Neuroenergetic Changes in Patients with X-Linked Dystonia-Parkinsonism and Female Carriers.

BACKGROUND: X-linked dystonia-parkinsonism (XDP) is a rare movement disorder characterized by profound neurodegeneration in the basal ganglia. The molecular consequences and the bioenergetic state of affected individuals remain largely unexplored. OBJECTIVES: To investigate the bioenergetic state in male patients with XDP and female carriers using 31phosphorus magnetic resonance spectroscopy imaging and to correlate these findings with clinical manifestations. METHODS: We examined the levels of high-energy phosphorus-containing metabolites (HEP) in the basal ganglia and cerebellum of five male patients with XDP, 10 asymptomatic female heterozygous carriers, and 10 SVA-insertion-free controls. RESULTS: HEP levels were reduced in the basal ganglia of patients with XDP (PwXDP) compared to controls, but increased in the cerebellum of both male patients and female carriers. CONCLUSIONS: Our findings suggest a potential compensatory mechanism in the cerebellum of female carriers regardless of sex. Our study highlights alterations in HEP levels in PwXDP patients and female carriers.

Diffusion tensor imaging in pediatric patients with dystonia.

BACKGROUND: Childhood-onset dystonia is often progressive and severely impairs a child´s life. The pathophysiology is very heterogeneous and treatment responses vary in patients with dystonia. Factors influencing treatment effects remain to be elucidated. We hypothesize that differences in brain connectivity and fiber coherence contribute to the heterogeneity in treatment response among pediatric patients with inherited and acquired dystonia. METHODS: Twenty patients with childhood-onset dystonia were retrospectively recruited including twelve patients with inherited or idiopathic, and eight patients with acquired dystonia (mean age 10 years; 8 female/12 male). Fiber density between the internal part of the globus pallidus and selective target regions, as well as the diffusion measures of fractional anisotropy (FA) and mean diffusivity (MD) were analyzed and compared between different etiologies. RESULTS: Patients with acquired dystonia presented higher fiber density to the premotor cortex and putamen and lower FA values in the thalamus compared to patients with inherited/idiopathic dystonia. MD in the premotor cortex was higher in patients with acquired dystonia, while it was lower in the thalamus. CONCLUSION: Diffusion MRI reveals microstructural and network alterations in patients with dystonia of different etiologies.

Dystonia and Parkinsonism in COA7-related disorders: expanding the phenotypic spectrum.

BACKGROUND AND OBJECTIVE: Biallelic mutations in the COA7 gene have been associated with spinocerebellar ataxia with axonal neuropathy type 3 (SCAN3), and a notable clinical diversity has been observed. We aim to identify the genetic and phenotypic spectrum of COA7-related disorders. METHODS: We conducted comprehensive genetic analyses on the COA7 gene within a large group of Japanese patients clinically diagnosed with inherited peripheral neuropathy or cerebellar ataxia. RESULTS: In addition to our original report, which involved four patients until 2018, we identified biallelic variants of the COA7 gene in another three unrelated patients, and the variants were c.17A > G (p.D6G), c.115C > T (p.R39W), and c.449G > A (p.C150Y; novel). Patient 1 presented with an infantile-onset generalized dystonia without cerebellar ataxia. Despite experiencing an initial transient positive response to levodopa and deep brain stimulation, he became bedridden by the age of 19. Patient 2 presented with cerebellar ataxia, neuropathy, as well as parkinsonism, and showed a slight improvement upon levodopa administration. Dopamine transporter SPECT showed decreased uptake in the bilateral putamen in both patients. Patient 3 exhibited severe muscle weakness, respiratory failure, and feeding difficulties. A haplotype analysis of the mutation hotspot in Japan, c.17A > G (p.D6G), uncovered a common haplotype block. CONCLUSION: COA7-related disorders typically encompass a spectrum of conditions characterized by a variety of major (cerebellar ataxia and axonal polyneuropathy) and minor (leukoencephalopathy, dystonia, and parkinsonism) symptoms, but may also display a dystonia-predominant phenotype. We propose that COA7 should be considered as a new causative gene for infancy-onset generalized dystonia, and COA7 gene screening is recommended for patients with unexplained dysfunctions of the central and peripheral nervous systems.

Macro- and micro-structural insights into primary dystonia: a UK Biobank study.

BACKGROUND: Dystonia is a hyperkinetic movement disorder with key motor network dysfunction implicated in pathophysiology. The UK Biobank encompasses > 500,000 participants, of whom 42,565 underwent brain MRI scanning. This study applied an optimized pre-processing pipeline, aimed at better accounting for artifact and improving data reliability, to assess for grey and white matter structural MRI changes between individuals diagnosed with primary dystonia and an unaffected control cohort. METHODS: Individuals with dystonia (n = 76) were identified from the UK Biobank using published algorithms, alongside an age- and sex-matched unaffected control cohort (n = 311). Grey matter morphometric and diffusion measures were assessed, together with white matter diffusion tensor and diffusion kurtosis metrics using tractography and tractometry. Post-hoc Neurite Orientation and Density Distribution Imaging (NODDI) was also undertaken for tracts in which significant differences were observed. RESULTS: Grey matter tremor-specific striatal differences were observed, with higher radial kurtosis. Tractography identified no white matter differences, however segmental tractometry identified localised differences, particularly in the superior cerebellar peduncles and anterior thalamic radiations, including higher fractional anisotropy and lower orientation distribution index in dystonia, compared to controls. Additional tremor-specific changes included lower neurite density index in the anterior thalamic radiations. CONCLUSIONS: Analysis of imaging data from one of the largest dystonia cohorts to date demonstrates microstructural differences in cerebellar and thalamic white matter connections, with architectural differences such as less orientation dispersion potentially being a component of the morphological structural changes implicated in dystonia. Distinct tremor-related imaging features are also implicated in both grey and white matter.

The functional anatomy of dystonia: Recent developments.

While dystonia has traditionally been viewed as a disorder of the basal ganglia, the involvement of other key brain structures is now accepted. However, just what these structures are remains to be defined. Neuroimaging has been an especially valuable tool in dystonia, yet traditional cross-sectional designs have not been able to separate causal from compensatory brain activity. Therefore, this chapter discusses recent studies using causal brain lesions, and animal models, to converge upon the brain regions responsible for dystonia with increasing precision. This evidence strongly implicates the basal ganglia, thalamus, brainstem, cerebellum, and somatosensory cortex, yet shows that different types of dystonia involve different nodes of this brain network. Nearly all of these nodes fall within the recently identified two-way networks connecting the basal ganglia and cerebellum, suggesting dysfunction of these specific pathways. Localisation of the functional anatomy of dystonia has strong implications for targeted treatment options, such as deep brain stimulation, and non-invasive brain stimulation.

Cranial geometry in patients with dystonia and Parkinson's disease.

Abnormal skull shape has been reported in brain disorders. However, no studies have investigated cranial geometry in neurodegenerative disorders. This study aimed to evaluate the cranial geometry of patients with dystonia or Parkinson's disease (PD). Cranial computed tomography images of 36 patients each with idiopathic dystonia (IDYS), PD, and chronic subdural hematoma (CSDH) were analyzed. Those with IDYS had a significantly higher occipital index (OI) than those with CSDH (p = 0.014). When cephalic index (CI) was divided into the normal and abnormal groups, there was a significant difference between those with IDYS and CSDH (p = 0.000, α = 0.017) and between PD and CSDH (p = 0.031, α = 0.033). The age of onset was significantly correlated with the CI of IDYS (τ = - 0.282, p = 0.016). The Burke-Fahn-Marsden Dystonia Rating Scale motor score (BFMDRS-M) showed a significant correlation with OI in IDYS (τ = 0.372, p = 0.002). The cranial geometry of patients with IDYS was significantly different from that of patients with CSDH. There was a significant correlation between age of onset and CI, as well as between BFMDRS-M and OI, suggesting that short heads in the growth phase and skull balance might be related to the genesis of dystonia and its effect on motor symptoms.

A Network Imaging Biomarker of X-Linked Dystonia-Parkinsonism.

OBJECTIVE: The purpose of this study was to characterize a metabolic brain network associated with X-linked dystonia-parkinsonism (XDP). METHODS: Thirty right-handed Filipino men with XDP (age = 44.4 ± 8.5 years) and 30 XDP-causing mutation negative healthy men from the same population (age = 37.4 ± 10.5 years) underwent [18 F]-fluorodeoxyglucose positron emission tomography. Scans were analyzed using spatial covariance mapping to identify a significant XDP-related metabolic pattern (XDPRP). Patients were rated clinically at the time of imaging according to the XDP-Movement Disorder Society of the Philippines (MDSP) scale. RESULTS: We identified a significant XDPRP topography from 15 randomly selected subjects with XDP and 15 control subjects. This pattern was characterized by bilateral metabolic reductions in caudate/putamen, frontal operculum, and cingulate cortex, with relative increases in the bilateral somatosensory cortex and cerebellar vermis. Age-corrected expression of XDPRP was significantly elevated (p < 0.0001) in XDP compared to controls in the derivation set and in the remaining 15 patients (testing set). We validated the XDPRP topography by identifying a similar pattern in the original testing set (r = 0.90, p < 0.0001; voxel-wise correlation between both patterns). Significant correlations between XDPRP expression and clinical ratings for parkinsonism-but not dystonia-were observed in both XDP groups. Further network analysis revealed abnormalities of information transfer through the XDPRP space, with loss of normal connectivity and gain of abnormal functional connections linking network nodes with outside brain regions. INTERPRETATION: XDP is associated with a characteristic metabolic network associated with abnormal functional connectivity among the basal ganglia, thalamus, motor regions, and cerebellum. Clinical signs may relate to faulty information transfer through the network to outside brain regions. ANN NEUROL 2023;94:684-695.

Clinical Implications of Dystonia as a Neural Network Disorder.

Isolated dystonia is a neurological disorder of diverse etiology, multifactorial pathophysiology, and wide spectrum of clinical presentations. We review the recent neuroimaging advances that led to the conceptualization of dystonia as a neural network disorder and discuss how current knowledge is shaping the identification of biomarkers of dystonia and the development of novel pharmacological therapies.

Fixel-Based Analysis Reveals Whole-Brain White Matter Abnormalities in Cervical Dystonia.

BACKGROUND: Cervical dystonia (CD) is a form of isolated focal dystonia typically associated to abnormal head, neck, and shoulder movements and postures. The complexity of the clinical presentation limits the investigation of its pathophysiological mechanisms, and the neural networks associated to specific motor manifestations are still the object of debate. OBJECTIVES: We investigated the morphometric properties of white matter fibers in CD and explored the networks associated with motor symptoms, while regressing out nonmotor scores. METHODS: Nineteen patients affected by CD and 21 healthy controls underwent diffusion-weighted magnetic resonance imaging. We performed fixel-based analysis, a novel method evaluating fiber orientation within specific fiber bundles, and compared fiber morphometric properties between groups. Moreover, we correlated fiber morphometry with the severity of motor symptoms in patients. RESULTS: Compared to controls, patients exhibited decreased white matter fibers in the right striatum. Motor symptom severity negatively correlated with white matter fibers passing through inferior parietal areas and the head representation area of the motor cortex. CONCLUSIONS: Abnormal white matter integrity at the basal ganglia level may affect several functional networks involved, for instance, in motor preparation and execution, visuomotor coordination, and multimodal integration. This may result in progressive maladaptive plasticity, culminating in overt symptoms of dystonia. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Neuroimaging findings in DYT1 dystonia and the pathophysiological implication: A systematic review.

BACKGROUND: Primary generalized dystonia due to the DYT1 gene is an autosomal dominant disorder caused by a GAG deletion on chromosome 9q34. It is a well-defined, genetically proven, isolated dystonia syndrome. However, its pathophysiology remains unclear. OBJECTIVES: This study was aimed at profiling the functional neuroimaging findings in DYT1 dystonia and harmonizing the pathophysiological implications for DYT1 dystonia from the standpoint of different neuroimaging techniques. METHODS: A systematic review was conducted using identified studies published in English from Medline, PsycINFO, Embase, CINAHL, and the Cochrane Database of Systematic Reviews (CDSR), between 1985 and December 2019 (PROSPERO protocol CRD42018111211). RESULTS: All DYT1 gene carriers irrespective of clinical penetrance have reduced striatal GABA, dopamine receptors and increased metabolic activity in the lentiform nucleus, supplementary motor area, and cerebellum in addition to an abnormal cerebellothalamocortical pathway. Nonmanifesting carriers on the other hand have a disruption of the distal (thalamocortical) segment and have larger putaminal volumes than manifesting carriers and healthy controls. Activation of the midbrain, thalamus, and sensorimotor cortex was only found in the manifesting carriers. CONCLUSIONS: Therefore, we propose that DYT1 dystonia is a cerebellostriatothalamocortical network disorder affecting either the structure or function of the different structures or nodes in the network.

Disordered network structure and function in dystonia: pathological connectivity vs. adaptive responses.

Primary dystonia is thought to emerge through abnormal functional relationships between basal ganglia and cerebellar motor circuits. These interactions may differ across disease subtypes and provide a novel biomarker for diagnosis and treatment. Using a network mapping algorithm based on resting-state functional MRI (rs-fMRI), a method that is readily implemented on conventional MRI scanners, we identified similar disease topographies in hereditary dystonia associated with the DYT1 or DYT6 mutations and in sporadic patients lacking these mutations. Both networks were characterized by contributions from the basal ganglia, cerebellum, thalamus, sensorimotor areas, as well as cortical association regions. Expression levels for the two networks were elevated in hereditary and sporadic dystonia, and in non-manifesting carriers of dystonia mutations. Nonetheless, the distribution of abnormal functional connections differed across groups, as did metrics of network organization and efficiency in key modules. Despite these differences, network expression correlated with dystonia motor ratings, significantly improving the accuracy of predictions based on thalamocortical tract integrity obtained with diffusion tensor MRI (DTI). Thus, in addition to providing unique information regarding the anatomy of abnormal brain circuits, rs-fMRI functional networks may provide a widely accessible method to help in the objective evaluation of new treatments for this disorder.

Basal Ganglia Atrophy as a Marker for Prodromal X-Linked Dystonia-Parkinsonism.

In neurodegenerative diseases, the characterization of the prodromal phase is essential for the future application of disease-modifying therapies. X-linked dystonia-parkinsonism is a hereditary neurodegenerative movement disorder characterized by severe adult-onset dystonia accompanied by parkinsonism. Distinct striatal and pallidal atrophy is present already in early disease stages indicating a long-lasting presymptomatic degenerative process. To gain insight into the prodromal phase of X-linked dystonia-parkinsonism, structural and iron-sensitive magnetic resonance imaging (MRI) was performed in 10 non-manifesting carriers and 24 healthy controls in a double-blind fashion. Seventeen patients with X-linked dystonia-parkinsonism were recruited to replicate previous findings of basal ganglia pathology and iron accumulation. Age at onset was estimated in non-manifesting carriers and patients using the repeat length of the hexanucleotide expansion and 3 single-nucleotide polymorphisms associated with age at onset. Voxel-based morphometry and subcortical volumetry showed striatal and pallidal atrophy in non-manifesting carriers (~10%) and patients (~40%). Substantia nigra volume was similarly reduced in patients (~40%). Caudate volume correlated with time to estimated onset in non-manifesting carriers. Susceptibility-weighted imaging confirmed iron deposition in the anteromedial putamen in patients. Non-manifesting carriers also showed small clusters of iron accumulation in the same area after lowering the statistical threshold. In conclusion, basal ganglia atrophy and iron accumulation precede the clinical onset of X-linked dystonia-parkinsonism and can be detected years before the estimated disease manifestation. It thereby highlights the potential of multimodal imaging to identify clinically unaffected mutation carriers with incipient neurodegeneration and to monitor disease progression independent of clinical measures. Longitudinal studies are needed to further elucidate the onset and progression rate of neurodegeneration in prodromal X-linked dystonia-parkinsonism. ANN NEUROL 2023;93:999-1011.

Multimodal imaging of essential tremor and dystonic tremor.

Despite recent advances in tremor and dystonia classification, it remains difficult to discriminate essential tremor from dystonic tremor as they are similar in appearance and no biomarker exists. Further, tremor can appear in the same or a different body part than the dystonia. The aim of the current study was to better understand the differential pathophysiology of these tremors. We designed a cross-sectional case-control study and recruited 16 patients with essential tremor, 16 patients with dystonic tremor, and 17 age-matched healthy volunteers. We used multi-modal imaging combining resting-state functional MRI, diffusion tensor imaging, and magnetic resonance spectroscopy. We measured functional connectivity of resting-state fMRI to assess connectivity in the tremor network, fractional anisotropy and mean diffusivity with diffusion tensor imaging, and GABA+, Glutamate/Glutamine, Choline, and N-Acetylaspartate with spectroscopy (adjusted to Creatine). Our results showed reduced functional connectivity of resting-state fMRI between the cerebellum and dentate nucleus bilaterally for the essential tremor group, but not the dystonic tremor group, compared to healthy volunteers. There was higher fractional anisotropy in the middle cerebellar peduncle bilaterally for the dystonic tremor group compared to the essential tremor group as well as for essential tremor group compared to healthy volunteers. There was also higher fractional anisotropy in the red nucleus and corticospinal tract for essential tremor and dystonic tremor groups compared to healthy volunteers. We also showed reduced mean diffusivity in the cerebellum of both essential tremor and dystonic tremor groups compared to healthy volunteers. Finally, we found elevated GABA+/Cr in the cerebellum of the essential tremor and dystonic tremor groups compared to healthy volunteers, but no difference emerged between essential tremor and dystonic tremor groups. We did not find group differences in the other metabolites. Our results indicate cerebellar alterations in essential tremor and dystonic tremor patients compared to healthy volunteers, and further changes in the cerebellum network for the dystonic tremor patients. suggesting that the cerebellum is affected differently in both tremors.

Probabilistic mapping of deep brain stimulation in childhood dystonia.

OBJECTIVES: In adults with dystonia Probabilistic Stimulation Mapping (PSM) has identified putative "sweet spots" for stimulation. We aimed to apply PSM to a cohort of Children and Young People (CYP) following DBS surgery. METHODS: Pre-operative MRI and post-operative CT images were co-registered for 52 CYP undergoing bilateral pallidal DBS (n = 31 genetic/idiopathic dystonia, and n = 21 Cerebral Palsy (CP)). DBS electrodes (n = 104) were automatically detected, and Volumes of Tissue Activation (VTA) derived from individual patient stimulation settings. VTAs were normalised to the MNI105 space, weighted by percentage improvement in Burke-Fahn-Marsden Dystonia Rating scale (BFMDRS) at one-year post surgery and mean improvement was calculated for each voxel. RESULTS: For the genetic/idiopathic dystonia group, BFMDRS improvement was associated with stimulation across a broad volume of the GPi. A spatial clustering of the upper 25th percentile of voxels corresponded with a more delineated volume within the posterior ventrolateral GPi. The MNI coordinates of the centroid of this volume (X = -23.0, Y = -10.5 and Z = -3.5) were posterior and superior to the typical target for electrode placement. Volume of VTA overlap with a previously published "sweet spots" correlated with improvement following surgery. In contrast, there was minimal BFMDRS improvement for the CP group, no spatial clustering of efficacious clusters and a correlation between established "sweet spots" could not be established. CONCLUSIONS: PSM in CYP with genetic/idiopathic dystonia suggests the presence of a "sweet spot" for electrode placement within the GPi, consistent with previous studies. Further work is required to identify and validate putative "sweet spots" across different cohorts of patients.

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

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 cerebello-thalamic 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.

Short- and Long-term Central Action of Botulinum Neurotoxin Treatment in Laryngeal Dystonia.

BACKGROUND AND OBJECTIVES: Laryngeal dystonia (LD) is isolated task-specific focal dystonia selectively impairing speech production. The first choice of LD treatment is botulinum neurotoxin (BoNT) injections into the affected laryngeal muscles. However, whether BoNT has a lasting therapeutic effect on disorder pathophysiology is unknown. We investigated short-term and long-term effects of BoNT treatment on brain function in patients with LD. METHODS: A total of 161 participants were included in the functional MRI study. Statistical analyses examined central BoNT effects in patients with LD who were stratified based on the effectiveness and duration of treatment. RESULTS: Patients with LD who were treated and benefited from BoNT injections had reduced activity in the left precuneus compared with BoNT-naive and treatment nonbenefiting patients. In addition, BoNT-treated patients with adductor LD had decreased activity in the right thalamus, whereas BoNT-treated abductor patients with LD had reduced activity in the left inferior frontal cortex. No statistically significant differences in brain activity were found between patients with shorter (1-5 years) and longer (13-28 years) treatment durations. However, patients with intermediate treatment duration of 6-12 years showed reduced activity in the right cerebellum compared with patients with both shorter and longer treatment durations and reduced activity in the right prefrontal cortex compared with patients with shorter treatment duration. DISCUSSION: Our findings suggest that the left precuneus is the site of short-term BoNT central action in patients with LD, whereas the prefrontal-cerebellar axis is engaged in the BoNT response in patients with intermediate treatment duration of 6-12 years. Involvement of these structures points to indirect action of BoNT treatment on the dystonic sensorimotor network through modulation of motor sequence planning and coordination.

L-Dopa response, choreic dyskinesia, and dystonia in Perry syndrome.

INTRODUCTION: A marked response to L-Dopa and L-Dopa-induced dyskinesia (LID) make the diagnosis of Parkinson's disease (PD) highly likely. This paper evaluates response to L-Dopa in Perry syndrome (PS), parkinsonism with distinct molecular and neuropathologic characteristics. METHODS: Six patients with PS with a mean follow-up of 5 years (0.5-12) were assessed by movement disorder specialists and video recorded in states off and on. Additionally, DATSCAN-SPECT was performed in 3 subjects. RESULTS: Four patients displayed a marked and sustained response to L-Dopa and LID. Additionally, we observed a distinct pattern of off-state predominant craniocervical dystonia responsive to L-Dopa in 4 patients, truncal dystonia in one, and dystonic head tremor in another. DATSCAN-SPECT was abnormal in 3 patients. CONCLUSIONS: Patients with PS may present PD-like parkinsonism with a marked and sustained response to L-Dopa and LID. The characteristic pattern of craniocervical dystonia may be a helpful clue to the diagnosis of PS.

Tissue-specific and repeat length-dependent somatic instability of the X-linked dystonia parkinsonism-associated CCCTCT repeat.

X-linked dystonia-parkinsonism (XDP) is a progressive adult-onset neurodegenerative disorder caused by insertion of a SINE-VNTR-Alu (SVA) retrotransposon in the TAF1 gene. The SVA retrotransposon contains a CCCTCT hexameric repeat tract of variable length, whose length is inversely correlated with age at onset. This places XDP in a broader class of repeat expansion diseases, characterized by the instability of their causative repeat mutations. Here, we observe similar inverse correlations between CCCTCT repeat length with age at onset and age at death and no obvious correlation with disease duration. To gain insight into repeat instability in XDP we performed comprehensive quantitative analyses of somatic instability of the XDP CCCTCT repeat in blood and in seventeen brain regions from affected males. Our findings reveal repeat length-dependent and expansion-based instability of the XDP CCCTCT repeat, with greater levels of expansion in brain than in blood. The brain exhibits regional-specific patterns of instability that are broadly similar across individuals, with cerebellum exhibiting low instability and cortical regions exhibiting relatively high instability. The spectrum of somatic instability in the brain includes a high proportion of moderate repeat length changes of up to 5 repeats, as well as expansions of ~ 20- > 100 repeats and contractions of ~ 20-40 repeats at lower frequencies. Comparison with HTT CAG repeat instability in postmortem Huntington's disease brains reveals similar brain region-specific profiles, indicating common trans-acting factors that contribute to the instability of both repeats. Analyses in XDP brains of expansion of a different SVA-associated CCCTCT located in the LIPG gene, and not known to be disease-associated, reveals repeat length-dependent expansion at overall lower levels relative to the XDP CCCTCT repeat, suggesting that expansion propensity may be modified by local chromatin structure. Together, the data support a role for repeat length-dependent somatic expansion in the process(es) driving the onset of XDP and prompt further investigation into repeat dynamics and the relationship to disease.