Current Progress in CNS Imaging of Myotonic Dystrophy

Abstract

Neuroimaging in myotonic dystrophies provided a major contribution to the insight into brain involvement which is highly prevalent in these multisystemic disorders. Particular in Myotonic Dystrophy Type 1, conventional MRI first revealed hyperintense white matter lesions, predominantly localized in the anterior temporal lobe. Brain atrophy and ventricle enlargement were additional early findings already described almost 30 years ago. Since then, more advanced and sophisticated imaging methods have been applied in Myotonic Dystrophy Types 1 and 2. Involvement of actually normal appearing white matter and widespread cortical affection in PET studies were key results toward the recognition of diffuse and not only focally localized brain pathology in vivo. Later, structural abnormalities of both, gray and white matter, have been found in both forms of the disorder, albeit more prominent in myotonic dystrophy type 1. In Type 1, a consistent widespread cortical and subcortical involvement of gray and white matter affecting all lobes, brainstem and cerebellum was observed. Spectroscopy studies gave additional evidence of neuronal and glial damage in both types. Central questions regarding the origin and spatiotemporal evolution of the CNS involvement and its relevance for clinical symptoms had already been raised 30 years ago, however are still not answered. Results of correlation analyses between neuroimaging and clinical parameters are diverse and with few exceptions not well reproducible across studies. It may be related to the fact that most of the reported studies included only small numbers of subjects, sometimes even not separating Myotonic Dystrophy Type 1 from Type 2. But this heterogeneity may also support the current point of view that the clinical impairments are not simply linked to specific and regionally circumscribed structural or functional brain alterations. It seems more convincing that disturbed networks build the functional and structural substrate of clinical symptoms in these disorders as it is proposed in other neuropsychiatric diseases. Consecutively, structural and functional network analyses may provide additional information regarding the link between brain pathology and clinical symptoms. Up to now, only cross-sectional neuroimaging studies have been published. To analyze the temporal evolution of brain affection, longitudinal studies are urgently needed, and systematic natural history data would be useful to identify potential biomarkers for therapeutic studies.

MECP2-related pathways are dysregulated in a cortical organoid model of myotonic dystrophy

“…1K). Our results support the validity of our DM1 cortical organoid models, which recapitulate central nervous system (CNS) phenotypes identified in patients with early forms of DM1 including cortical neuron loss and elevations in glial content ( 13 , 14 ).…”

MECP2-related pathways are dysregulated in a cortical organoid model of myotonic dystrophy

“…1K). Our results support the validity of our DM1 cortical organoid models, which recapitulate central nervous system (CNS) phenotypes identified in patients with early forms of DM1 including cortical neuron loss and elevations in glial content ( 13 , 14 ).…”

Elevated serum Neurofilament Light chain (NfL) as a potential biomarker of neurological involvement in Myotonic Dystrophy type 1 (DM1)

“…Thus, in DM1 patients, increased NfL release might be also consequent to the known disruption of specific neural networks regulating mood and/or behavior [ 43 – 51 ]. In this regard, in a very recent study [ 36 ], circulating Nfl levels in DM1 patients also correlated with white matter DTI changes, a measure of abnormal brain connectivity [ 36 ], and accordingly, we found a correlation between Nfl levels and the Fazekas score, an outcome measure of structural brain MRI white matter changes, confirming that white matter damage would be predominant in DM1 brains [ 28 ].…”

Differences in splicing defects between the grey and white matter in myotonic dystrophy type 1 patients

“…VBM and DWI tensor studies have shown that the effect of DM1 on the WM is more prominent than on the GM and that WM T2 hyperintensity lesions were found in the frontal, temporal (especially at the anterior temporal poles), and parietal lobes [21,22]. However, this study showed more splicing defects in the GM than in the WM.…”

MECP2-related pathways are dysregulated in a cortical organoid model of myotonic dystrophy

“…1K). Our results support the validity of our DM1 cortical organoid models, which recapitulate central nervous system (CNS) phenotypes identified in patients with early forms of DM1 including cortical neuron loss and elevations in glial content ( 13 , 14 ).…”

Elevated serum Neurofilament Light chain (NfL) as a potential biomarker of neurological involvement in Myotonic Dystrophy type 1 (DM1)

“…Thus, in DM1 patients, increased NfL release might be also consequent to the known disruption of specific neural networks regulating mood and/or behavior [ 43 – 51 ]. In this regard, in a very recent study [ 36 ], circulating Nfl levels in DM1 patients also correlated with white matter DTI changes, a measure of abnormal brain connectivity [ 36 ], and accordingly, we found a correlation between Nfl levels and the Fazekas score, an outcome measure of structural brain MRI white matter changes, confirming that white matter damage would be predominant in DM1 brains [ 28 ].…”

Differences in splicing defects between the grey and white matter in myotonic dystrophy type 1 patients

“…VBM and DWI tensor studies have shown that the effect of DM1 on the WM is more prominent than on the GM and that WM T2 hyperintensity lesions were found in the frontal, temporal (especially at the anterior temporal poles), and parietal lobes [21,22]. However, this study showed more splicing defects in the GM than in the WM.…”

MECP2-related pathways are dysregulated in a cortical organoid model of myotonic dystrophy

“…1K). Our results support the validity of our DM1 cortical organoid models, which recapitulate central nervous system (CNS) phenotypes identified in patients with early forms of DM1 including cortical neuron loss and elevations in glial content ( 13 , 14 ).…”

Elevated serum Neurofilament Light chain (NfL) as a potential biomarker of neurological involvement in Myotonic Dystrophy type 1 (DM1)

“…Thus, in DM1 patients, increased NfL release might be also consequent to the known disruption of specific neural networks regulating mood and/or behavior [ 43 – 51 ]. In this regard, in a very recent study [ 36 ], circulating Nfl levels in DM1 patients also correlated with white matter DTI changes, a measure of abnormal brain connectivity [ 36 ], and accordingly, we found a correlation between Nfl levels and the Fazekas score, an outcome measure of structural brain MRI white matter changes, confirming that white matter damage would be predominant in DM1 brains [ 28 ].…”

Differences in splicing defects between the grey and white matter in myotonic dystrophy type 1 patients

“…VBM and DWI tensor studies have shown that the effect of DM1 on the WM is more prominent than on the GM and that WM T2 hyperintensity lesions were found in the frontal, temporal (especially at the anterior temporal poles), and parietal lobes [21,22]. However, this study showed more splicing defects in the GM than in the WM.…”