We performed a one-year longitudinal MRI study of 14 MSA patients to investigate the progression of brain tissue loss in MSA. Comparison of MSA patients with controls confirmed a reduction of gray matter in the cerebellum and certain cortical areas and a reduction of white matter in the cerebellum, cerebellar peduncles and brainstem, already detectable at baseline. Analysis of the follow-up MRIs revealed further progression of brain matter loss.
The MSA within-group comparison between baseline and follow-up as well as the comparison of MSA patients and controls at follow-up showed progressive gray and white matter reduction mainly in regions that were already affected at baseline. Interestingly, these areas show partly resemblance with areas normally affected by age-related shrinkage (i.e., in healthy subjects). For example, the progressive reduction of the brainstem and cerebellum is well documented to occur during normal aging and is most prominent after the age of 50 years.22,23
This might also explain why the comparison of difference maps between MSA and controls did not reveal progressive tissue loss in all those regions, but only confirmed progressive white matter reduction of the middle cerebellar peduncles. As the latter approach (comparison of the difference maps) takes into account normal age-related decline of the brain, it may be more appropriate to depict disease-specific changes.
White matter tissue reduction along the middle cerebellar peduncles likely reflects a degeneration of the pontocerebellar tract as a particularly prominent and progressive morphological alteration in MSA brains. This finding is in line with the results of recent morphometric studies investigating tissue-specific properties such as diffusivity (diffusion-weighted images, diffusion tensor imaging) instead of MRI-signal alterations (VBM). These studies similarly identified degeneration of the middle cerebellar peduncles as a MSA-specific feature.12,24–28
Therefore, atrophy of the middle cerebellar peduncles seems to be the most robust, aging-independent, and disease-specific atrophy in MSA.
MSA within-group comparison between baseline and follow-up revealed not only reduction of white matter in typically affected regions like middle cerebellar peduncles and corticospinal tract but also across the entire corpus callosum. VBM - primarily developed to study gray matter - generates smoothed probability maps of white matter for the final statistical comparison. Due to methodological constraints, anatomical information contained within those maps may have only a limited precision regarding the exact anatomical localisation of affected callosal subregions. The prominent involvement of the corpus callosum was therefore independently validated by a second morphometric method to explore the regional pattern of callosal atrophy in MSA patients, in great detail. For this purpose, we investigated corpus callosum thickness at 100 points across the callosal surface. At baseline, we found a deficit in callosal thickness in MSA patients compared to controls in the anterior and posterior body, extending even further posteriorly at follow-up. According to recent DTI-based study of callosal connectivity, the anterior midbody connects cortical premotor and supplementary motor regions between both hemispheres.29
The posterior midbody contains the highest density of fibres with a large diameter30
and is linked to the primary motor cortex.29
Thus, the observed pattern of callosal atrophy agrees closely with the predominant impairment of motor functions in MSA patients. As we investigated a mixed patient sample including MSA-C and MSA-P patients, further studies will need to determine whether callosal atrophy is equally associated with both clinical subtypes.
So far, little attention has been paid to callosal atrophy in MSA, although glial cytoplasmic inclusions have been observed in the corpus callosum as well.3,31
Watanabe et al. used a ROI-based MRI approach and detected callosal atrophy in a subgroup of MSA patients, not correlating with disease duration.7
Since they also found signs of cortical atrophy in MSA patients with callosal atrophy, the authors suggested a link between cortical and callosal atrophy. Another study found callosal atrophy only in MSA-P but not in MSA-C patients.32
Cerebellar atrophy, especially of the middle cerebellar peduncles, is one of the most prominent findings in MSA, but its degree depends on the clinical subtype and is highly variable, whereas the degree of cortical atrophy was more similar in both subtypes.10,33,34
To validate new therapies it would be advantageous to have morphological markers of disease progression independently of the clinically dominant symptom. If callosal atrophy occurs as a result of Wallerian degeneration, it can serve as an indirect neuroanatomical marker for cortical atrophy. Especially neuronal loss in the third cortical layer results in axonal degeneration and consecutive callosal atrophy and has been described in neurodegenerative disorders like Alzheimer’s disease, frontotemporal dementia, progressive supranuclear palsy and corticobasal degeneration.35–37
Separation of age-related from disease-related callosal atrophy is critical and essential for its use as morphological marker in follow-up investigations. However, regionally circumscribed callosal atrophy as described here for MSA may possibly reflect a disease-specific pattern of neurodegeneration and cortical atrophy respectively.