Deep brain stimulation and climbing fiber synaptic pathology in essential tremor

Kuo, Sheng‐Han; Lin, Chi‐Ying; Wang, Jie; Liou, Jyun-you; Pan, Ming‐Kai; Louis, Ravi J.; Wu, Wei Pu; Gutierrez, Jesús; Louis, Elan D.; Faust, Phyllis L.

doi:10.1002/ana.24728

Cited by 25 publications

(22 citation statements)

References 22 publications

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“…In this study, we found that ET cases and controls differ with respect to CF-PC synaptic pathology, confirming results from previous studies [4–7]. Specifically, ET cases have lower CF synaptic densities and higher percentages of CFs extending into the PF territory compared to controls.…”

Section: Discussionsupporting

confidence: 91%

“…Clinical and neuroimaging evidence both suggest the importance of the cerebellum in tremor generation in ET [2,3]. In recent studies, we observed climbing fiber-Purkinje cell (CF-PC) synaptic abnormalities in the ET cerebellum; compared to controls, ET cases exhibited decreased CF synaptic density and an increased percentage of CFs extending into the parallel fiber (PF) territory [4–7]. These changes coexist with a host of other pathological changes in PCs in ET, such as a decrease in PC counts [8] and an increase in torpedoes and associated PC axonal pathologies [8,9], although PC loss is a finding that is variably reproduced [10–12].…”

Section: Introductionmentioning

confidence: 99%

“…Although we recently described climbing fiber-Purkinje cell (CF-PC) synaptic abnormalities in ET [4–7], we have not explored whether these abnormalities differ across disease subtypes. Therefore, we now investigate CF-PC synaptic abnormalities across disease subtypes in ET: early vs. late onset ET, familial vs. sporadic ET, and ET cases with vs. without head tremor.…”

Section: Introductionmentioning

confidence: 99%

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Climbing fiber-Purkinje cell synaptic pathology across essential tremor subtypes

Lee

Gan

Faust

et al. 2018

Parkinsonism & Related Disorders

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Background Essential tremor (ET) is heterogeneous in nature and cases may be subdivided based on clinical features. ET patients may thus be subdivided by age of onset, family history of tremor, and presence of head tremor. We recently described climbing fiber-Purkinje cell (CF-PC) synaptic abnormalities in ET; however, these CF pathological features have not been studied across different ET subtypes. Objectives To explore whether these CF-PC synaptic abnormalities differ across ET subtypes. Methods We studied two climbing fiber (CF-PC) synaptic pathologies (CF synaptic density and percentage of CFs in the parallel fiber [PF] territory) in the cerebella of 60 ET cases with a range of clinical presentations and 30 age-matched controls. Results Compared to controls, ET cases had lower CF synaptic density and a higher percentage of CFs in the PF territory. ET cases with tremor onset <50 years and tremor onset ≥ 50 years did not differ significantly with respect to CF synaptic density and percentage of CFs in the PF territory. Similar results were found when comparing familial vs. sporadic ET cases, and ET cases with head tremor vs. those without head tremor. Among all ET cases, lower CF synaptic density was associated with lower PC counts and higher torpedo counts. In addition, higher percentage of CFs in the PF territory was associated with lower PC counts and higher torpedo counts. Conclusions These findings support the notion that changes in the distribution of CF-PC synapses are broadly part of the neurodegenerative process in the ET cerebellum.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Climbing fiber-Purkinje cell synaptic pathology across essential tremor subtypes

Lee

Gan

Faust

et al. 2018

Parkinsonism & Related Disorders

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“…Instead, we have noted the presence of abnormalities in CF-PC synapses in ET cases: (1) decreased CF-PC synaptic density on proximal PC dendrites, the normal synaptic domain of climbing fibers and (2) abnormal CF-PC synapses in extending into the PF-PC synaptic territory [31]. The number of abnormal distal CF-PC synapses inversely correlated with tremor severity [31, 41] and could be modulated by the deep brain stimulations [28], suggesting a link between this pathological feature and tremor.…”

Section: Introductionmentioning

confidence: 99%

Climbing fiber-Purkinje cell synaptic pathology in tremor and cerebellar degenerative diseases

et al. 2016

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Changes in climbing fiber-Purkinje cell (CF-PC) synaptic connections have been found in the essential tremor (ET) cerebellum, and these changes are correlated with tremor severity. Whether these postmortem changes are specific to ET remains to be investigated. We assessed CF-PC synaptic pathology in the postmortem cerebellum across a range of degenerative movement disorders [10 Parkinson’s disease (PD) cases, 10 multiple system atrophy (MSA) cases, 10 spinocerebellar ataxia type 1 (SCA1) cases, and 20 ET cases] and 25 controls. We observed differences in terms of CF pathological features across these disorders. Specifically, PD cases and ET cases both had more CFs extending into the parallel fiber (PF) territory, but ET cases had more complex branching and increased length of CFs in the PF territory along with decreased CF synaptic density compared to PD cases. MSA cases and SCA1 cases had the most severely reduced CF synaptic density and a marked paucity of CFs extending into the PF territory. Furthermore, CFs in a subset of MSA cases formed collateral branches parallel to the PC layer, a feature not seen in other diagnostic groups. Using unsupervised cluster analysis, the cases and controls could all be categorized into four clusters based on the CF pathology and features of PC pathology, including counts of PCs and their axonal torpedoes. ET cases and PD cases co-segregated into two clusters, whereas SCA1 cases and MSA cases formed another cluster, separate from the control cluster. Interestingly, the presence of resting tremor seemed to be the clinical feature that separated the cases into the two ET-PD clusters. In conclusion, our study demonstrates that these degenerative movement disorders seem to differ with respect to the pattern of CF synaptic pathology they exhibit. It remains to be determined how these differences contribute to the clinical presentations of these diseases.

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“…In ET they are more concentrated on the distal dendrites and this finding is inversely correlated with tremor severity. Interestingly, this inverse correlation is lost in ET patients treated with DBS confirming the plasticity of these relations . The comparison of ET with PD, spinocerebellar ataxia type 1 and multiple system atrophy patients showed that PD and ET had an increased number of distal climbing fiber terminations whilst multiple system atrophy and spinocerebellar ataxia type 1 patients had fewer climbing fibers terminating in the distal territory .…”

Section: Pathologymentioning

confidence: 73%

Is essential tremor a single entity?

Hopfner

Deuschl

2017

Euro J of Neurology

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Essential tremor (ET) is a frequent movement disorder. The new tremor classification has subdivided ET into the classical form with bilateral action tremor of the hands with or without involvement of further tremor locations and without any other explaining signs or symptoms for the tremor and into 'ET plus' which comes additionally with further neurological signs of unknown origin. This will provide a better foundation for subclassifying the condition. The immediate cause of ET is a preformed oscillating network within the central nervous system as revealed with electrophysiological methods. The reason why this network is getting into the tremor mode is unclear. Pathology has so far not convincingly proved neurodegeneration for the condition but possibly adaptive changes of the brain particularly in the cerebellum are likely. Genetics have not yet provided insight into the molecular causes of the condition but several genetic diseases presenting with an ET syndrome have been uncovered. Treatment options cover medication (propranolol, primidone, topiramate) and surgical interventions with deep brain stimulation, gamma-knife surgery and the recently introduced magnetic resonance imaging guided focused ultrasound lesioning. Further progress is awaited from the better integration of large prospective cohort assessment and basic science studies on the possible etiologies. In particular, aging-related tremor may explain a large number of the patients seen in clinical practice. Currently ET is considered a clinically relatively uniform condition with presumably various underlying etiologies.

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Deep brain stimulation and climbing fiber synaptic pathology in essential tremor

Cited by 25 publications

References 22 publications

Climbing fiber-Purkinje cell synaptic pathology across essential tremor subtypes

Climbing fiber-Purkinje cell synaptic pathology across essential tremor subtypes

Climbing fiber-Purkinje cell synaptic pathology in tremor and cerebellar degenerative diseases

Is essential tremor a single entity?

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