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.

Objectives The aim of this study was to examine the natural history of brain involvement in adult-onset myotonic dystrophies type 1 and 2 (DM1, DM2). Methods We conducted a longitudinal observational study to examine functional and structural cerebral changes in myotonic dystrophies. We enrolled 16 adult-onset DM1 patients, 16 DM2 patients, and 17 controls. At baseline and after 5.5 ± 0.4 years participants underwent neurological, neuropsychological, and 3T-brain MRI examinations using identical study protocols that included voxel-based morphometry and diffusion tensor imaging. Data were analyzed by (i) group comparisons between patients and controls at baseline and follow-up, and (ii) group comparisons using difference maps (baseline–follow-up in each participant) to focus on disease-related effects over time. Results We found minor neuropsychological deficits with mild progression in DM1 more than DM2. Daytime sleepiness was restricted to DM1, whereas fatigue was present in both disease entities and stable over time. Comparing results of cross-sectional neuroimaging analyses at baseline and follow-up revealed an unchanged pattern of pronounced white matter alterations in DM1. There was mild additional gray matter reduction in DM1 at follow-up. In DM2, white matter reduction was of lesser extent, but there were some additional alterations at follow-up. Gray matter seemed unaffected in DM2. Intriguingly, longitudinal analyses using difference maps and comparing them between patients and controls did not reveal any significant differences of cerebral changes over time between patients and controls. Conclusion The lack of significant disease-related progression of gray and white matter involvement over a period of five years in our cohort of DM1 and DM2 patients suggests either a rather slowly progressive process or even a stable course of cerebral changes in middle-aged adult-onset patients. Being the first longitudinal neuroimaging trial in DM1 and DM2, this study provides useful additional information regarding the natural history of brain involvement.

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Enabled/vasodilator stimulated phosphoproteins (Ena/VASP) proteins are important regulators of the cytoskeleton, linking kinase signaling pathways to actin assembly. In mammals, the Ena/VASP family of proteins consists of mammalian enabled (Mena), VASP, and Ena-VASP-like protein (EVL). The proteins are well known targets of cAMP- and cGMP-dependent protein kinases, PKA and PKG, respectively. Given the importance of cyclic nucleotide signaling in mediating vasodilation, we investigated the role of Ena/VASP protein in vascular smooth muscle relaxation. Whereas VASP and Mena were strongly expressed in vascular smooth muscle cells, EVL was undetectable in the arterial wall and EVL-deficiency had no impact on agonist-induced smooth muscle relaxation. VASP deletion impaired the acetylcholine (ACh)- and nitric oxide (NO)-induced relaxation murine mesenteric arteries ex vivo. Similarly, the ACh-induced and NO-dependent relaxation of aorta from 7-month-old but not 3-month-old VASP-/- mice was also reduced. Aortas from animals lacking VASP and expressing only minimal amounts of Mena displayed significantly impaired relaxations in response to NO, cAMP and cGMP stimulation. These results suggest that Mena and VASP play an important role in agonist induced smooth muscle relaxation and functionally compensate for each other.