Objective: DYT1 and DYT6 are autosomal dominant mutations for primary dystonia with incomplete penetrance. We have found that expression levels for a distinct dystonia-related functional pattern (DytRP) are elevated in mutation carriers whether clinically penetrant or not. Here, we considered the possibility that in mutation carriers, clinical penetrance is associated with assortativity, a descriptor of the DytRP wiring pattern.

Background: A DytRP network has been identified using resting state fMRI [1]. Recently, we have applied graph theory methods to functional imaging data to study wiring changes in disease states [2-5]. It is unclear, however, whether these changes represent maladaptive or compensatory responses to the underlying pathology.

Method: We studied 20 carriers of the DYT1 and DYT6 mutations for primary dystonia (10 clinically manifesting (MAN) and 10 non-manifesting (NM)) and 10 healthy control subjects (HC) [Table1]. All subjects underwent rs-fMRI on a 3T GE MRI scanner. We identified a significant DytRP [1,6], and partitioned it into core and periphery as described elsewhere [7-8]. For each subgraph, we computed assortativity and other graph measures, in MAN, NM and HC subjects. Corresponding values were compared across groups.

Results: The DytRP network [Figure1A] was partitioned into core and periphery. The core included the cerebellum, thalamus, putamen, and the precentral and perirolandic areas, while the periphery was composed mainly of prefrontal, superior temporal, and parietal regions. In the core, assortativity [Figure1B] was increased in MAN compared HC, but was reduced in NM. Of note, assortativity did not differ in MAN and NM in the periphery. In MAN, the core subgraph [Figure1C] exhibited assortative features: a cluster of interconnected high degree nodes was present at the center, comprising the putamen, globus pallidus, thalamus, and cerebellar hemispheres. In NM, by contrast, core wiring was disassortative, with lower degree nodes in the putamen, thalamus, and motor cortex linking with higher degree nodes in the globus pallidus, cerebellum and frontal region.

Conclusion: In MAN dystonia mutation carriers, core assortativity was increased in the dystonia-related network, but was reduced in their NM counterparts. The results suggest that maladaptive and compensatory wiring responses in dystonia gene carriers can be distinguished by assortativity in the DytRP core.

References: 1. Fujita, K. (2016), ‘Brain networks revealed by resting state functional MRI in familial and sporadic primary dystonia’ [abstract], Movement Disorders, vol. 31, no. suppl 2. 2. Niethammer, M. (2018), ‘Gene therapy reduces Parkinson’s disease symptoms by reorganizing functional brain connectivity’, Sci Transl Med, vol.10, no. 469. 3. Schindlbeck, KA. (2019), ‘LRRK2 and GBA variants exert distinct influences on Parkinson’s disease-specific metabolic networks’. Cerebral Cortex. 4. Vo, A. (2018), ‘Three-dimensional network architecture of dystonia in resting state functional MRI’ [abstract], The 2018 OHBM Annual Meeting, Singapore. June 17-21. 5. Vo, A. (2019), ‘Resting state functional connectivity changes in dystonia’ [abstract], Movement Disorders, vol. 34, no. suppl 2. 6. Vo, A. (2017), ‘Parkinson’s disease-related network topographies characterized with resting state functional MRI’, Hum Brain Mapp, vol. 38, no. 2, pp. 617-630. 7. Newman, ME. (2006), ‘Modularity and community structure in networks’, Proc Natl Acad Sci U S A. vol. 103, no. 23, pp. 8577-8582. 8. Rubinov, M. (2015), ‘Wiring cost and topological participation of the mouse brain connectome’, Proc Natl Acad Sci U S A. vol. 112, no. 32, pp. 10032-10037.

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