Regional metabolism in primary torsion dystonia

Carbon, Maren; Su, Sherwin L.; Dhawan, Vijay; Raymond, Deborah; Bressman, Susan; Eidelberg, David

doi:10.1212/01.wnl.0000120541.97467.fe

Cited by 124 publications

(109 citation statements)

References 52 publications

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“…Animals with cerebellar defects, for instance, oftentimes display considerable increases in both frontand hind-base widths (Wietholter et al, 1990;Jiao et al, 2005). In agreement with functional imaging studies, the increased hind-base width noted in hMT1 mice suggests that mutant torsinA may contribute to cerebellar dysfunction in humans with DYT1 dystonia (Carbon et al, 2004).…”

Section: Discussionsupporting

confidence: 59%

Abnormal motor function and dopamine neurotransmission in DYT1 ΔGAG transgenic mice

Zhao

DeCuypere

LeDoux

2008

Experimental Neurology

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A single GAG deletion in Exon 5 of the TOR1A gene is associated with a form of early-onset primary dystonia showing less than 40% penetrance. To provide a framework for cellular and systems study of DYT1 dystonia, we characterized the genetic, behavioral, morphological and neurochemical features of transgenic mice expressing either human wild-type torsinA (hWT) or mutant torsinA (hMT1 and hMT2) and their wild-type (WT) littermates. Relative to human brain, hMT1 mice showed robust neural expression of human torsinA transcript (3.90X). In comparison with WT littermates, hMT1 mice had prolonged traversal times on both square and round raised-beam tasks and more slips on the round raised-beam task. Although there were no effects of genotype on rotarod performance and rope climbing, hMT1 mice exhibited increased hind-base widths in comparison to WT and hWT mice. In contrast to several other mouse models of DYT1 dystonia, we were unable to identify either torsinA-and ubiquitin-positive cytoplasmic inclusion bodies or nuclear bleb formation in hMT1 mice. High-performance liquid chromatography with electrochemical detection was used to determine cerebral cortical, striatal, and cerebellar levels of dopamine (DA), norepinephrine, epinephrine, serotonin, 3, 4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid. Although there were no differences in striatal DA levels between WT and hMT1 mice, DOPAC and HVA concentrations and DA turnover (DOPAC/DA and HVA/DA) were significantly higher in the mutants. Our findings in DYT1 transgenic mice are compatible with previous neuroimaging and postmortem neurochemical studies of human DYT1 dystonia. Increased striatal dopamine turnover in hMT1 mice suggests that the nigrostriatal pathway may be a site of functional neuropathology in DYT1 dystonia.

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Section: Discussionsupporting

confidence: 59%

Abnormal motor function and dopamine neurotransmission in DYT1 ΔGAG transgenic mice

Zhao

DeCuypere

LeDoux

2008

Experimental Neurology

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“…The clinical spectrum of dystonia may indeed be broader than previously suspected, 109 with separate structural/functional abnormalities underlying the motor and nonmotor manifestations of the disorder. 110,111 How genotypic and phenotypic patterns are altered by the treatment of dystonia, particularly DBS, is a topic of ongoing investigation.…”

Section: Torsion Dystoniamentioning

confidence: 99%

Neuroimaging and therapeutics in movement disorders

Eckert

Eidelberg

2005

Neurotherapeutics

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Summary:In this review, we discuss the role of neuroimaging in assessing treatment options for movement disorders, particularly Parkinson's disease (PD). Imaging methods to assess dopaminergic function have recently been applied in trials of potential neuroprotective agents. Other imaging methods using regional metabolism and/or cerebral perfusion have been recently introduced to quantify the modulation of network activity as an objective marker of the treatment response. Both imaging strategies have provided novel insights into the mechanisms underlying a variety of pharmacological and stereotaxic surgical treatment strategies for PD and other movement disorders.

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“…DYT1 gene carriers exhibit abnormal increases in regional metabolic activity in the cerebellum, putamen/globus pallidus, and supplementary motor cortex, irrespective of clinical penetrance (8, 9). Indeed, these metabolic changes are present during sleep when no involuntary movements are present, suggesting an association with genotype rather than phenotype (8,10,11). Magnetic resonance DTI shows white matter abnormalities in dystonia gene carriers (12,13), and tractographic analysis of these abnormalities has associated these changes with reduced integrity of cerebellothalamocortical (CbTC) motor pathways (6), which modulate the excitability and synaptic plasticity of the sensorimotor cortex (14).…”

mentioning

confidence: 99%

Cerebellothalamocortical pathway abnormalities in torsinA DYT1 knock-in mice

Uluğ

Árgyelán

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

112

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The factors that determine symptom penetrance in inherited disease are poorly understood. Increasingly, magnetic resonance diffusion tensor imaging (DTI) and PET are used to separate alterations in brain structure and function that are linked to disease symptomatology from those linked to gene carrier status. One example is DYT1 dystonia, a dominantly inherited movement disorder characterized by sustained muscle contractions, postures, and/or involuntary movements. This form of dystonia is caused by a 3-bp deletion (i.e., ΔE) in the TOR1A gene that encodes torsinA. Carriers of the DYT1 dystonia mutation, even if clinically nonpenetrant, exhibit abnormalities in cerebellothalamocortical (CbTC) motor pathways. However, observations in human gene carriers may be confounded by variability in genetic background and age. To address this problem, we implemented a unique multimodal imaging strategy in a congenic line of DYT1 mutant mice that contain the ΔE mutation in the endogenous mouse torsinA allele (i.e., DYT1 knock-in). Heterozygous knock-in mice and littermate controls underwent micro-PET followed by ex vivo high-field DTI and tractographic analysis. Mutant mice, which do not display abnormal movements, exhibited significant CbTC tract changes as well as abnormalities in brainstem regions linking cerebellar and basal ganglia motor circuits highly similar to those identified in human nonmanifesting gene carriers. Moreover, metabolic activity in the sensorimotor cortex of these animals was closely correlated with individual measures of CbTC pathway integrity. These findings further link a selective brain circuit abnormality to gene carrier status and demonstrate that DYT1 mutant torsinA has similar effects in mice and humans.connectivity | regional metabolism | brain networks I n recent years, advanced imaging technologies such as PET and magnetic resonance diffusion tensor imaging (DTI) have provided unique information regarding the impact of specific genetic mutations on brain structure and function. However, to control for variability in genetic background and additional confounders such as age and sex, many more mutation carriers (and control subjects) are required than can conveniently be scanned, even in a multicenter design. Human imaging studies may also suffer from relatively low spatial resolution and sensitivity. These considerations motivated the current study in which high field magnetic resonance DTI was performed ex vivo in an experimental genetic model of a brain disorder.Primary dystonia is a childhood-onset neurological illness characterized by disabling abnormal involuntary movements without consistent brain lesions on routine structural brain imaging or at postmortem analysis (1). This disorder is associated with several genotypes (2). DYT1 dystonia, the most common inherited form of the disease, is caused by a dominantly inherited 3-bp in-frame deletion in the TOR1A gene that removes a single glutamic acid (ΔE) from the torsinA protein (3). This lowprevalence mutation (approximately 1 in 30,000...

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Regional metabolism in primary torsion dystonia

Cited by 124 publications

References 52 publications

Abnormal motor function and dopamine neurotransmission in DYT1 ΔGAG transgenic mice

Abnormal motor function and dopamine neurotransmission in DYT1 ΔGAG transgenic mice

Neuroimaging and therapeutics in movement disorders

Cerebellothalamocortical pathway abnormalities in torsinA DYT1 knock-in mice

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