Cognitive Impairment in Myotonic Dystrophy Type 1 Is Associated with White Matter Damage

Abstract

ObjectiveTo investigate grey (GM) and white matter (WM) abnormalities and their effects on cognitive and behavioral deficits in a large, phenotypically and genotypically well-characterized cohort of classic adult (aDM1, age at onset ≥20 years) or juvenile (jDM1, age at onset <20 years) patients with myotonic dystrophy type 1 (DM1).MethodsA case-control study including 51 DM1 patients (17 jDM1 and 34 aDM1) and 34 controls was conducted at an academic medical center. Clinical, cognitive and structural MRI evaluations were obtained. Quantitative assessments of regional GM volumes, WM hyperintensities (WMHs), and microstructural WM tract damage were performed. The association between structural brain damage and clinical and cognitive findings was assessed.ResultsDM1 patients showed a high prevalence of WMHs, severe regional GM atrophy including the key nodes of the sensorimotor and main cognitive brain networks, and WM microstructural damage of the interhemispheric, corticospinal, limbic and associative pathways. WM tract damage extends well beyond the focal WMHs. While aDM1 patients had severe patterns of GM atrophy and WM tract damage, in jDM1 patients WM abnormalities exceeded GM involvement. In DM1, WMHs and microstructural damage, but not GM atrophy, correlated with cognitive deficits.ConclusionsWM damage, through a disconnection between GM structures, is likely to be the major contributor to cognitive impairment in DM1. Our MRI findings in aDM1 and jDM1 patients support the hypothesis of a degenerative (premature aging) origin of the GM abnormalities and of developmental changes as the principal substrates of microstructural WM alterations in DM1.

Tracking the brain in myotonic dystrophies: A 5-year longitudinal follow-up study

“…Patterns of white matter changes were consistent, highly similar at baseline and follow-up, and also similar to our previous study [10]. This indicates strong, reproducible and robust effects that had been shown previously [8, 9, 11, 13, 14, 52, 53]. Using VBM and DTI difference maps analyses, we could demonstrate that there were no relevant differences in brain morphological changes over time between myotonic dystrophy patients and controls within the observation period.…”

Tracking the brain in myotonic dystrophies: A 5-year longitudinal follow-up study

“…Patterns of white matter changes were consistent, highly similar at baseline and follow-up, and also similar to our previous study [10]. This indicates strong, reproducible and robust effects that had been shown previously [8, 9, 11, 13, 14, 52, 53]. Using VBM and DTI difference maps analyses, we could demonstrate that there were no relevant differences in brain morphological changes over time between myotonic dystrophy patients and controls within the observation period.…”

Relationship of white and gray matter abnormalities to clinical and genetic features in myotonic dystrophy type 1

“…multiple T2-hyperintense white matter lesions associated with different degrees of lateral ventricle enlargement, ranging from mild to severe. Our conventional imaging data are consistent with previous studies showing brain alterations in DM1 ( Antonini et al, 2004 , Giorgio et al, 2006 , Ota et al, 2006 , Weber et al, 2010 , Minnerop et al, 2011 , Wozniak et al, 2011 , Franc et al, 2012 , Wozniak et al, 2013 , Caso et al, 2014 , Wozniak et al, 2014 , Serra et al, 2015 ), although, compared to previous studies that quantified white matter lesion load ( Antonini et al, 2004 , Caso et al, 2014 , Serra et al, 2015 ), our patients presented a more severe white matter involvement, in absence of overall significant cognitive deficits.…”

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

“…Further, adult/late onset patients showed a GM decrease that remained confined to the basal ganglia. Subcortical involvement in DM1 has repeatedly been reported 26,28,29,40–42 and this is confirmed in our study. Moreover only in the adult/late subgroup was the opposite result found, primarily located in the temporal lobe.…”

“…Subcortical involvement in DM1 has repeatedly been ª 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association reported 26,28,29,[40][41][42] and this is confirmed in our study. Moreover only in the adult/late subgroup was the opposite result found, primarily located in the temporal lobe.…”

Tracking the brain in myotonic dystrophies: A 5-year longitudinal follow-up study

“…Patterns of white matter changes were consistent, highly similar at baseline and follow-up, and also similar to our previous study [10]. This indicates strong, reproducible and robust effects that had been shown previously [8, 9, 11, 13, 14, 52, 53]. Using VBM and DTI difference maps analyses, we could demonstrate that there were no relevant differences in brain morphological changes over time between myotonic dystrophy patients and controls within the observation period.…”

Relationship of white and gray matter abnormalities to clinical and genetic features in myotonic dystrophy type 1

“…multiple T2-hyperintense white matter lesions associated with different degrees of lateral ventricle enlargement, ranging from mild to severe. Our conventional imaging data are consistent with previous studies showing brain alterations in DM1 ( Antonini et al, 2004 , Giorgio et al, 2006 , Ota et al, 2006 , Weber et al, 2010 , Minnerop et al, 2011 , Wozniak et al, 2011 , Franc et al, 2012 , Wozniak et al, 2013 , Caso et al, 2014 , Wozniak et al, 2014 , Serra et al, 2015 ), although, compared to previous studies that quantified white matter lesion load ( Antonini et al, 2004 , Caso et al, 2014 , Serra et al, 2015 ), our patients presented a more severe white matter involvement, in absence of overall significant cognitive deficits.…”

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

“…Further, adult/late onset patients showed a GM decrease that remained confined to the basal ganglia. Subcortical involvement in DM1 has repeatedly been reported 26,28,29,40–42 and this is confirmed in our study. Moreover only in the adult/late subgroup was the opposite result found, primarily located in the temporal lobe.…”

“…Subcortical involvement in DM1 has repeatedly been ª 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association reported 26,28,29,[40][41][42] and this is confirmed in our study. Moreover only in the adult/late subgroup was the opposite result found, primarily located in the temporal lobe.…”

Tracking the brain in myotonic dystrophies: A 5-year longitudinal follow-up study

“…Patterns of white matter changes were consistent, highly similar at baseline and follow-up, and also similar to our previous study [10]. This indicates strong, reproducible and robust effects that had been shown previously [8, 9, 11, 13, 14, 52, 53]. Using VBM and DTI difference maps analyses, we could demonstrate that there were no relevant differences in brain morphological changes over time between myotonic dystrophy patients and controls within the observation period.…”

Relationship of white and gray matter abnormalities to clinical and genetic features in myotonic dystrophy type 1

“…multiple T2-hyperintense white matter lesions associated with different degrees of lateral ventricle enlargement, ranging from mild to severe. Our conventional imaging data are consistent with previous studies showing brain alterations in DM1 ( Antonini et al, 2004 , Giorgio et al, 2006 , Ota et al, 2006 , Weber et al, 2010 , Minnerop et al, 2011 , Wozniak et al, 2011 , Franc et al, 2012 , Wozniak et al, 2013 , Caso et al, 2014 , Wozniak et al, 2014 , Serra et al, 2015 ), although, compared to previous studies that quantified white matter lesion load ( Antonini et al, 2004 , Caso et al, 2014 , Serra et al, 2015 ), our patients presented a more severe white matter involvement, in absence of overall significant cognitive deficits.…”

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

“…Further, adult/late onset patients showed a GM decrease that remained confined to the basal ganglia. Subcortical involvement in DM1 has repeatedly been reported 26,28,29,40–42 and this is confirmed in our study. Moreover only in the adult/late subgroup was the opposite result found, primarily located in the temporal lobe.…”

“…Subcortical involvement in DM1 has repeatedly been ª 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association reported 26,28,29,[40][41][42] and this is confirmed in our study. Moreover only in the adult/late subgroup was the opposite result found, primarily located in the temporal lobe.…”