Loss of Intrinsic Organization of Cerebellar Networks in Spinocerebellar Ataxia Type 1: Correlates with Disease Severity and Duration

Abstract

The spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of cerebellar degenerative disorders, characterized by progressive gait unsteadiness, hand incoordination, and dysarthria. The mutational mechanism in SCA1, a dominantly inherited form of SCA, consists of an expanded trinucleotide CAG repeat. In SCA1, there is loss of Purkinje cells, neuronal loss in dentate nucleus, olives, and pontine nuclei. In the present study, we sought to apply intrinsic functional connectivity analysis combined with diffusion tensor imaging to define the state of cerebellar connectivity in SCA1. Our results on the intrinsic functional connectivity in lateral cerebellum and thalamus showed progressive organizational changes in SCA1 noted as a progressive increase in the absolute value of the correlation coefficients. In the lateral cerebellum, the anatomical organization of functional clusters seen as parasagittal bands in controls is lost, changing to a patchy appearance in SCA1. Lastly, only fractional anisotropy in the superior peduncle and changes in functional organization in thalamus showed a linear dependence to duration and severity of disease. The present pilot work represents an initial effort describing connectivity biomarkers of disease progression in SCA1. The functional changes detected with intrinsic functional analysis and diffusion tensor imaging suggest that disease progression can be analyzed as a disconnection syndrome.

CAG repeat length does not associate with the rate of cerebellar degeneration in spinocerebellar ataxia type 3

“…The alteration of the brain network is found to be associated with disease severity and disease duration in SCA1 (Solodkin et al, 2011), cognitive and motor performance (Hernandez-Castillo et al, 2015) and onset of parkinsonism in SCA2 (Wu et al, 2013), visual task performance in SCA6 (Falcon et al, 2015) and CAG repeat length in SCA7 (Hernandez-Castillo et al, 2013). These studies, although mostly based on fMRI, suggest that brain network alteration is associated with clinical variables such as the CAG repeat length, disease severity, disease duration, and task performance in SCAs.…”

Early development of the nervous system of the eutherian <i>Tupaia belangeri</i>

“…Other groups have subsequently studied zebrin-IIimmunoreactive cerebellar compartments in order to carry out the following investigations: (1) interspecific comparison with the tammar wallaby (Macropus eugenii) (Marzban et al 2012), microchiropteran bats (Kim et al, 2009), hummingbirds (Aves: Trochilidae) (Iwaniuk et al, 2009), chicks (Gallus domesticus) (Marzban et al, 2010), pigeons (Columba livia) (Pakan et al, 2007; for an overview, see Marzban and Hawkes, 2011); (2) visualization of aldolase C with fluorescence through gene manipulation with the help of aldolase CVenus knock-in mice to facilitate studies on cerebellar compartmentalization (Fujita et al, 2014); (3) presentation of parasagittal stripes in the vermis which, complementary to zebrin II, are immunoreactive for neurofilament H (Demilly et al, 2011); (4) identification of links between the olivocerebellar projection and zebrin-immunoreactive compartments in the laboratory mouse (Sugihara and Quy, 2007) and in marmoset (Callithrix jacchus) (Fujita et al, 2010); (5) clarification of the role played by the helix-loop-helix (HLH) transcription factor early B-cell factor 2 (EBF2) (Croci et al, 2006); and (6) evaluation of the cerebellar connectivity in spinocerebellar ataxia type 1 (Solodkin et al, 2011). The second main research area of Wolfgang Knabe and colleagues, whose roots date back to the former anatomical department of Hans-Jürg Kuhn, continued previous projects on the retina, then served as a bridge between the retina and the forebrain, and, thereafter, was successively expanded to include the entire brain, spinal cord, neural crest, and the placodes.…”

Consensus Paper: Radiological Biomarkers of Cerebellar Diseases

“…The ponto-cerebellar brunt in SCA1 is further supported by alterations in white matter, as assessed with VBM and diffusion tensor imaging (DTI) including mean diffusivity (MD) and Tract-based spatial statistics (TBSS) [35, 36]. Structural and functional connectivity analyses using functional MRI and DTI revealed a loss of intrinsic organization of cerebellar networks, which correlated with disease severity and duration in this disconnection syndrome [37]. …”