The cerebellum in idiopathic cervical dystonia: A specific pattern of structural abnormalities?

Pontillo, Giuseppe; Castagna, Anna; Vola, Elena Augusta; Macerollo, Antonella; Peluso, Silvio; Russo, Camilla; Baglio, Francesca; Manganelli, Fiore; Brunetti, Arturo; Cocozza, Sirio; Esposito, Marcello

doi:10.1016/j.parkreldis.2020.09.033

Cited by 13 publications

(17 citation statements)

References 29 publications

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“…Previous DTI studies adopting whole‐brain or ROI‐based approaches reported diffuse white matter structural changes in CD, but also microstructural changes in deep gray matter representing, or (like posterior cerebellar cortex 10 ) projecting directly to, DRTT nodes 10‐16 . Despite some inconsistencies, these studies indicate disruption of white matter architecture involving regions associated with sensorimotor regulation, which aligns with previous observations of decreased gray matter volume in thalamic 27 and cerebellar regions 28 . Unlike our study, previous studies did not perform DRTT tractography by reconstructing the whole tract.…”

Section: Discussionsupporting

confidence: 87%

“…[10][11][12][13][14][15][16] Despite some inconsistencies, these studies indicate disruption of white matter architecture involving regions associated with sensorimotor regulation, which aligns with previous observations of decreased gray matter volume in thalamic 27 and cerebellar regions. 28 Unlike our study, previous studies did not perform DRTT tractography by reconstructing the whole tract. Furthermore, except for a report using a 1.5T MRI scanner, 29 most studies enrolled smaller samples.…”

Section: Discussionmentioning

confidence: 75%

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Microstructural Abnormalities of the Dentatorubrothalamic Tract in Cervical Dystonia

et al. 2021

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Background The dentatorubrothalamic tract (DRTT) remains understudied in idiopathic cervical dystonia (CD), despite evidence that the pathway is relevant in the pathophysiology of the disorder. Objective The aim of this study was to examine the DRTT in patients with CD using diffusion tensor imaging (DTI)–based tractography. Methods Magnetic resonance imaging scans from 67 participants were collected to calculate diffusion tractography metrics using a binary tractography‐based DRTT template. Fractional anisotropy and diffusivity measures of left and right DRTT were computed and compared between 32 subjects with CD and 35 age‐matched healthy volunteers. Results Fractional anisotropy of right DRTT and mean and axial diffusivity of left DRTT were significantly reduced in patients with CD. Similar abnormalities were observed in patients with focal CD and patients with CD without tremor. DTI metrics did not correlate with disease duration or severity. Conclusions Significant reductions in DTI measures suggest microstructural abnormalities within the DRTT in CD, characterized by a tractography pattern consistent with decreased axonal integrity. © 2021 International Parkinson and Movement Disorder Society

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 75%

Microstructural Abnormalities of the Dentatorubrothalamic Tract in Cervical Dystonia

et al. 2021

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“…Approaches used in the volumetric studies included volume measurements (using voxel‐based morphometry [VBM] or another volume approach) ( n = 30) [15–24, 26–28, 30, 33, 44, 46, 54, 55, 67, 69, 71, 73, 74, 76–81], assessment of cortical thickness ( n = 3) [29, 44, 57] or both ( n = 6) [14, 25, 52, 58, 72, 75]. Differences in these measures are often attributed to hypertrophy or atrophy of associated brain regions, with inference of underlying pathological processes.…”

Section: Resultsmentioning

confidence: 99%

Structural magnetic resonance imaging in dystonia: A systematic review of methodological approaches and findings

MacIver

Tax

Jones

et al. 2022

Euro J of Neurology

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Background and purpose: Structural magnetic resonance techniques have been widely applied in neurological disorders to better understand tissue changes, probing characteristics such as volume, iron deposition and diffusion. Dystonia is a hyperkinetic movement disorder, resulting in abnormal postures and pain. Its pathophysiology is poorly understood, with normal routine clinical imaging in idiopathic forms. More advanced tools provide an opportunity to identify smaller scale structural changes which may underpin pathophysiology. This review aims to provide an overview of methodological approaches undertaken in structural brain imaging of dystonia cohorts, and to identify commonly identified pathways, networks or regions that are implicated in pathogenesis.Methods: Structural magnetic resonance imaging studies of idiopathic and genetic forms of dystonia were systematically reviewed. Adhering to strict inclusion and exclusion criteria, PubMed and Embase databases were searched up to January 2022, with studies reviewed for methodological quality and key findings. Results:Seventy-seven studies were included, involving 1945 participants. The majority of studies employed diffusion tensor imaging (DTI) (n = 45) or volumetric analyses (n = 37), with frequently implicated areas of abnormality in the brainstem, cerebellum, basal ganglia and sensorimotor cortex and their interconnecting white matter pathways. Genotypic and motor phenotypic variation emerged, for example fewer cerebellothalamic tractography streamlines in genetic forms than idiopathic and higher grey matter volumes in task-specific than non-task-specific dystonias.Discussion: Work to date suggests microstructural brain changes in those diagnosed with dystonia, although the underlying nature of these changes remains undetermined.Employment of techniques such as multiple diffusion weightings or multi-exponential relaxometry has the potential to enhance understanding of these differences.

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“… 81 , 82 , 83 , 84 Although overt demyelination has not been specifically documented in dystonia, neuroimaging studies have reported white matter abnormalities in multiple forms of the disease, including (1) syndromes associated with genetic variation in TOR1A , THAP1 , SGCE (MIM: 604149 , DYT11 [MIM: 159900 ]), TAF1 , KMT2B , and COL6A3 (MIM: 120250 , DYT27 [MIM: 616411 ]) 20 , 69 , 85 , 86 , 87 , 88 , 89 and (2) idiopathic cases of cervical dystonia, writer’s cramp, laryngeal dystonia, and blepharospasm. 90 , 91 , 92 , 93 The mechanisms underlying these disturbances in white matter tracts are not known, and further investigation is needed to determine whether they reflect common defects in any of the pathways perturbed by genetic variation in THAP1 .…”

Section: Discussionmentioning

confidence: 99%

Dystonia-specific mutations in THAP1 alter transcription of genes associated with neurodevelopment and myelin

Domingo

Yadav

Shah

et al. 2021

The American Journal of Human Genetics

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Dystonia is a neurologic disorder associated with an increasingly large number of genetic variants in many genes, resulting in characteristic disturbances in volitional movement. Dissecting the relationships between these mutations and their functional outcomes is critical in understanding the pathways that drive dystonia pathogenesis. Here we established a pipeline for characterizing an allelic series of dystonia-specific mutations. We used this strategy to investigate the molecular consequences of genetic variation in THAP1, which encodes a transcription factor linked to neural differentiation. Multiple pathogenic mutations associated with dystonia cluster within distinct THAP1 functional domains and are predicted to alter DNA-binding properties and/or protein interactions differently, yet the relative impact of these varied changes on molecular signatures and neural deficits is unclear. To determine the effects of these mutations on THAP1 transcriptional activity, we engineered an allelic series of eight alterations in a common induced pluripotent stem cell background and differentiated these lines into a panel of near-isogenic neural stem cells (n ¼ 94 lines). Transcriptome profiling followed by joint analysis of the most robust signatures across mutations identified a convergent pattern of dysregulated genes functionally related to neurodevelopment, lysosomal lipid metabolism, and myelin. On the basis of these observations, we examined mice bearing Thap1disruptive alleles and detected significant changes in myelin gene expression and reduction of myelin structural integrity relative to control mice. These results suggest that deficits in neurodevelopment and myelination are common consequences of dystonia-associated THAP1 mutations and highlight the potential role of neuron-glial interactions in the pathogenesis of dystonia.

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The cerebellum in idiopathic cervical dystonia: A specific pattern of structural abnormalities?

Cited by 13 publications

References 29 publications

Microstructural Abnormalities of the Dentatorubrothalamic Tract in Cervical Dystonia

Microstructural Abnormalities of the Dentatorubrothalamic Tract in Cervical Dystonia

Structural magnetic resonance imaging in dystonia: A systematic review of methodological approaches and findings

Dystonia-specific mutations in THAP1 alter transcription of genes associated with neurodevelopment and myelin

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