We present a comprehensive study of brain structure and function in a comparably large series of patients with myotonic dystrophy types 1 and 2. Our neuroimaging findings confirmed the major hypotheses of our study: we found severe white matter effects in patients with myotonic dystrophy type 1, more than in patients with myotonic dystrophy type 2, which extensively exceeded grey matter involvement in both disorders. We applied DTI based on diffusion MRI, which is a suitable method for white matter evaluation. Even though VBM is not the method of choice for white matter evaluation, our DTI results were strongly supported by VBM analyses.
White matter effects were found throughout the whole brain in myotonic dystrophy types 1 and 2, affecting association fibres, commissural fibres (mainly corpus callosum), and projection fibres in the brainstem, internal and external capsules, the latter connecting prefrontal and temporal cortical areas with the striatum. Thalamocortical pathways (e.g. anterior thalamic radiation) and prefrontal connections are represented in anterior limbs of internal capsules, which were affected in myotonic dystrophy types 1 and 2. Interestingly, anterior limb lesions had previously been described in the context of behavioural problems and cognitive dysfunction (Mamah et al., 2010
). In contrast, central motor pathways (e.g. corticospinal tracts located in posterior limbs of internal capsules) were exclusively affected in myotonic dystrophy type 1.
Our data on white matter in adult patients with myotonic dystrophy type 1 give evidence that callosal body affection is not restricted to congenital myotonic dystrophy type 1. Current results confirm callosal body affection in patients with myotonic dystrophy type 2 as previously demonstrated by our VBM and surface-based morphometry analyses (Minnerop et al., 2008
), and demonstrate a predominant affection of anterior callosal fibres connecting frontal lobes in myotonic dystrophy type 2. We further found degradation of major pathways of the limbic system (e.g. fornix, cingulum bundle) in patients with myotonic dystrophy type 1, more than in patients with myotonic dystrophy type 2. This finding could be associated with behavioural abnormalities and emotional disturbances in myotonic dystrophies. This question should be addressed in future studies investigating personality traits in both disorders.
In the current patient series, cortical grey matter affection was only found in myotonic dystrophy type 1. Cortical grey matter loss was located in frontal and parietal regions, whereas subcortical grey matter loss was detected in thalamic and basal ganglia structures. This is in line with the literature, describing widespread cortical and subcortical grey matter alterations in myotonic dystrophy type 1 (Antonini et al., 2004
; Weber et al., 2010
). Previous analyses, including one of our own studies, also found grey matter changes in myotonic dystrophy type 2 (Minnerop et al., 2008
; Weber et al., 2010
). This discrepancy to our present data may be attributed to differences in sample size as earlier studies investigated smaller patient cohorts.
Though our patients with myotonic dystrophy type 2 were older than our patients with myotonic dystrophy type 1, the myotonic dystrophy type 2 cohort encompassed rather ‘young’ subjects regarding the common disease manifestation at higher ages. With respect to the clinical course of myotonic dystrophy type 2, an older cohort with longer disease durations might have been more appropriate. Less pronounced cerebral grey and white matter affection in patients with myotonic dystrophy type 2 compared with patients with myotonic dystrophy type 1 might be partially explained by this fact.
White matter lesions and brain atrophy are well known in myotonic dystrophy types 1 and 2, but current data stress that the underlying pathology seems to (i) affect white matter much more than grey matter and (ii) affect white matter far beyond circumscribed white matter lesions visible on T2
-weighted MRIs. These findings link myotonic dystrophies to the growing group of brain disconnection disorders. The neuropathological background of white matter changes in myotonic dystrophies is still not fully understood. Neuropathological findings in myotonic dystrophy type 1 brains include abnormalities like intracytoplasmic inclusions in thalamus, striatum, cerebral cortex and brainstem (Rosman and Kakulas, 1966
; Wiśniewski et al., 1975
; Ono et al., 1987
). Further studies in myotonic dystrophy type 1 and myotonic dystrophy type 2 brains found evidence of neurofibrillary degeneration with intracellular aggregation of microtubule-associated tau protein (Vermersch et al., 1996
; Sergeant et al., 2001
; Maurage et al., 2005
; Itoh et al., 2010
). Most changes are located in neurons; however, white matter alterations including disordered arrangement of myelin sheaths and axons have been described (Abe et al., 1994
; Ogata et al., 1998
; Itoh et al., 2010
). It is widely accepted that the integrity of axonal membranes and myelin sheaths are the main biological causes of anisotropy in DTI (Beaulieu, 2002
). Reduced fractional anisotropy values in the current study were primarily linked with an increase of radial diffusivity. Increased radial diffusivity can be either caused by reduced myelin sheaths/defect axonal membranes or as a consequence of neuronal cell loss with Wallerian degeneration. A likely explanation for our finding of an additional increase of axial diffusivity (theoretically leading to an increase of fractional anisotropy) in some areas with fractional anisotropy reduction is increased water content in the context of atrophy as described in the ‘healthy’ ageing brain (Moseley, 2002
). This phenomenon leads to an increase of both radial more than axial diffusivity, finally resulting in a decrease of fractional anisotropy. The changes of diffusivity in white matter fibre tracts were more prominent in myotonic dystrophy type 1 than type 2. This is possibly a consequence of genetic differences with a disease-specific pathomechanism of tissue destruction, which however results in abnormal increases of water diffusion perpendicular to axons in both disorders. We have to consider that reduced fractional anisotropy values in genetically determined disorders might not reflect ongoing destructive processes, but instead a developmental defect with disturbed assembly of myelin and/or axonal membranes. The widespread changes in myotonic dystrophy type 1 may point towards a generalized white matter defect. However, the correlation of lower fractional anisotropy values with longer disease duration and higher age in myotonic dystrophy type 1 and myotonic dystrophy type 2 strongly argue for an ongoing destruction of myelin and/or axonal loss over time. The fact that white matter changes by far dominated the extent of grey matter changes in myotonic dystrophy types 1 and 2 might further argue against Wallerian degeneration as the major cause of white matter alterations as formerly postulated (Ota et al., 2006
Relation of white matter integrity and motor function
Impaired motor function due to muscle affection is one of the most characteristic symptoms in myotonic dystrophy types 1 and 2. However, subclinical dysfunction of the central motor system had been described in myotonic dystrophy type 1 (Oliveri et al., 1997
; Mitsuoka et al., 2003
). We found reduced fractional anisotropy values in posterior limbs of internal capsules (corticospinal tract) in myotonic dystrophy type 1, not in myotonic dystrophy type 2, which correlated with motor performance in a simple motor task (bimanual pegboard). In the group comparison, we found reduced fractional anisotropy values along external capsules in patients with myotonic dystrophy types 1 and 2, correlating with the Muscular Impairment Rating Scale score (measuring muscular impairment) in myotonic dystrophy type 1 and motor performance in myotonic dystrophy type 1 and type 2. The external capsule contains corticostriatal projection fibres connecting (pre)-frontal and temporal areas with basal ganglia, known to play a major role in motion planning and execution. A recent functional MRI study in myotonic dystrophy type 1 showed activation patterns in central motor system areas that resembled those in healthy older subjects (Caramia et al., 2010
). Taken together, these findings give evidence of impaired central motor functioning in myotonic dystrophies, potentially reflecting an accelerated or increased ageing process.
Neuropsychological deficits, especially of executive and visuospatial functions, have been frequently described in myotonic dystrophy types 1 and 2 (Meola et al., 1999
; Gaul et al., 2006
; Meola and Sansone, 2007
; Romeo et al., 2010
). However, most tests investigating frontal functions depend on some motor response, which may be impaired in myotonic dystrophies. While several neuropsychological studies did not address impaired motor performance as a possible confounding factor in their study design, other studies tried to solve this issue by excluding patients with a certain degree of muscular impairment (Meola et al., 2003
; Gaul et al., 2006
) or to select motor-independent tests (Modoni et al., 2004
; Gaul et al., 2006
). We tried to correct for motor performance by including a score for fine motor skills as covariate. We found only minor neuropsychological deficits in our patients. Patients with myotonic dystrophy type 1, usually thought to be more cognitively impaired than patients with myotonic dystrophy type 2, even showed a better performance in the verbal memory task compared with controls. This is not explained by age differences of patients with myotonic dystrophy type 1 and controls, since patients with myotonic dystrophy type 1 still performed above average in comparison to age-matched normative data. Increased liability for interference was the only significant neuropsychological deficit in our myotonic dystrophy type 1 series and also significantly present in myotonic dystrophy type 2, which additionally showed impaired focused attention, pointing towards frontal lobe dysfunction in both myotonic dystrophy types 1 and 2. These results are in line with earlier studies showing that impaired frontal lobe function is a predominant finding in myotonic dystrophies (Meola et al., 2003
). The discrepancy regarding the extent of cognitive deficits between previous studies and our results might be at least partially explained by methodological differences as correction for fine motor performance. This is supported by findings of Gaul et al. (2006)
who also found only subtle prefrontal lobe dysfunction when excluding patients with severe motor impairment and selecting more motor-independent tests. The clinical impression of cognitive decline particularly in adult patients with myotonic dystrophy type 1 may thus be partly unjustified and rather due to a combination of facial muscular weakness, depression and the highly underestimated, however frequent and treatable, symptoms of fatigue/increased daytime sleepiness. One further explanation for the presence of only minor neuropsychological deficits in our patient series might be a selection bias towards cognitively less severely affected individuals. The study participation lasted about 4–5
h in an outpatient setting, and patients with a serious mental impairment might have been more likely to refuse study participation. Third, there is some evidence that neuropsychological deficits in myotonic dystrophies might partially escape commonly applied neuropsychological test batteries due to still unclear reasons. This observation is primarily based on the personal experience of neurologists and neuropsychologists specialized in myotonic dystrophies. Consequently, a current international intention is to find a consensus on neuropsychological tests to be generally recommended for use in patients with myotonic dystrophy worldwide. Accordingly, the most sensitive and reliable, best validated, and most applicable tests are expected to be selected in the near future. Our neuropsychological test selection was a compromise resulting from our experience in patients with neurological/neurodegenerative disorders and the time constraints that were dictated by the study protocol (combined neuroimaging study). For practical reasons, we used (i) the German NeuroCogFX
, which is validated in a variety of neurological disorders and has also been applied to other trinucleotide repeat disorders (Fliessbach et al., 2006
; Hoppe et al., 2009
; Klinke et al., 2010
) and (ii) the Cerebraler Insuffizienztest
(Lehrl and Fischer, 1997
), which assesses attention and interference in a reliable and fast way compared with other frontal lobe function tests. However, some of the applied tests had not previously been systematically used in myotonic dystrophies. Thus, the selection of the neuropsychological test battery might have additionally influenced the neuropsychological profiling of our patients.
Relation of white matter integrity and depression
Depressive symptoms are well known in myotonic dystrophy types 1 and 2, but do not seem to be a prominent feature if DSM-IV (Diagnostic and Statistical Manual of Mental Disorders) criteria are applied (Meola and Sansone, 2007
). Using the self-rating questionnaire BDI, Winblad et al. (2010)
found signs of mostly mild depression in 32% of examined patients with myotonic dystrophy type 1, which is identical to our findings in myotonic dystrophy type 1 (32%) and type 2 (38%). However, it is still a matter of debate if depression might be a consequence of structural brain damage or rather a reactive adjustment disorder. We therefore investigated the interaction between fractional anisotropy reduction and BDI scores and found higher BDI scores associated with higher fractional anisotropy values in myotonic dystrophy type 1, whereas higher BDI scores were associated with lower fractional anisotropy values in myotonic dystrophy type 2. Regression analyses in myotonic dystrophy type 1 and type 2 revealed a decline of fractional anisotropy with increasing age and disease duration. Thus, our results implicate that depressed mood in myotonic dystrophy type 1 might be more pronounced in earlier disease stages, whereas depression is more likely to be found in later disease stages of myotonic dystrophy type 2. Our results are supported by recent data of Winblad et al. (2010)
: the authors found less depressive symptoms in patients with myotonic dystrophy type 1 with a longer disease duration and presence of white matter lesions, whereas patients with myotonic dystrophy type 1 without white matter lesions had more depressive symptoms (Winblad et al., 2010
). If depressed mood was a consequence of structural brain affection, a continuous worsening of depression would be expected as myotonic dystrophy types 1 and 2 progress. Our results indicate that depression might be a reactive adjustment disorder rather than a consequence of structural brain damage in myotonic dystrophies. Myotonic dystrophy type 1 is more severe in general and leads to a more serious impairment in earlier life than myotonic dystrophy type 2. Therefore, patients with myotonic dystrophy type 1 are more likely to notice early limitations in everyday activities and develop reactive depression. As disease progresses, these patients may develop efficient coping strategies or may be less able to perceive their limitations due to cognitive deficits or personality changes. Since we found only minor neuropsychological deficits, the so called ‘lack of awareness’ may explain the presence of a less depressed mood in advanced disease stages (Meola and Sansone, 2007
; Winblad et al., 2010
). This condition has previously been linked to localized brain lesions in other disorders, affecting regions (prefrontal cortex, frontal and parietotemporal areas, thalamus) that also show structural abnormalities in myotonic dystrophy type 1 (Orfei et al., 2008
; Winblad et al., 2010
). Myotonic dystrophy type 2 is usually less severe, and patients may not notice serious limitations in everyday life in early disease stages. Symptoms worsen over time and may cause depression in advanced disease stages. However, we did not find direct correlations between BDI scores and age or disease duration in myotonic dystrophy type 1 or 2.
The use of additional depression scores would have been favourable, though was not practicable in the present comprehensive study setting, which took several hours and required careful consideration of patients' psychophysical limits as well as time constraints.
Relation of white matter integrity and increased daytime sleepiness/fatigue
Increased daytime sleepiness and fatigue are among the most frequent non-muscular symptoms in patients with myotonic dystrophy type 1 and type 2 (Hilton-Jones, 1997
; van der Werf et al., 2003
; Meola and Sansone, 2007
; Laberge et al., 2009a
; Tieleman et al., 2010
). Weak oropharyngeal and respiratory muscles leading to obstructive sleep apnoea and alveolar hypoventilation have been regarded as causative factors of daytime sleepiness. However, there is increasing evidence that tiredness primarily results from CNS dysfunction rather than progressive respiratory weakness (van der Meché et al., 1994
; Park and Radtke, 1995
; Rubinsztein et al., 1998
; Laberge et al., 2009a
; Romigi et al., 2011
; Yu et al., 2011
). An association with the hypocretin neurotransmission system had been suggested. However, data regarding the role of hypocretin-1, a hypothalamic neuropeptide essential in the regulation of the sleep/wakefulness cycle and vigilance, are still controversial (Martínez-Rodriguez et al., 2003
; Ciafaloni et al., 2008
Fatigue, equivocally defined as a lack of energy and feeling of exhaustion (Shen et al., 2006
), is a prominent and common complaint in myotonic dystrophy type 1 (60–80%; Kalkman et al., 2005
; Meola and Sansone, 2007
; Laberge et al., 2009b
; Tieleman et al., 2010
). The prevalence of fatigue in myotonic dystrophy type 2 has been investigated only very recently, finding a similar result of 66% (Tieleman et al., 2010
). These data are in accordance with our findings, showing a prevalence of 68–70% fatigue in patients with myotonic dystrophy types 1 and 2. While our patients with myotonic dystrophy type 1 differed from controls in all sleepiness and fatigue scales, patients with myotonic dystrophy type 2 differed from controls only in PSQI and KFSS scores, not in daytime sleepiness scales. This again is in line with findings of Tieleman et al. (2010)
. Subjective sleep quality, as measured by the total PSQI score, was impaired in ~40% of both patient groups, which might be an indicator of a disturbed sleep/awakening cycle in myotonic dystrophy types 1 and 2 and should be further examined by polysomnographic studies.
We performed correlation analyses to evaluate the relation between fatigue (KFSS score) and white matter integrity (fractional anisotropy values). Similar to results of regression analyses with BDI scores, we found that higher fractional anisotropy values were associated with more pronounced fatigue in myotonic dystrophy type 1. In contrast, lower fractional anisotropy values were associated with more pronounced fatigue in myotonic dystrophy type 2. In contrast to previous findings, anterior corpus callosum integrity did not correlate with fatigue in our study (Giubilei et al., 1999
Damage to the reticular activating system of the upper brainstem and/or to its cortical projections has already been discussed as related to the chronic fatigue syndrome (Dickinson, 1997
). Morphological brainstem changes in myotonic dystrophy type 1 include neurofibrillary tangles, Marinesco bodies, as well as a decrease of serotonergic neurons in raphe nuclei and catecholaminergic neurons in the medullary reticular formation (Ono et al., 1987
; Oyamada et al., 2006
). Interestingly, sleep disturbances and apathy were more frequent in patients with myotonic dystrophy type 1 with fewer neurofibrillary tangles (Oyamada et al., 2006
). We comparably depicted less fatigue with more pronounced brainstem affection in patients with myotonic dystrophy type 1. Thus, myotonic dystrophy type 1 specific brainstem changes might prevent the feeling of fatigue or again might result in a lack of self-awareness.
Laberge et al. (2009b)
found higher depression scores, more muscular impairment, and higher number of CTG repeats in patients with myotonic dystrophy type 1 with fatigue and/or increased sleepiness. This in accordance with our results in myotonic dystrophy type 1, as we found higher KFSS scores correlating with both poorer motor performance and higher BDI scores. In contrast, we did not find a correlation of KFSS with BDI scores in myotonic dystrophy type 2, whereas higher KFSS scores correlated with poorer motor performance similar to myotonic dystrophy type 1 and to controls.
Thus, depressed mood and fatigue were closely related at least in myotonic dystrophy type 1. BDI and KFSS may overlap with regard to the target symptoms, and some questions of the BDI are known to target on symptoms of sleepiness and fatigue. In myotonic dystrophy type 2, we found similar directed correlations of fractional anisotropy values, BDI and KFSS scores. However, we did not find BDI and KFSS scores correlating with each other as shown in myotonic dystrophy type 1. Thus, one might conclude that the applied questionnaires are measuring partially overlapping, but not entirely identical conditions.
Polysomnographic studies as well as the use of further fatigue, anxiety and apathy scales like the Checklist Individual Strength or the Hospital Anxiety and Depression Scale would have been of interest but were not applicable in the current study setting. However, the present data warrant further investigations in the near future.
Relation of white matter integrity and age, disease duration and CTG repeat size
The pattern of affected fibre tracts in correlation analyses with age and disease duration was identical in our myotonic dystrophy type 1 but not the myotonic dystrophy type 2 group. Disease onset in general is earlier in myotonic dystrophy type 1, usually resulting in a parallel progression of disease and ageing. Consequently, the effect of age and disease duration cannot be easily separated in myotonic dystrophy type 1. However, since age and disease duration were not correlated in our patient groups, it is tempting to speculate that the effect of the disease itself on white matter structure resembles effects of ageing in myotonic dystrophy type 1. In myotonic dystrophy type 2, we found more frontally located areas with fractional anisotropy reduction that correlated with age but not with disease duration. This might be interpreted as a stronger effect of age in these distinct regions. Accelerated or premature ageing has been discussed in myotonic dystrophy type 1 (Toscano et al., 2005
; Oyamada et al., 2006
; Romigi et al., 2011
), and age-specific translational dysfunctions have been described in myotonic dystrophy type 2 (Jin et al., 2009
). Frontal-lobe accentuated white matter changes in myotonic dystrophy type 2, which correlated with age, may support this hypothesis since fractional anisotropy reduction in frontal regions had been described in normal ageing previously (Damoiseaux et al., 2009
). A recent study investigated the time course of radial and axial diffusivity changes during ageing in the callosal body, which strikingly mirrors diffusivity changes present in our myotonic dystrophy type 1 and type 2 groups (; Lebel et al., 2010
). The same study showed a sharp drop of fractional anisotropy values in anterior regions of the corpus callosum and a more substantial fractional anisotropy drop in outer sections of the callosal body with increasing age. While fractional anisotropy values were reduced along the entire corpus callosum in our myotonic dystrophy type 1 series, mainly anterior parts of the callosal body were affected in myotonic dystrophy type 2. These anterior callosal body fractional anisotropy reductions correlated with age and showed the peak fractional anisotropy loss with age in right outer sections. This might further underline similarities with normal ageing and might suggest an accelerated or more pronounced ageing process in patients with myotonic dystrophy types 2 and 1 compared with controls.
CTG repeat expansion sizes in blood are traditionally used as ‘biomarkers’ for disease severity in myotonic dystrophy type 1. Thus, there are a multitude of neuroimaging studies that have examined the relation of brain affection and CTG repeat lengths. However, results are highly controversial, and most studies failed to find any correlations (Kassubek et al., 2003
; Antonini et al., 2004
; Di Costanzo et al., 2008
). This might be due to the marked somatic mosaicism of CTG repeat lengths. There are considerable tissue variations in repeat sizes with rather small expansions in blood and much larger expansions in heart or skeletal muscle tissue. Moreover, repeat sizes may increase throughout life even in post-mitotic tissues, which suggests that repeat lengths in blood might not correlate with repeat lengths in brain and cerebral affection. Nevertheless, a variety of neuroimaging studies did show more serious morphological cerebral changes with larger repeat expansions in adult patients (Ota et al., 2006
; Romeo et al., 2010
). Our present findings equally showed that larger CTG repeat sizes were associated with more severe white matter affection in several brain regions. Remarkably, the pattern of fibre tract degradation that was associated with larger CTG repeats was similar to the pattern that was associated with higher age and longer disease duration. These findings again may indicate that the effect of the disease itself on white matter structure resembles the effects of ageing in myotonic dystrophy type 1. Specific brain regions might be particularly susceptible to the disease effects that are reflected by CTG repeat lengths and disease duration.
Altogether, our data suggest that white matter affection is progressive over time in myotonic dystrophies. Despite this tempting speculation, cross-sectional data and correlation analyses, as obtained in our study, do not sufficiently allow analyses of the age- and disease duration-related impact on brain morphology in myotonic dystrophy types 1 and 2. Longitudinal MRI studies investigating the progress of grey and white matter changes over time and its role in clinical deterioration in both types of myotonic dystrophies are strongly required to address these issues appropriately in the future.