Beyond motor neurons: new insights on amyotrophic lateral sclerosis neurodegeneration provided by advanced MRI technique

Aim Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, characterized by the progressive degeneration of upper and lower motor neurons, but does not spare extra-motor areas, causing cognitive and behavioural syndromes. To better investigate structural and functional abnormalities in ALS, we used resting-state fMRI data combined to VBM analysis and a quantitative DTI approach, by a TBSS analysis, in a population of behaviour impaired ALS patients. Methods We investigated 20 ALS patients (10 women and 10 men) ranging from 34 to 80 years (mean age 60.7 ± 11.1) of age, fulfilling the diagnostic criteria for probable or definite ALS, according to the revised El Escorial criteria of the World Federation of Neurology. The control group comprised 20 healthy controls (10 men, 10 women) aged from 46 to 78 years (mean age 62.1 + 8.5 years) with no history of neurological or psychiatric diseases and without any abnormalities detected on conventional MRI T1 and T2 weighted images. Magnetic resonance images were acquired on a 3-T GE Medical System scanner equipped with an 8-channel parallel head coil. Results The sensori-motor network (SMN) showed significant disease effects, with signal suppression in patients in the primary and the supplementary motor cortices. The same was visible frontally in the right fronto-parietal network, possibly reflecting the patients' frontal dysfunction. Compared with controls, ALS patients had significant clusters of reduced GM density in the left premotor and right fronto-parietal cortex. DTI analysis showed reduced FA values in the body of corpus callosum (CC) and bilaterally in WM tracts from the central CC to primary motor and premotor cortices, also including, with slight prevalence in the left hemisphere, corona radiata, anterior cingulate, superior longitudinal, inferior longitudinal, inferior occipito-frontal and uncinate fasciculi. The DTI pattern of predominantly frontal WM injury clearly reflects the frontal executive dysfunction that characterizes our ALS patients, and is in agreement with the growing body of evidence that degeneration of the frontotemporal lobar type may occur in ALS with a variable range of behavioral and cognitive impairments among patients. In patients a significant decrease of FA compared to controls mainly in the midbody of the CC, where for reduced FA vs increased UMN score a strong significant correlation was also seen. Additionally, for reduced FA vs lower ALS functional rating scale revised (ALSFRS-R), index of patients' disability, a striking trend of correlation was found both in in the WM underneath the left premotor cortex, especially the left paracentral lobule, including also anterior cingulate and superior longitudinal fasciculus. We confirmed the effect of ALS on the SMN network and investigated the possible extramotor involvement in ALS. The correlations between reduction of FA in the body of CC with the UMN score indicate that the WM degeneration in the CC is strictly related to the ALS pyramidal impairment, whilst the correlation between FA and ALSFRS-R in the associative tracts underneath the left premotor cortex might reflect the progressive spread of the disease from motor towards extra-motor areas