Silvia Basaia1, Federica Agosta1, Alexandra Tomic2, Elisabetta Sarasso1, Nikola Kresojević2, Sebastiano Galantucci1, Marina Svetel2, Vladimir S. Kostic2, and Massimo Filippi1,3
1Neuroimaging Research Unit, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy, 2Clinic of Neurology, Faculty of Medicine, University of Belgrade, Belgrade, Yugoslavia, 3Department of Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
Synopsis
We investigated structural neural pathways in asymptomatic and symptomatic mutation carriers with
several dystonia (DYT) genotypes using a network approach. Both symptomatic and
asymptomatic mutation carriers showed an alteration of structural connectivity
compared to controls, beyond the basal ganglia/sensorimotor cortex regions. No
differences were found between symptomatic and asymptomatic DYT subjects. The
structural connectome offered the possibility of identifying genotype-related
trait characteristics, even in the preclinical phase of the disease, providing
new insights into understanding DYT generation.Purpose
Primary dystonia (DYT) has traditionally been
attributed to basal ganglia dysfunction. Recent studies expanded this picture
suggesting primary DYT as a circuit disorder. This study investigated
structural neural pathways in clinically manifesting and non-manifesting
individuals with several DYT genotypes using a network approach.
Methods
This study included a large series of clinically
manifesting and non-manifesting DYT mutation carriers. Specifically, we
enrolled 9 asymptomatic mutation carriers (4 DYT1, 4 DYT6, 1 DYT10) and 26
symptomatic mutation carriers (7 DYT1, 7 DYT6, 9 DYT5 or dopa-responsive
dystonia, 1 DYT18, 1 DYT10, and 1 DYT25). 37 age- and sex-matched healthy
controls were also studied. Subjects underwent 3D T1 weighted and diffusion
tensor (DT) MRI. The human macroscale connectome – a comprehensive map
describing all neural connections between large-scale brain regions – was
constructed from DT MRI. Tissue segmentation was performed on T1 images using
Freesurfer. Parcellation of
the segmented gray matter mask into 83 distinct brain regions was based on
Desikan atlas, including basal ganglia. Tractography was performed to
reconstruct the white matter tracts forming the structural brain network. From
the total collection of reconstructed streamlines those connecting each couple
of nodes i and j were selected. Then, from the selected fiber
streamlines, the average fractional anisotropy (FA) and mean diffusivity (MD)
values were computed. This value entered into cell c(i,j) in the matrix.
The affected structural
connections in patients with manifesting and non-manifesting DYT relative to
healthy controls and each other were investigated using Network-Based Statistic
(p<0.01, 10.000 permutations).
Results
Compared
to controls, asymptomatic mutation carriers showed a basal ganglia/frontal subnetwork
characterized by decreased FA and increased MD including the left putamen, precentral
gyrus, middle and superior frontal gyri, middle temporal, and insula (Fig. 1).
Clinically manifesting DYT mutation carriers relative to controls showed an
altered subnetwork characterized by increased MD connecting left putamen,
middle and superior frontal gyri, orbitofrontal cortex, middle temporal, insula
and right anterior cingulate cortex (Fig. 2). No differences were found between
symptomatic and asymptomatic DYT subjects. A trend toward a greater
disconnection was observed in symptomatic DYT1 relative to DYT6 subjects.
Conclusions
Our findings suggest that structural brain
abnormalities in both clinically manifesting and non-manifesting DYT mutation
carriers are distributed at a network level, beyond the basal
ganglia/sensorimotor cortex regions. Studying of asymptomatic mutation carriers
offered the possibility of identifying genotype-related trait characteristics
without the confound of clinical symptoms providing new insights into
understanding DYT generation.
Acknowledgements
No acknowledgement found.References
No reference found.