Visuoconstructional impairment in DM1: exploring underlying cognitive processes through the Rey complex figure

Introduction Among the cognitive difficulties shown by myotonic dystrophy type 1 (DM1) patients, visuoconstructional impairment – specifically measured with the Rey-Osterrieth Complex Figure Test (RCFT) – is particularly notable. This study aimed to analyze the performance of DM1 patients and healthy controls (HC) in the RCFT, using different correction systems in order to explore the cognitive processes underlying the poor performance and its associations with other signs and symptoms. Methods Data from 66 DM1 patients and 68 HC were included in this study. All participants had a comprehensive neuropsychological assessment, including the RCFT, which was scored using both the traditional Osterrieth and the Boston Qualitative Scoring System (BQSS) procedures. ANCOVA and Spearman’s correlation analyses were conducted. Results DM1 Patients obtained significantly poorer scores than HC on the RCFT using both correction systems. Regarding BQSS, patients performed worse than HC in both main indexes (Copy Presence Accuracy-CPA and Organization-ORG), and specifically on scores of Configural accuracy, Planning, and Perseveration. Both main indexes – but especially CPA – showed significant and strong correlations with several clinical and cognitive variables. Conclusions Both visuoconstruction and organizational impairments underlie the poor RCFT performance in DM1. Moreover, visuoconstruction ability appears to be sensitive to the clinical hallmarks of DM1 patients. The RCFT is proposed as a gold standard in DM1 assessment and the merits of using alternative scoring systems are discussed.This work was supported by the Institute of Health Carlos III and co-funded by the European Union under Grant number PI17/01231 and PI22/01118; Basque Government under Grant number S-PE13UN030 and 2022111031; and University of the Basque Country (UPV/EHU) under Grant number PIF 20/238 and GU 20/057

Social cognition in myotonic dystrophy type 1: Specific or secondary impairment?

Aims The cognitive profile of Myotonic Dystrophy type 1 (DM1) has been described in recent decades. Moreover, DM1 patients show lowered social engagement and difficulties in social-cognitive functions. The aim of the present study is to explore whether social cognition impairment is present in DM1 taking into account the overall cognitive condition. Method 38 patients and a control group paired in age and gender participated in the study. All the participants had an IQ within the normal range. Subjects were administered an abbreviated neuropsychological battery which comprised a facial emotion recognition test (POFA) and Faux Pas Test, as well as a self-report questionnaire on cognitive and affective empathy (TECA). Results Statistically significant differences were found only for facial emotion recognition (U = 464.0, p = .006) with a moderate effect size (.31), with the controls obtaining a higher score than the patients. Analyzing each emotion separately, DM1 patients scored significantly lower than controls on the recognition of anger and disgust items. Emotion recognition did not correlate with genetic load, but did correlate negatively with age. No differences were found between patients and controls in any of the other variables related to Theory of Mind (ToM) and empathy. Conclusion DM1 does not manifest specific impairments in ToM since difficulties in this area predominantly rely on the cognitive demand of the tasks employed. However, a more basic process such as emotion recognition appears as a core deficit. The role of this deficit as a marker of aging related decline is discussed.The present study has been supported by grants of the Instituto de Salud Carlos III co-founded by Fondo Europeo de Desarrollo Regional - FEDER (Ref: PI17/01231)

Regional brain atrophy in gray and white matter is associated with cognitive impairment in Myotonic Dystrophy type 1

Background: Myotonic Dystrophy type 1 (DM1) is a slowly progressive myopathy characterized by varying multisystemic involvement. Several cerebral features such as brain atrophy, ventricular enlargement, and white matter lesions (WMLs) have frequently been described. The aim of this study is to investigate the structural organization of the brain that defines the disease through multimodal imaging analysis, and to analyze the relation between structural cerebral changes and DM1 clinical and neuropsychological profiles. Method: 31 DM1 patients and 57 healthy controls underwent an MRI scan protocol, including T1, T2 and DTI. Global gray matter (GM), global white matter (WM), and voxel-level Voxel Based Morphometry (VBM) and voxel-level microstructural WM abnormalities through Diffusion Tensor Imaging (DTI) were assessed through group comparisons and linear regression analysis with age, degree of muscular impairment (MIRS score), CTG expansion size and neuropsychological outcomes from a comprehensive assessment. Results: Compared with healthy controls, DM1 patients showed a reduction in both global GM and WM volume; and further regional GM decrease in specific primary sensory, multi-sensory and association cortical regions. Fractional anisotropy (FA) was reduced in both total brain and regional analysis, being most marked in frontal, paralimbic, temporal cortex, and subcortical regions. Higher ratings on muscular impairment and longer CTG expansion sizes predicted a greater volume decrease in GM and lower FA values. Age predicted global GM reduction, specifically in parietal regions. At the cognitive level, the DM1 group showed significant negative correlations between IQ estimate, visuoconstructive and executive neuropsychological scores and both global and regional volume decrease, mainly distributed in the frontal, parietal and subcortical regions. Conclusions: In this study, we describe the structural brain signatures that delineate the involvement of the CNS in DM1. We show that specific sensory and multi-sensory — as well as frontal cortical areas — display potential vulnerability associated with the hypothesized neurodegenerative nature of DM1 brain abnormalities

Shedding light on motor premanifest myotonic dystrophy type 1: A molecular, muscular and central nervous system follow-up study

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.This work was supported by the Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (Ref: 609), from the Institute of Health Carlos III co-founded by Fondo Europeo de Desarrollo Regional (PI17/01231 to A.S.; PI17/01841 to A.L.); Basque Government (S-PE13UN030 to A.S.); and University of the Basque Country (UPV/EHU) (PIF 20/238 to J.G.; GU 20/057 to J.G., G.L. and A.S.)

Small for gestational age moderate to late preterm children: a neuropsychological follow-up

[EN] Determine whether SGA constitutes a neurodevelopmental risk-factor of MLP, exploring if potential developmental difficulties at toddlerhood persist and are related to school-age performance. 109 SGA and 109 adequate for gestational age MLP children were evaluated at 2 and at 6.5 y.o. SGA children obtained poorer results in several areas at both timepoints; and their development at toddlerhood strongly correlated with only some results at school-age. SGA confers vulnerability to MLP, evolving from global/unspecific difficulties in toddlerhood to a domain-specific profile (attentional/dysexecutive) at 6.5. Findings claim the need for neuropsychological follow-up in MLP to identify emerging difficulties

Neurodegeneration trajectory in pediatric and adult/late DM1: A follow‐up MRI study across a decade

Objective: To characterize the progression of brain structural abnormalities in adults with pediatric and adult/late onset DM1, as well as to examine the potential predictive markers of such progression. Methods: 21 DM1 patients (pediatric onset: N = 9; adult/late onset: N = 12) and 18 healthy controls (HC) were assessed longitudinally over 9.17 years through brain MRI. Additionally, patients underwent neuropsychological, genetic, and muscular impairment assessment. Inter-group comparisons of total and voxel-level regional brain volume were conducted through Voxel Based Morphometry (VBM); cross-sectionally and longitudinally, analyzing the associations between brain changes and demographic, clinical, and cognitive outcomes. Results: The percentage of GM loss did not significantly differ in any of the groups compared with HC and when assessed independently, adult/late DM1 patients and their HC group suffered a significant loss in WM volume. Regional VBM analyses revealed subcortical GM damage in both DM1 groups, evolving to frontal regions in the pediatric onset patients. Muscular impairment and the outcomes of certain neuropsychological tests were significantly associated with follow-up GM damage, while visuoconstruction, attention, and executive function tests showed sensitivity to WM degeneration over time. Interpretation: Distinct patterns of brain atrophy and its progression over time in pediatric and adult/late onset DM1 patients are suggested. Results indicate a possible neurodevelopmental origin of the brain abnormalities in DM1, along with the possible existence of an additional neurodegenerative process. Fronto-subcortical networks appear to be involved in the disease progression at young adulthood in pediatric onset DM1 patients. The involvement of a multimodal integration network in DM1 is discussed.CIBERNED609 Eusko JaurlaritzaPRE_ 2016_1_0187PRE_2019_1_0070SAIO08- PE08BF01 Institute of Health Carlos III cofounded by Fondo Europeo de Desarrollo Regional-FEDERPI17/01231 PI17/0184

Transcriptional signatures of synaptic vesicle genes define myotonic dystrophy type I neurodegeneration

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

White matter integrity changes and neurocognitive functioning in adult-late onset DM1: a follow-up DTI study

[EN] 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.The present study has been supported by funding from the Institute of Health Carlos III co-founded by Fondo Europeo de Desarrollo Regional-FEDER [Grant Numbers PI17/01231 and PI17/01841], CIBERNED (Grant Number: 609), the Basque Government [SAIO08-PE08BF01] and the University of the Basque Country (Neurosciences group: GIU20-057). BC was supported by a predoctoral grant from the Basque Government [PRE-2020-1-0187]. AJM was supported by a predoctoral grant from the Basque Government [PRE-2019-1-0070]. JG was supported by a predoctoral grant from the University of the Basque Country [PIF20/238]

Patient-reported outcome measures in neuromuscular diseases : a scoping review

Patient-reported outcome measures (PROMs) are valuable in comprehensively understanding patients' health experiences and informing healthcare decisions in research and clinical care without clinicians' input. Until now, no central resource containing information on all PROMS in neuromuscular diseases (NMD) is available, hindering the comparison and choice of PROMs used to monitor NMDs and appropriately reflect the patient’s voice. This scoping review aimed to present a comprehensive assessment of the existing literature on using PROMs in children and adults with NMD. A scoping methodology was followed using Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) and COnsensus-based Standards for the selection of health Measurement Instruments (COSMIN) guidelines to assess the literature on PROMs in NMDs. Eligibility criteria encompassed articles describing psychometric development or evaluation of generic or disease-specific PROM-based instruments for adults and children with specific NMDs. The data charting process involved extracting measurement properties of included PROMs, comprising validity, reliability, responsiveness, and interpretability information. The review identified 190 PROMs evaluated across 247 studies in individuals with NMDs. The majority of PROMs were disease specific. The physical functioning domain was most assessed. Validity was the most frequently investigated measurement property, with a limited number of PROMs sufficiently evaluated for a range of psychometric characteristics. There is a strong need for further research on the responsiveness and interpretability of PROMs and the development of PROMs on social functioning in NMD

Aging in Myotonic Dystrophy Type 1: Analysis from a neuropsychological and neuroradiological approach

xvii, 181 p.La Distrofia Miotónica Tipo 1 (DM1) es la forma más común de Distrofia Muscular en adultos, ymuestra una prevalencia especialmente elevada en el área geográfica de Gipuzkoa, situándonos en elescenario idóneo para el estudio de esta población.Se trata de una enfermedad con base genética transmitida de manera autosómica dominante, cuya basemolecular corresponde a la mutación del gen proteinquinasa de la distrofia miotónica (DMPK),produciendo la expansión e inestabilidad de la repetición CTG. La DM1 se clasifica en base a la edad deinicio de la enfermedad y se han descrito distintos fenotipos.La afectación de la enfermedad es multisistémica, incluyendo alteraciones del SNC en grado variable.Entre la sintomatología del SNC se han descrito una variedad de déficits cognitivos, incluyendodificultades en cognición social. La presente tesis tiene como objetivo ahondar en las lagunas existentes adía de hoy en el campo de la investigación de la afectación del SNC en la DM1, mediante el estudioneuropsicológico y radiológico de estos pacientes, a lo que se da respuesta mediante cuatro estudioscientíficos.El primero de ellos analiza los déficits en cognición social de una muestra de pacientes y controles sanos,con el objetivo de estudiar si dichas dificultades representan un déficit central o, por el contrario, sonsecundarios a un funcionamiento cognitivo globalmente reducido. Los pacientes obtuvieron unrendimiento significativamente menor tan solo en una tarea de reconocimiento de emociones faciales. Enconclusión, se sugiere que los déficits que los pacientes con DM1 presentan en cognición social podríanestar supeditados al rendimiento cognitivo global, a excepción del reconocimiento de emociones faciales,que aparece como un déficit central en esta población.El segundo manuscrito consiste en un estudio de resonancia magnética (RM) transversal, en el que sehalló que los pacientes con DM1 presentan una atrofia global y difusa en comparación con controlessanos, tanto en sustancia blanca (SB) como en sustancia gris (SG), con un patrón de mayor afectación enáreas sensoriales primarias, multi-sensoriales y áreas corticales de asociación: fronto-temporo-parietal ysubcortical. La edad, la afectación muscular y la carga genética se asociaron al nivel de afectacióncerebral y las pruebas neuropsicológicas mostraron una alta sensibilidad al daño cerebral.El tercer estudio presentado en esta tesis tiene como objetivo el análisis longitudinal a nivel cognitivo deuna cohorte de pacientes y controles sanos a lo largo de 11 años de evolución. Los pacientes con DM1mostraron un mayor empeoramiento en tareas visuoconstructivas/visoespaciales y de memoria visual. Laprogresión de estos déficits se relacionó tanto el grado de severidad muscular que los pacientespresentaban en la línea base así como con la edad.Por último, se analizan longitudinalmente dos cohortes de pacientes (de inicio pediátrico y de inicioadulto) y controles sanos a través de RM. Los resultados sugieren que los pacientes con DM1 presentanuna trayectoria de desarrollo cerebral propio, así como un patrón de atrofia progresivo distinto alesperado en población sana. Paralelamente, los resultados apoyan que mientras los pacientes de iniciopediátrico sufren un daño subcortical que con el tiempo se expande a regiones frontales los pacientes deinicio adulto mantienen el daño en regiones subcorticales.Esta tesis amplia el conocimiento previamente existente en torno a la afectación del SNC en la DM1 yproporciona resultados que contribuyen a la discusión sobre la existencia de un envejecimiento aceleradoen la DM