be performed using the same hard- and software at baseline and follow-up.
Controls; Healthy control subjects who meet all inclusion and exclusion criteria for healthy controls. To be assessed at baseline and follow-up: medical history, neurological clinical examination, neuropsychological testing, brain MRI	Other: medical history; The complete medical history (including cardiovascular risk factors and medication) will be assessed at baseline and follow-up.; Other: neurological clinical examination; Neurological examination will be performed at baseline and follow-up.; Other: neuropsychological testing; Neuropsychological testing using a 13 item test battery will be performed at baseline and follow-up.; Other: brain MRI; Brain MRI ( 3.0 T) will be performed using the same hard- and software at baseline and follow-up.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in diffusivity indices as assessed by brain MRI with diffusion tensor imaging (DTI) sequences	First analysis at baseline and after 5 years at follow-up
Gray matter changes assessed by magnetic resonance imaging (MRI)-voxel-based morphometry (VBM)	First analysis at baseline and after 5 years at follow-up
Quantification of white matter lesions using age-related white matter changes (ARWMC) rating scale	First analysis at baseline and after 5 years at follow-up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MIRS (Muscular impairment rating scale)	Rating scale to assess disease severity in myotonic dystrophy type 1 patients	First analysis at baseline and after 5 years at follow-up
Motor performance (Purdue Pegboard, bimanual)	A bimanual task to assess fine motor function in patients and controls. Results are used as a covariate for neuropsychological tests	First analysis at baseline and after 5 years at follow-up
Beck Depression Inventory (BDI)	To assess depressive symptoms	First analysis at baseline and after 5 years at follow-up
Boston Naming Test	A test to evaluate semantic memory.	First analysis at baseline and after 5 years at follow-up
Verbal memory recognition task, a subtest of a computerised neuropsychological screening test battery, named NeuroCogFX (Fliessbach et al., 2006).	Word list learning: 3 repetitions of word list presentation, 12 words. Yes/No recognition test (items:distractors 1 : 2) (reaction intervall: 2 seconds). Data measurement: reaction time, number of correct hits	First analysis at baseline and after 5 years at follow-up
Figural memory recognition task, a subtest of a computerised neuropsychological screening test battery, named NeuroCogFX (Fliessbach et al., 2006).	Figural pattern learning: 12 different checkerboard patterns are presented, 3 repetitions of checkboard pattern presentation. Checkerboard consists of 3x3 fields, each pattern consists of 4 highlighted fields. Yes/No recognition test (items:distractors 1 : 2) (reaction interval: 2 seconds). Data measurement: reaction time, number of correct hits	First analysis at baseline and after 5 years at follow-up
Focussed Attention. Focussed attention concerning processing speed is assessed with a symbol-counting task (subtest 1 of the "Cerebraler Insuffizienztest", c.I.T.S. (Lehrl, 1997)).	Data measurement: time	First analysis at baseline and after 5 years at follow-up
Psychomotoric Speed. Psychomotoric speed is assessed using the Trail-Making Test, TMT A (Reitan, 1958).	The TMT-A test consists of 25 numbered circles randomly distributed over a sheet of paper. The study participant needs to draw lines to connect the numbers in ascending order. Data measurement: time	First analysis at baseline and after 5 years at follow-up
Reaction time, a subtest of a computerised neuropsychological screening test battery, named NeuroCogFX (Fliessbach et al., 2006).	Data measurement: time	First analysis at baseline and after 5 years at follow-up
Selective attention (Choice reaction time), a subtest of a computerised neuropsychological screening test battery, named NeuroCogFX (Fliessbach et al., 2006).	Data measurement: time	First analysis at baseline and after 5 years at follow-up
Interference. Interference is analysed using two tasks.	Response inhibition subtest of the "Cerebraler Insuffizienztest" (c.I.T.I; Lehrl and Fischer, 1997).; Inverted choice reaction with reversed conditions of a choice reaction task, a subtest of a computerised neuropsychological screening test battery, named NeuroCogFX (Fliessbach et al., 2006). Data measurement: reaction time	First analysis at baseline and after 5 years at follow-up
Attention shift. Attentional shift is analysed using the the Trail-Making Test, TMT B (Reitan, 1958).	The TMT B test consists of 25 circles randomly distributed over a sheet of paper. These circles include both numbers and letters. The study participant needs to draw lines to connect the numbers and letters in an ascending order, but alternating between numbers and letters. Data measurement: time	First analysis at baseline and after 5 years at follow-up
Visual-spatial / visual-constructive abilities. Visual-spatial / visual-constructive abilities are investigated using the Block design Test (part of "Hamburg-Wechsler Intelligenztest für Erwachsene"-Revision (HAWIE-R); Tewes, 1991).	The block design test consists of 9 blocks and 9 pictures. The study participant needs to look at the picture and reconstruct each picture by arranging all 9 blocks. Data measurement: time	First analysis at baseline and after 5 years at follow-up
Phonematic fluency. Phonemic verbal word fluency is assessed using the oral word-fluency test, subtest 6 of the "Leistungsprüfsystem"; Horn, 1983.	In a given time (one minute) the study participant needs to list as many words that begin with a certain letter. Data measurement: number of correct words	First analysis at baseline and after 5 years at follow-up
Semantic fluency. Semantic word fluency is assessed using a test by Strauss et al.,2006.	A certain category is provided and in a given time (one minute) the study participant needs to list as many items belonging to that category. Data measurement: number of correct items	First analysis at baseline and after 5 years at follow-up
Daytime Sleepiness Scale (DSS)		First analysis at baseline and after 5 years at follow-up
Krupp's Fatigue Severity Scale (KFSS)		First analysis at baseline and after 5 years at follow-up
Epworth Sleepiness Scale (ESS)		First analysis at baseline and after 5 years at follow-up
Pittsburgh Sleep Quality Index (PSQI)		First analysis at baseline and after 5 years at follow-up
Ullanlinna-Narcolepsy Scale (UNS)		First analysis at baseline and after 5 years at follow-up

Collaborators and Investigators

• Sponsor: University Hospital, Bonn
• Collaborators: Forschungszentrum Juelich; The Marigold Foundation; Life and Brain Center Bonn
• Investigators: Study Chair: Cornelia Kornblum, Prof. Dr., Department of Neurology, University Hospital of Bonn, Bonn, Germany; Study Chair: Bernd Weber, Prof. Dr., Life and Brain Center, Department of NeuroCognition-Imaging, Bonn, Germany

Study record dates

Study Major Dates

• Study Start: May 1, 2007
• Primary Completion (Actual): December 1, 2014
• Study Completion (Actual): August 1, 2015

Study Registration Dates

• First Submitted: March 23, 2016
• First Submitted That Met QC Criteria: April 5, 2016
• First Posted (Estimate): April 6, 2016

Study Record Updates

• Last Update Posted (Estimate): April 6, 2016
• Last Update Submitted That Met QC Criteria: April 5, 2016
• Last Verified: April 1, 2016

More Information

Terms related to this study

• Keywords: MRI; brain; white matter; myotonic dystrophy; neuromuscular disorders
• Additional Relevant MeSH Terms: Nervous System Diseases; Genetic Diseases, Inborn; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Muscular Disorders, Atrophic; Heredodegenerative Disorders, Nervous System; Muscular Dystrophies; Myotonic Disorders; Myotonic Dystrophy
• Other Study ID Numbers: DM-1-2

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided