Dystonia最新文献

{"title":"Transcriptional regulatory network for neuron-glia interactions and its implication for DYT6 dystonia","authors":"Dhananjay Yellajoshyula","doi":"10.3389/dyst.2023.11796","DOIUrl":"https://doi.org/10.3389/dyst.2023.11796","url":null,"abstract":"Advances in sequencing technologies have identified novel genes associated with inherited forms of dystonia, providing valuable insights into its genetic basis and revealing diverse genetic pathways and mechanisms involved in its pathophysiology. Since identifying genetic variation in the transcription factor coding THAP1 gene linked to isolated dystonia, numerous investigations have employed transcriptomic studies in DYT-THAP1 models to uncover pathogenic molecular mechanisms underlying dystonia. This review examines key findings from transcriptomic studies conducted on in vivo and in vitro DYT-THAP1 models, which demonstrate that the THAP1-regulated transcriptome is diverse and cell-specific, yet it is bound and co-regulated by a common set of proteins. Prominent among its functions, THAP1 and its co-regulatory network target molecular pathways critical for generating myelinating oligodendrocytes that ensheath axons and generate white matter in the central nervous system. Several lines of investigation have demonstrated the importance of myelination and oligodendrogenesis in motor function during development and in adults, emphasizing the non-cell autonomous contributions of glial cells to neural circuits involved in motor function. Further research on the role of myelin abnormalities in motor deficits in DYT6 models will enhance our understanding of axon-glia interactions in dystonia pathophysiology and provide potential therapeutic interventions targeting these pathways.","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":"40 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136102305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-motor symptoms in dystonia: from diagnosis to treatment","authors":"Kathryn J. Peall, Brian D. Berman, Norbert Bruggemann, Giovanni Defazio, Hortensia Gimeno, H. A. Jinnah, Joel S. Perlmutter, Sarah E. Pirio Richardson, Emmanuel Roze, Anette Schrag, Michele Tinazzi, Marie Vidailhet, Aparna Wagle Shukla, Yulia Worbe, Jan K. Teller, Davide Martino","doi":"10.3389/dyst.2023.11860","DOIUrl":"https://doi.org/10.3389/dyst.2023.11860","url":null,"abstract":"The Dystonia Medical Research Foundation organized an expert virtual workshop in March 2023 to review the evidence on non-motor symptoms across the spectrum of dystonia, discuss existing assessment methods, need for their harmonisation and roadmap to achieve this, and evaluate potential treatment approaches. Albeit the most investigated non-motor domains, experts highlighted the need to identify the most accurate screening procedure for depression and anxiety, clarify their mechanistic origin and quantify their response to already available therapies. Future exploration of sleep disruption in dystonia should include determining the accuracy and feasibility of wearable devices, understanding the contribution of psychotropic medication to its occurrence, and defining the interaction between maladaptive plasticity and abnormal sleep patterns. Despite recent advances in the assessment of pain in dystonia, more research is needed to elucidate the relative importance of different mechanisms called into play to explain this impactful sensory feature and the most appropriate treatments. Amongst the different non-motor features investigated in dystonia, cognitive dysfunction and fatigue require an in-depth observation to evaluate their functional impact, their clinical profile and assessment methods and, in the case of cognition, whether impairment represents a prodrome of dementia. Finally, experts identified the development and field validation of a self-rated screening tool encompassing the full spectrum of non-motor symptoms as the most urgent step towards incorporating the management of these features into routine clinical practice.","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":"7 6","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135266082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional imaging of deep brain stimulation in dystonia: a review","authors":"Ian O. Bledsoe, Melanie A. Morrison","doi":"10.3389/dyst.2023.11440","DOIUrl":"https://doi.org/10.3389/dyst.2023.11440","url":null,"abstract":"Much remains to be learned about the mechanism of benefit of deep brain stimulation in movement disorders in general and dystonia specifically. A full accounting of the pathophysiology of dystonia additionally remains unclear. Given its ability to evaluate whole-brain network changes, functional neuroimaging is an important tool to advance understanding of the effects of deep brain stimulation, which in turn could offer insight into the pathophysiology of dystonia and suggest novel deep brain stimulation targets for the disorder. This review surveys the published literature of functional neuroimaging studies evaluating deep brain stimulation effects in dystonia, including PET, SPECT, and functional MRI studies. To date, study cohorts have been relatively small, though several general patterns emerge when studies are viewed collectively, including reduced functional activation patterns with stimulation turned on during motor tasks, particularly in frontal cortical regions. During rest with stimulation on, several studies showed areas of relatively decreased perfusion only in those participants who experienced clinical benefit from deep brain stimulation. Future research may benefit from larger cohorts with more homogeneous forms of dystonia, potentially enabled by multi-center initiatives. Additional benefits may result from more detailed longitudinal assessments and greater use of functional MRI, with study designs that take into account the technical limitations of this modality in the context of movement disorders and deep brain stimulation.","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":"48 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135345562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of protein kinase R in dystonia","authors":"Benjamin Dodd, Stephanie L. Moon","doi":"10.3389/dyst.2023.11718","DOIUrl":"https://doi.org/10.3389/dyst.2023.11718","url":null,"abstract":"Dystonia is a progressive neurological motor disease with few treatment options and no cure. This review synthesizes the results of recent studies that implicate protein kinase R in mediating the molecular mechanisms of dystonia pathogenesis. Mutations in the PKR gene EIF2AK2 and the PKR activator protein PACT are associated with early-onset generalized dystonia. Protein kinase R (PKR) is important for neuronal function. Genetic depletion or inhibition of PKR is associated with increased long-term potentiation and memory, while also causing neuronal hyper-excitability and seizures in mouse models. PKR also senses double stranded RNA within cells and activates the integrated stress response (ISR). The ISR is a conserved signaling pathway that hinges on controlled translational suppression to remodel gene expression during stress. When PKR is activated through binding double stranded RNA or the PKR activator protein PACT, PKR dimerizes, autophosphorylates, and phosphorylates the translation initiation factor eIF2. Translation suppression by p-eIF2 causes stress granule formation and the upregulation of stress-induced genes. The ISR is thought to drive cellular resilience during acute stress. However, chronic ISR activation is associated with neurological diseases, traumatic brain injury, and aging. Neurodevelopmental and neurodegenerative diseases are associated with mutations in other integrated stress response genes, suggesting a critical role for ISR regulation in neuronal health. A growing body of work suggests the ISR is also dysfunctional in dystonia. Future research investigating the molecular mechanisms of the ISR in dystonia will likely reveal therapeutic targets and treatment strategies for this currently incurable disease.","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":"57 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136061112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial: Models, mechanisms, and maturation in developmental dystonia","authors":"Jason S. Gill, Meike E. van der Heijden, A. Shaikh, R. Sillitoe","doi":"10.3389/dyst.2023.11922","DOIUrl":"https://doi.org/10.3389/dyst.2023.11922","url":null,"abstract":"","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139341067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disrupted sleep in dystonia depends on cerebellar function but not motor symptoms in mice","authors":"Luis E. Salazar Leon, Roy V. Sillitoe","doi":"10.3389/dyst.2023.11487","DOIUrl":"https://doi.org/10.3389/dyst.2023.11487","url":null,"abstract":"Although dystonia is the third most common movement disorder, patients often also experience debilitating nonmotor defects including impaired sleep. The cerebellum is a central component of a “dystonia network” that plays various roles in sleep regulation. Importantly, the primary driver of sleep impairments in dystonia remains poorly understood. The cerebellum, along with other nodes in the motor circuit, could disrupt sleep. However, it is unclear how the cerebellum might alter sleep and mobility. To disentangle the impact of cerebellar dysfunction on motion and sleep, we generated two mouse genetic models of dystonia that have overlapping cerebellar circuit miswiring but show differing motor phenotype severity: Ptf1a Cre ; Vglut2 fx/fx and Pdx1 Cre ; Vglut2 fx/fx mice. In both models, excitatory climbing fiber to Purkinje cell neurotransmission is blocked, but only the Ptf1a Cre ; Vglut2 fx/fx mice have severe twisting. Using in vivo ECoG and EMG recordings we found that both mutants spend greater time awake and in NREM sleep at the expense of REM sleep. The increase in awake time is driven by longer awake bouts rather than an increase in bout number. We also found a longer latency to reach REM in both mutants, which is similar to what is reported in human dystonia. We uncovered independent but parallel roles for cerebellar circuit dysfunction and motor defects in promoting sleep quality versus posture impairments in dystonia.","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":"56 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135420542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcranial magnetic stimulation: the road to clinical therapy for dystonia","authors":"Patrick J. Mulcahey, Angel V. Peterchev, Nicole Calakos, Noreen Bukhari-Parlakturk","doi":"10.3389/dyst.2023.11660","DOIUrl":"https://doi.org/10.3389/dyst.2023.11660","url":null,"abstract":"Despite many research studies, transcranial magnetic stimulation (TMS) is not yet an FDA-approved clinical therapy for dystonia patients. This review describes the four major challenges that have historically hindered the clinical translation of TMS. The four challenges described are limited types of clinical trial designs, limited evidence on objective behavioral measures, variability in the TMS clinical response, and the extensive TMS parameters to optimize for clinical therapy. Progress has been made to diversify the types of clinical trial design available to clinical researchers, identify evidence-based objective behavioral measures, and reduce the variability in TMS clinical response. Future studies should identify objective behavioral measures for other dystonia subtypes and expand the optimal TMS stimulation parameters for clinical therapy. Our review highlights the key progress made to overcome these barriers and gaps that remain for TMS to develop into a long-lasting clinical therapy for dystonia patients.","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136391349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spinal dystonia and other spinal movement disorders","authors":"Shlok Sarin, Temitope Lawal, H. Abboud","doi":"10.3389/dyst.2023.11303","DOIUrl":"https://doi.org/10.3389/dyst.2023.11303","url":null,"abstract":"While traditionally considered a disorder of the basal ganglia, brainstem, and cerebellum, multiple reports have shown that spinal cord pathologies may lead to dystonia. In this article, we first discuss various spinal movement disorders and the differences between tonic spasms, spinal dystonia, spinal myoclonus, spinal tremors, and paroxysmal dyskinesia. We review potential pathogenesis of spinal dystonia. We then focus on reports of dystonia secondary to spinal cord demyelinating diseases such as multiple sclerosis and neuromyelitis optica spectrum disorders. We conclude by discussing the potential treatment options for spinal dystonia.","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48419445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gait and balance in cervical dystonia and dystonic head tremor","authors":"A. Wagle Shukla, Angela Gurrala, V. Vedam-Mai","doi":"10.3389/dyst.2023.11231","DOIUrl":"https://doi.org/10.3389/dyst.2023.11231","url":null,"abstract":"Background: Previous studies have found gait and balance abnormalities in patients with cervical dystonia. However, the characteristics of gait and balance in cervical dystonia with head tremors have not been ascertained. A midline constant head tremor when walking would likely render gait and balance more difficult. The pathophysiology of dystonia has also been increasingly linked with cerebellar function abnormality, commonly implicated in gait and balance disorders.Methods: We examined the gait and balance characteristics of cervical dystonia presenting with head tremors. We used the timed up-and-go (TUG) walk test, 10 m walk test, Berg Balance Scale (BBS), and Gait and Freezing questionnaire. We then assessed the gait on an instrumented walkway system to capture spatiotemporal measures such as speed, cadence, step time, step length, stride width, swing%, stance%, single support%, double support%, and gait variability index (GVI). We also assessed whether the gait in dystonic tremor (DT) differed from essential tremor (ET) and orthostatic tremor (OT), as these tremor disorders share the cerebello-thalamo-cortical pathway as the common pathological pathway.Results: 50 participants comprising DT (20 patients), ET (15 patients), and OT (15 patients) were enrolled. While the gait abnormalities were subclinical, 11/20 DT patients (55%) walked at a slower speed on the TUG, 11/20 (55%) had reduced scores on the BBS, 9/20 (45%) had increased step time, 4/20 (20%) had reduced step length, 4/20 (20%) had wider stride width, 9/20 (45%) spent greater time during double support and 8/20 (40%) patients had an abnormal GVI. Comparisons of DT with healthy control data revealed a slower gait velocity (p = 0.001) and a reduced step length (p = 0.001). Compared to DT, the ET group revealed a reduced cadence (p = 0.04) and the OT group revealed an increased TUG time (p = 0.03), reduced BBS scores (p = 0.02), reduced step length (p = 0.02), reduced cadence (p = 0.03), reduced GVI (p = 0.01), and increased double support phase (p = 0.045).Conclusion: DT is accompanied by multiple abnormalities affecting gait and balance, albeit subclinical and less pronounced than ET and OT, possibly related to more effective compensatory mechanisms. Nevertheless, these abnormalities indicate that rehabilitative measures warrant consideration when managing in clinical settings.","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44311404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bradykinesia and dystonia","authors":"G. Paparella, A. Guerra, S. Galosi, A. Cannavacciuolo, Luca Angelini, Traian Popa, A. Berardelli, M. Bologna","doi":"10.3389/dyst.2023.11448","DOIUrl":"https://doi.org/10.3389/dyst.2023.11448","url":null,"abstract":"Background: Bradykinesia has been reported in patients with dystonia. Despite this, the pathophysiological mechanisms of bradykinesia in dystonia remain largely unknown.Methods: We here performed a comprehensive literature search and reviewed clinical and experimental studies on bradykinesia in patients with dystonia.Results: Many studies have documented the presence of bradykinesia in patients with idiopathic and inherited isolated dystonia, regardless of the presence of parkinsonism. In addition, bradykinesia has been observed as a side effect in dystonic patients who have undergone deep brain stimulation, in those with functional dystonia as well as in those with combined dystonia, e.g., dystonia-parkinsonism. These clinical and experimental findings support the hypothesis that dysfunction in a brain network involving the basal ganglia, primary sensorimotor cortex, and cerebellum may play a key role in the pathophysiology of both bradykinesia and dystonia.Conclusion: Bradykinesia is frequently observed in dystonia. We may gain insights into the pathophysiological underpinnings of two distinct movement disorders by investigating this issue. Furthermore, a deeper understanding of bradykinesia in dystonia may have terminological implications in this field.","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48434823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}