Lesion distribution and substrate of white matter damage in myotonic dystrophy type 1: Comparison with multiple sclerosis

Macromolecular proton fraction (MPF) is a quantitative MRI parameter describing the magnetization transfer (MT) effect and defined as a relative amount of protons bound to biological macromolecules with restricted molecular motion, which participate in magnetic cross-relaxation with water protons. MPF attracted significant interest during past decade as a biomarker of myelin. The purpose of this mini review is to provide a brief but comprehensive summary of MPF mapping methods, histological validation studies, and MPF applications in neuroscience. Technically, MPF maps can be obtained using a variety of quantitative MT methods. Some of them enable clinically reasonable scan time and resolution. Recent studies demonstrated the feasibility of MPF mapping using standard clinical MRI pulse sequences, thus substantially enhancing the method availability. A number of studies in animal models demonstrated strong correlations between MPF and histological markers of myelin with a minor influence of potential confounders. Histological studies validated the capability of MPF to monitor both demyelination and re-myelination. Clinical applications of MPF have been mainly focused on multiple sclerosis where this method provided new insights into both white and gray matter pathology. Besides, several studies used MPF to investigate myelin role in other neurological and psychiatric conditions. Another promising area of MPF applications is the brain development studies. MPF demonstrated the capabilities to quantitatively characterize the earliest stage of myelination during prenatal brain maturation and protracted myelin development in adolescence. In summary, MPF mapping provides a technically mature and comprehensively validated myelin imaging technology for various preclinical and clinical neuroscience applications.

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“…Reduced MPF in WM lesions, no differences between patients and controls in NAWM (Leddy et al, 2021).…”

Section: Myotonic Dystrophy Typementioning

confidence: 79%

Macromolecular Proton Fraction as a Myelin Biomarker: Principles, Validation, and Applications

2022

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“…Cognitive and behavioral impairment is accompanied by a broad spectrum of imaging changes widely dispersed throughout the brain [ 6 ]. Brain structural abnormalities include prevalent white matter lesions [ 7 ], some of which may denote focal demyelination [ 8 ]. Reduced grey matter volume has also been reported in cortical brain regions and in the hippocampus of DM1 patients [ 7 , 9 , 10 ], corroborating histopathological evidence of diffusing cerebral atrophy and neuronal loss [ 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

DM1 Transgenic Mice Exhibit Abnormal Neurotransmitter Homeostasis and Synaptic Plasticity in Association with RNA Foci and Mis-Splicing in the Hippocampus

Potier

Lallemant

Parrot

et al. 2022

IJMS

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Myotonic dystrophy type 1 (DM1) is a severe neuromuscular disease mediated by a toxic gain of function of mutant RNAs. The neuropsychological manifestations affect multiple domains of cognition and behavior, but their etiology remains elusive. Transgenic DMSXL mice carry the DM1 mutation, show behavioral abnormalities, and express low levels of GLT1, a critical regulator of glutamate concentration in the synaptic cleft. However, the impact of glutamate homeostasis on neurotransmission in DM1 remains unknown. We confirmed reduced glutamate uptake in the DMSXL hippocampus. Patch clamp recordings in hippocampal slices revealed increased amplitude of tonic glutamate currents in DMSXL CA1 pyramidal neurons and DG granule cells, likely mediated by higher levels of ambient glutamate. Unexpectedly, extracellular GABA levels and tonic current were also elevated in DMSXL mice. Finally, we found evidence of synaptic dysfunction in DMSXL mice, suggestive of abnormal short-term plasticity, illustrated by an altered LTP time course in DG and in CA1. Synaptic dysfunction was accompanied by RNA foci accumulation in localized areas of the hippocampus and by the mis-splicing of candidate genes with relevant functions in neurotransmission. Molecular and functional changes triggered by toxic RNA may induce synaptic abnormalities in restricted brain areas that favor neuronal dysfunction.

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“…Neurological involvement in the DM1 has aroused lots of interest in the recent years and several brain MRI studies have reported white matter lesions and brain atrophy (Minnerop et al, 2011;Baldanzi et al, 2016;Zanigni et al, 2016;Okkersen et al, 2017b;Koscik et al, 2021;Leddy et al, 2021;Lopez-Titla et al, 2021). Diffusion tensor imaging studies have demonstrated widespread white matter lesions with reduced fractional anisotropy (FA) and increased mean diffusivity in patients with DM1 compared with controls (Cabada et al, 2017;Yoo et al, 2017;van Dorst et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Altered Local Brain Amplitude of Fluctuations in Patients With Myotonic Dystrophy Type 1

Huang

Luan

Xie

et al. 2021

Front. Aging Neurosci.

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This study is aimed at investigating the characteristics of the spontaneous brain activity in patients with myotonic dystrophy type 1 (DM1). A total of 18 patients with DM1 and 18 healthy controls (HCs) were examined by resting-state functional MRI. Combined methods include amplitude of low-frequency fluctuations (ALFFs), the fractional amplitude of low-frequency fluctuations (fALFFs), and Wavelet transform-based ALFFs (Wavelet-ALFFs) with standardization, percent amplitude of fluctuation (PerAF) with/without standardization were applied to evaluate the spontaneous brain activity of patients with DM1. Compared with HCs, patients with DM1 showed decreased ALFFs and Wavelet-ALFFs in the bilateral precuneus (PCUN), angular gyrus (ANG), inferior parietal, but supramarginal and angular gyri (IPL), posterior cingulate gyrus (PCG), superior frontal gyrus, medial (SFGmed), middle occipital gyrus (MOG), which were mainly distributed in the brain regions of default mode network (DMN). Decreased ALFFs and Wavelet-ALFFs were also seen in bilateral middle frontal gyrus (MFG), inferior frontal gyrus, opercular part (IFGoperc), which were the main components of the executive control network (ECN). Patients with DM1 also showed decreased fALFFs in SFGmed.R, the right anterior cingulate and paracingulate gyri (ACGR), bilateral MFG. Reduced PerAF in bilateral PCUN, ANG, PCG, MOG, and IPLL as well as decreased PerAF without standardization in PCUNR and bilateral PCG also existed in patients with DM1. In conclusion, patients with DM1 had decreased activity in DMN and ECN with increased fluctuations in the temporal cortex and cerebellum. Decreased brain activity in DMN was the most repeatable and reliable with PCUN and PCG being the most specific imaging biomarker of brain dysfunction in patients with DM1.

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Lesion distribution and substrate of white matter damage in myotonic dystrophy type 1: Comparison with multiple sclerosis

Abstract: Graphical abstract

Cited by 11 publications

References 77 publications

Macromolecular Proton Fraction as a Myelin Biomarker: Principles, Validation, and Applications

Macromolecular Proton Fraction as a Myelin Biomarker: Principles, Validation, and Applications

DM1 Transgenic Mice Exhibit Abnormal Neurotransmitter Homeostasis and Synaptic Plasticity in Association with RNA Foci and Mis-Splicing in the Hippocampus

Altered Local Brain Amplitude of Fluctuations in Patients With Myotonic Dystrophy Type 1

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