Publications by authors named "Laura E Habets"

8 Publications

  • Page 1 of 1

Motor Unit and Capillary Recruitment During Fatiguing Arm-Cycling Exercise in Spinal Muscular Atrophy Types 3 and 4.

J Neuromuscul Dis 2022 ;9(3):397-409

Department of Neurology and Neurosurgery, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands.

Background: Exercise intolerance is an important impairment in patients with SMA, but little is known about the mechanisms underlying this symptom.

Objective: To investigate if reduced motor unit and capillary recruitment capacity in patients with SMA contribute to exercise intolerance.

Methods: Adolescent and adult patients with SMA types 3 and 4 (n = 15) and age- and gender matched controls (n = 15) performed a maximal upper body exercise test. We applied respiratory gas analyses, non-invasive surface electromyography (sEMG) and continuous wave near-infrared spectroscopy (CW-NIRS) to study oxygen consumption, arm muscle motor unit- and capillary recruitment, respectively.

Results: Maximal exercise duration was twofold lower (p < 0.001) and work of breathing and ventilation was 1.6- and 1.8-fold higher (p < 0.05) in patients compared to controls, respectively. Regarding motor unit recruitment, we found higher normalized RMS amplitude onset values of sEMG signals from all muscles and the increase in normalized RMS amplitudes was similar in the m. triceps brachii, m. brachioradialis and m. flexor digitorum in SMA compared to controls. Median frequency, onset values were similar in patients and controls. We found a similar decrease in median frequencies of sEMG recordings from the m. biceps brachii, a diminished decrease from the m. brachioradialis and m. flexor digitorum, but a larger decrease from the m. triceps brachii. With respect to capillary recruitment, CW-NIRS recordings in m. biceps brachii revealed dynamics that were both qualitatively and quantitatively similar in patients and controls.

Conclusion: We found no evidence for the contribution of motor unit and capillary recruitment capacity of the upper arm muscles in adolescent and adult patients with SMA types 3 and 4 as primary limiting factors to premature fatigue during execution of a maximal arm-cycling task.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JND-210765DOI Listing
May 2022

Multi-parametric quantitative magnetic resonance imaging of the upper arm muscles of patients with spinal muscular atrophy.

NMR Biomed 2022 Jan 20:e4696. Epub 2022 Jan 20.

UMC Utrecht Brain Center, Department of Neurology and Neurosurgery, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Quantitative magnetic resonance imaging (qMRI) is frequently used to map the disease state and disease progression in the lower extremity muscles of patients with spinal muscular atrophy (SMA). This is in stark contrast to the almost complete lack of data on the upper extremity muscles, which are essential for carrying out daily activities. The aim of this study was therefore to assess the disease state in the upper arm muscles of patients with SMA in comparison with healthy controls by quantitative assessment of fat fraction, diffusion indices, and water T2 relaxation times, and to relate these measures to muscle force. We evaluated 13 patients with SMA and 15 healthy controls with a 3-T MRI protocol consisting of DIXON, diffusion tensor imaging, and T2 sequences. qMRI measures were compared between groups and related to muscle force measured with quantitative myometry. Fat fraction was significantly increased in all upper arm muscles of the patients with SMA compared with healthy controls and correlated negatively with muscle force. Additionally, fat fraction was heterogeneously distributed within the triceps brachii (TB) and brachialis muscle, but not in the biceps brachii muscle. Diffusion indices and water T2 relaxation times were similar between patients with SMA and healthy controls, but we did find a slightly reduced mean diffusivity (MD), λ1, and λ3 in the TB of patients with SMA. Furthermore, MD was positively correlated with muscle force in the TB of patients with SMA. The variation in fat fraction further substantiates the selective vulnerability of muscles. The reduced diffusion tensor imaging indices, along with the positive correlation of MD with muscle force, point to myofiber atrophy. Our results show the feasibility of qMRI to map the disease state in the upper arm muscles of patients with SMA. Longitudinal data in a larger cohort are needed to further explore qMRI to map disease progression and to capture the possible effects of therapeutic interventions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/nbm.4696DOI Listing
January 2022

Magnetic resonance reveals mitochondrial dysfunction and muscle remodelling in spinal muscular atrophy.

Brain 2021 Nov 11. Epub 2021 Nov 11.

Centre for Child Development, Exercise and Physical Literacy, Wilhelmina Children's Hospital, University Medical Centre Utrecht, P.O. Box 85090 3508 AB Utrecht, The Netherlands.

Genetic therapy has changed the prognosis of hereditary proximal spinal muscular atrophy, although treatment efficacy has been variable. There is a clear need for deeper understanding of underlying causes of muscle weakness and exercise intolerance in patients with this disease to further optimize treatment strategies. Animal models suggest that in addition to motor neuron and associated musculature degeneration, intrinsic abnormalities of muscle itself including mitochondrial dysfunction contribute to the disease etiology. To test this hypothesis in patients, we conducted the first in vivo clinical investigation of muscle bioenergetics. We recruited 15 patients and 15 healthy age and gender-matched control subjects in this cross-sectional clinico-radiological study. MRI and 31phosphorus magnetic resonance spectroscopy, the modality of choice to interrogate muscle energetics and phenotypic fiber type makeup, was performed of the proximal arm musculature in combination with fatiguing arm-cycling exercise and blood lactate testing. We derived bioenergetic parameter estimates including: blood lactate, intramuscular pH and inorganic phosphate accumulation during exercise, and muscle dynamic recovery constants. Linear correlation was used to test for associations between muscle morphological and bioenergetic parameters and clinico-functional measures of muscle weakness. MRI showed significant atrophy of triceps but not biceps muscles in patients. Maximal voluntary contraction force normalized to muscle cross-sectional area for both arm muscles was 1.4-fold lower in patients than in controls, indicating altered intrinsic muscle properties other than atrophy contributed to muscle weakness in this cohort. In vivo 31phosphorus magnetic resonance spectroscopy identified white-to-red remodeling of residual proximal arm musculature in patients on basis of altered intramuscular inorganic phosphate accumulation during arm-cycling in red versus white and intermediate myofibers. Blood lactate rise during arm-cycling was blunted in patients and correlated with muscle weakness and phenotypic muscle makeup. Post-exercise metabolic recovery was slower in residual intramuscular white myofibers in patients demonstrating mitochondrial ATP synthetic dysfunction in this particular fiber type. This study provides first in vivo evidence in patients that degeneration of motor neurons and associated musculature causing atrophy and muscle weakness in 5q spinal muscular atrophy type 3 and 4 is aggravated by disproportionate depletion of myofibers that contract fastest and strongest. Our finding of decreased mitochondrial ATP synthetic function selectively in residual white myofibers provides both a possible clue to understanding the apparent vulnerability of this particular fiber type in 5q spinal muscular atrophy type 3 and 4 as well as a new biomarker and target for therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awab411DOI Listing
November 2021

Motor unit reserve capacity in spinal muscular atrophy during fatiguing endurance performance.

Clin Neurophysiol 2021 03 28;132(3):800-807. Epub 2021 Jan 28.

Faculty of Behavioral and Movement Sciences, Vrije Universiteit Amsterdam, Van der Boechorststraat 7, 1081 BT Amsterdam, the Netherlands.

Objective: To investigate the availability of any motor unit reserve capacity during fatiguing endurance testing in patients with spinal muscular atrophy (SMA).

Methods: We recorded surface electromyography (sEMG) of various muscles of upper- and lower extremities of 70 patients with SMA types 2-4 and 19 healthy controls performing endurance shuttle tests (ESTs) of arm and legs. We quantitatively evaluated the development of fatigability and motor unit recruitment using time courses of median frequencies and amplitudes of sEMG signals. Linear mixed effect statistical models were used to evaluate group differences in median frequency and normalized amplitude at onset and its time course.

Results: Normalized sEMG amplitudes at onset of upper body ESTs were significantly higher in patients compared to controls, yet submaximal when related to maximal voluntary contractions, and showed an inverse correlation to SMA phenotype. sEMG median frequencies decreased and amplitudes increased in various muscles during execution of ESTs in patients and controls.

Conclusions: Decreasing median frequencies and increasing amplitudes reveal motor unit reserve capacity in individual SMA patients during ESTs at submaximal performance intensities.

Significance: Preserving, if not expanding motor unit reserve capacity may present a potential therapeutic target in clinical care to reduce fatigability in individual patients with SMA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clinph.2020.11.044DOI Listing
March 2021

Correlates of Fatigability in Patients With Spinal Muscular Atrophy.

Neurology 2021 02 20;96(6):e845-e852. Epub 2020 Nov 20.

From the Child Development and Exercise Center (B.B., L.E.H.) and Department of Pediatric Gastroenterology (E.E.S.N.), Wilhelmina Children's Hospital, and UMC Utrecht Brain Center (R.I.W., F.-L.A., R.P.A.v.E., H.S.G., W.L.v.d.P.), University Medical Center Utrecht; Knowledge Institute for Medical Specialists (J.F.d.G.), University of Applied Sciences; and Biostatistics & Research Support (R.P.A.v.E.), Julius Center for Health Sciences and Primary Care, Utrecht, the Netherlands.

Objective: To determine the associations between fatigability and muscle strength, motor function, neuromuscular junction (NMJ) function, and perceived fatigue in spinal muscular atrophy (SMA), we assessed 61 patients with SMA.

Methods: Fatigability was defined as the inability to continue a 20-minute submaximal repetitive task of either walking or proximal or distal arm function and expressed as drop-out on the Endurance Shuttle Test Combined Score (ESTCS). We assessed muscle strength with the Medical Research Council (MRC) sum score, motor function with the Hammersmith Functional Motor Scale Expanded (HFMSE) and Motor Function Measure (MFM), NMJ function with repetitive nerve stimulation of the accessory and ulnar nerve, and perceived fatigue with the PROMIS Fatigue Short Form questionnaire in 61 children and adults with SMA types 2-4. We applied Cox regression analysis to explore the associations between fatigability and these factors.

Results: The hazard of drop-out on the ESTCS decreased 0.8%, 2%, and 1.3% for each point increase in the MRC sum score, the HFMSE score, and the MFM percentual score, respectively. However, we observed prominent fatigability with preserved muscle function and vice versa in 13%-16% of patients. We did not find an association between NMJ dysfunction of the accessory ( = 0.37) and ulnar nerve ( = 0.063) and fatigability, which could be due to a large number of missing values. Perceived fatigue in SMA was comparable to reference values and was not associated with fatigability ( = 0.52).

Conclusion: Fatigability in SMA is associated with, yet not equivalent to, muscle strength and motor function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000011230DOI Listing
February 2021

Fatigability in spinal muscular atrophy: validity and reliability of endurance shuttle tests.

Orphanet J Rare Dis 2020 03 23;15(1):75. Epub 2020 Mar 23.

University Medical Center Utrecht, UMC Utrecht Brain Center, Utrecht, The Netherlands.

Background: To determine construct validity and test-retest reliability of Endurance Shuttle Tests as outcome measures for fatigability of remaining motor functions in children and adults with Spinal Muscular Atrophy (SMA) across the severity spectrum.

Results: We assessed the Endurance Shuttle - Nine Hole Peg Test (ESNHPT), - Box and Block Test (ESBBT) and - Walk Test (ESWT) in 61 patients with SMA types 2-4, 25 healthy controls (HC) and 15 disease controls (DC). Convergent validity, discriminative validity and test-retest reliability were investigated. Additionally, we compiled the Endurance Shuttle Combined Score (ESTCS) by selecting the most relevant endurance test of each individual. 54, 70 and 73% of patients with SMA demonstrated increased fatigability on the ESNHPT, ESBBT and the ESWT. Endurance response in SMA was characterized by a decrease in muscle strength, an increase in muscle fatigue and an increase in motor adaptions, thereby confirming convergent validity. Patients with SMA showed increased drop-out rates and a shorter endurance time compared to HC and DC demonstrating good discriminative validity. Test-retest reliability was moderate to excellent (ICC's ranging from .78 to .91) with a trend towards better performance on retest. The ESTCS increased sample size and drop-out rate up to 100 and 85%.

Conclusions: Fatigability is an important additional dimension of physical impairments across the severity spectrum in children and adults with SMA. The EST's are reliable and valid to document fatigability of walking, proximal- and distal arm function in SMA and thus are promising outcome measures for use in clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13023-020-1348-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7092552PMC
March 2020

Assessment of fatigability in patients with spinal muscular atrophy: development and content validity of a set of endurance tests.

BMC Neurol 2019 Feb 9;19(1):21. Epub 2019 Feb 9.

Child Development and Exercise Center, Wilhelmina Children's Hospital, University Medical Center Utrecht, PO Box 85090, KB 02.056.0, 3508, AB, Utrecht, The Netherlands.

Background: Fatigability has emerged as an important dimension of physical impairment in patients with Spinal Muscular Atrophy (SMA). At present reliable and valid outcome measures for both mildly and severely affected patients are lacking. Therefore the primary aim of this study is the development of clinical outcome measures for fatigability in patients with SMA across the range of severity.

Methods: We developed a set of endurance tests using five methodological steps as recommended by the 'COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN). In this iterative process, data from multiple sources were triangulated including a scoping review of scientific literature, input from a scientific and clinical multidisciplinary expert panel and three pilot studies including healthy persons (N = 9), paediatric patients with chronic disorders (N = 10) and patients with SMA (N = 15).

Results: Fatigability in SMA was operationalised as the decline in physical performance. The following test criteria were established; one method of testing for patients with SMA type 2-4, a set of outcome measures that mimic daily life activities, a submaximal test protocol of repetitive activities over a longer period; external regulation of pace. The scoping review did not generate suitable outcome measures. We therefore adapted the Endurance Shuttle Walk Test for ambulatory patients and developed the Endurance Shuttle Box and Block Test and the - Nine Hole Peg Test for fatigability testing of proximal and distal arm function. Content validity was established through input from experts and patients. Pilot testing showed that the set of endurance tests are comprehensible, feasible and meet all predefined test criteria.

Conclusions: The development of this comprehensive set of endurance tests is a pivotal step to address fatigability in patients with SMA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12883-019-1244-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368708PMC
February 2019

Protocol for a phase II, monocentre, double-blind, placebo-controlled, cross-over trial to assess efficacy of pyridostigmine in patients with spinal muscular atrophy types 2-4 (SPACE trial).

BMJ Open 2018 07 30;8(7):e019932. Epub 2018 Jul 30.

Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Introduction: Hereditary proximal spinal muscular atrophy (SMA) is caused by homozygous loss of function of the survival motor neuron 1 gene. The main characteristic of SMA is degeneration of alpha motor neurons in the anterior horn of the spinal cord, but recent studies in animal models and patients have shown additional anatomical abnormalities and dysfunction of the neuromuscular junction (NMJ). NMJ dysfunction could contribute to symptoms of weakness and fatigability in patients with SMA. We hypothesise that pyridostigmine, an acetylcholinesterase inhibitor that improves neuromuscular transmission, could improve NMJ function and thereby muscle strength and fatigability in patients with SMA.

Methods And Analysis: We designed a monocentre, placebo-controlled, double-blind cross-over trial with pyridostigmine and placebo to investigate the effect and efficacy of pyridostigmine on muscle strength and fatigability in patients with genetically confirmed SMA. We aim to include 45 patients with SMA types 2-4, aged 12 years and older in the Netherlands. Participants receive 8 weeks of treatment with pyridostigmine and 8 weeks of treatment with placebo in a random order separated by a washout period of 1 week. Treatment allocation is double blinded. Treatment dose will gradually be increased from 2 mg/kg/day to the maximum dose of 6 mg/kg/day in four daily doses, in the first week of each treatment period. The primary outcome measures are a change in the Motor Function Measure and repeated nine-hole peg test before and after treatment. Secondary outcome measures are changes in recently developed endurance tests, that is, the endurance shuttle nine-hole peg test, the endurance shuttle box and block test and the endurance shuttle walk test, muscle strength, level of daily functioning, quality of and activity in life, perceived fatigue and fatigability, presence of decrement on repetitive nerve stimulation and adverse events.

Ethics And Dissemination: The protocol is approved by the local medical ethical review committee at the University Medical Center Utrecht and by the national Central Committee on Research Involving Human Subjects. Findings will be shared with the academic and medical community, funding and patient organisations in order to contribute to optimisation of medical care and quality of life for patients with SMA.

Trial Registration Number: NCT02941328.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjopen-2017-019932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6067401PMC
July 2018
-->