Andone Sistiaga

Introduction: Myotonic dystrophy type 1 (DM1) patients show both structural and functional brain alterations, including abnormal resting-state (RS) functional connectivity. Although some studies have investigated RS functional connectivity in DM1, methodological differences make it challenging to draw consistent conclusions. Objectives: This study aims to analyze 1) RS functional connectivity in DM1 patients compared to healthy controls (HC), 2) graph theory metrics, 3) longitudinal connectivity variations, and 4) the relationship between connectivity and clinical, cognitive, and structural brain data. Methodology: Twenty-one DM1 patients and 21 matched HCs underwent 3 T MRI scans, including RS fMRI. Of these, 15 DM1 patients and 13 HCs participated in the follow-up after 3 years. Additionally, DM1 patients underwent baseline clinical, molecular and cognitive assessments. Functional connectivity analysis (ROI-to-ROI) and graph theory measures were employed. Longitudinal changes in connectivity were examined, and total hyperconnectivity and hypoconnectivity values were calculated to explore correlations with clinical, brain, and cognitive correlates. Results: DM1 patients showed widespread hyperconnectivity compared to HCs. Although no statistically significant differences were found in graph theory measures, patients tended to show decreased efficiency, strength, and clustering (with moderate effect sizes). Patients remained hyperconnected over time, with a progression similar to HCs. Hyperconnectivity was associated with more severe disease, greater muscular impairment, and molecular defects, as well as lower cognitive performance. Conversely, hypoconnectivity was associated with less severe disease. Discussion: DM1 patients are characterized by brain hyperconnectivity and a less efficient brain network organization. Hyperconnectivity is discussed as a compensatory mechanism and is suggested as a disease severity marker.

Myotonic dystrophy type 1 (DM1) is an inherited neuromuscular disorder often considered a model of accelerated aging due to the early appearance of certain age-related clinical manifestations and cellular and molecular aging markers. Frailty, a state of vulnerability related to aging, has been recently studied in neurological conditions but has received considerably less attention in neuromuscular disorders. This narrative review aims to describe 1) the common characteristics between Fried’s frailty phenotype criteria (muscular weakness, slow gait speed, weight loss, exhaustion/fatigue, and low physical activity) and DM1, and 2) the psychological and social factors potentially contributing to frailty in DM1. This review gathered evidence suggesting that DM1 patients meet four of the five frailty phenotype criteria. Additionally, longitudinal studies report the deterioration of these criteria over time in DM1. Patients also exhibit psychological/cognitive and social factors that might contribute to frailty. Monitoring frailty criteria in the DM1 population could help to implement timely preventions and interventions to reduce the disease burden and severity of frailty symptoms.

Introduction: Myotonic dystrophy type 1 (DM1) is a hereditary neuromuscular disorder affecting the central nervous system (CNS). Although sex differences have been explored in other neuromuscular disorders, research on this topic in DM1 remains limited. The present study aims to analyze sex differences (both the patient’s and disease-transmitting parent’s sex) with a focus on CNS outcomes.Methods: Retrospective data from 146 non-congenital DM1 patients were analyzed, including clinical, molecular, neuropsychological, and neuroradiological data. Sex and inheritance pattern differences were analyzed using t-tests, and ANOVA analyses were conducted to address the interactions.Results: Overall, no significant sex differences were observed except in certain cognitive domains. However, individuals with maternal inheritance showed larger CTG expansion size, lower estimated IQs, and poorer performance on visual memory, executive functions, and language domains than those with paternal inheritance. Notably, IQ performance was independently influenced by inheritance pattern and CTG expansion.Discussion: This study is the first to delve into sex differences in DM1 with a focus on CNS outcomes. While the results revealed the absence of a sex-specific clinic-molecular profile, more substantial CNS differences were observed between patients with maternal and paternal inheritance patterns. The hypothetical existence of genomic imprinting and its potential mechanism are discussed. These findings hold potential implications for aiding clinical management by improving genetic counseling and predicting disease severity and prognosis.

Background and purpose Myotonic dystrophy type 1 (DM1) is a hereditary and multisystemic disease that is characterized by heterogeneous manifestations. Although muscular impairment is central to DM1, a premanifest DM1 form has been proposed for those characterized by the absence of muscle signs in precursory phases. Nevertheless, subtle signs and/or symptoms related to other systems, such as the central nervous system (CNS), may emerge and progress gradually. This study aimed to validate the premanifest DM1 concept and to characterize and track affected individuals from a CNS centred perspective. Methods Retrospective data of 120 participants (23 premanifest DM1, 25 manifest DM1 and 72 healthy controls) were analysed transversally and longitudinally (over 11.17 years). Compiled data included clinical, neuropsychological and neuroradiological (brain volume and white matter lesion, WML) measures taken at two time points. Results Manifest DM1 showed significantly more molecular affectation, worse performance on neuropsychological domains, lower grey and white matter volumes and a different pattern of WMLs than premanifest DM1. The latter was slightly different from healthy controls regarding brain volume and WMLs. Additionally, daytime sleepiness and molecular expansion size explained 50% of the variance of the muscular deterioration at follow-up in premanifest individuals. Conclusions Premanifest DM1 individuals showed subtle neuroradiological alterations, which suggests CNS involvement early in the disease. Based on follow-up data, a debate emerges around the existence of a 'non-muscular DM1' subtype and/or a premanifest phase, as a precursory stage to other DM1 manifestations.

Myotonic Dystrophy Type 1 (DM1) is a multisystemic disease that affects gray and white matter (WM) tissues. WM changes in DM1 include increased hyperintensities and altered tract integrity distributed in a widespread manner. However, the precise temporal and spatial progression of the changes are yet undetermined. MRI data were acquired from 8 adult- and late-onset DM1 patients and 10 healthy controls (HC) at two different timepoints over 9.06 years. Fractional anisotropy (FA) and mean diffusivity (MD) variations were assessed with Tract-Based Spatial Statistics. Transversal and longitudinal intra- and intergroup analyses were conducted, along with correlation analyses with clinical and neuropsychological data. At baseline, reduced FA and increased MD values were found in patients in the uncinate, anterior-thalamic, fronto-occipital, and longitudinal tracts. At follow-up, the WM disconnection was shown to have spread from the frontal part to the rest of the tracts in the brain. Furthermore, WM lesion burden was negatively correlated with FA values, while visuo-construction and intellectual functioning were positively correlated with global and regional FA values at follow-up. DM1 patients showed a pronounced WM integrity loss over time compared to HC, with a neurodegeneration pattern that suggests a progressive anterior–posterior disconnection. The visuo-construction domain stands out as the most sensitive neuropsychological measure for WM microstructural impairment.

Aim: To delineate the neurogenetic profiles of brain degeneration patterns in myotonic dystrophy type I (DM1).Methods: In two cohorts of DM1 patients, brain maps of volume loss (VL) and neuropsychological deficits (NDs) were intersected to large‐scale transcriptome maps provided by the Allen Human Brain Atlas (AHBA). For validation, neuropathological and RNA analyses were performed in a small series of DM1 brain samples.Results: Twofold: (1) From a list of preselected hypothesis‐driven genes, confirmatory analyses found that three genes play a major role in brain degeneration: dystrophin (DMD), alpha‐synuclein (SNCA) and the microtubule‐associated protein tau (MAPT). Neuropathological analyses confirmed a highly heterogeneous Tau‐pathology in DM1, different to the one in Alzheimer's disease. (2) Exploratory analyses revealed gene clusters enriched for key biological processes in the central nervous system, such as synaptic vesicle recycling, localization, endocytosis and exocytosis, and the serotonin and dopamine neurotransmitter pathways. RNA analyses confirmed synaptic vesicle dysfunction.Conclusions: The combination of large‐scale transcriptome interactions with brain imaging and cognitive function sheds light on the neurobiological mechanisms of brain degeneration in DM1 that might help define future therapeutic strategies and research into this condition.