Climbing fiber synaptic changes correlate with clinical features in essential tremor

Louis, Ravi J.; Lin, Chi‐Ying; Faust, Phyllis L.; Koeppen, Arnulf H.; Kuo, Sheng‐Han

doi:10.1212/wnl.0000000000001636

Cited by 21 publications

(33 citation statements)

References 7 publications

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“…Another limitation is that we mainly studied the axonal compartment in the cerebellar cortex. Other synaptic pathology in the early vs. late onset ET cerebellum remains to be investigated [44, 45]. A third limitation is that we did not employ stereological methods for PC counts; nonetheless, we have previously validated PC counting with a random sampling approach [13].…”

Section: Discussionmentioning

confidence: 99%

Cerebellar Pathology in Early Onset and Late Onset Essential Tremor

et al. 2016

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Early onset and late onset essential tremor (ET) cases differ in several respects. Whether they differ with respect to cerebellar pathologic changes remains to be determined. We quantified a broad range of postmortem features (Purkinje cell (PC) counts, PC axonal torpedoes and associated axonal changes, heterotopic PCs, and hairy basket ratings) in 30 ET cases with age of tremor onset <50 years, 30 ET cases with age of tremor onset ≥50 years, and 30 controls (total n = 90). We also used two alternative age of onset cut-points (<40 vs. ≥40 years, and <60 vs. ≥60 years) to define early onset vs. late onset ET. We found that ET cases with tremor onset <50 years and tremor onset ≥50 years had similar PC counts (8.78 ± 1.70 vs. 8.86 ± 1.24, p = 0.839), PC axonal torpedo counts (17.87 ± 18.27 [median =13.00] vs. 12.90 ± 10.60 [median =9.0], p = 0.486) and associated axonal pathology (all p values >0.05), heterotopic PC counts (9.90 ± 11.55 [median =6.00] vs. 5.40 ± 5.10 [median =3.50], p = 0.092), and hairy basket ratings (1.95 ± 0.62 [median =2.00] vs. 2.05 ± 0.92 [median =2.00], p = 0.314). When using the age of onset cut-points of 40 or 60 years, results were similar. Early onset and late onset ET cases share similar cerebellar postmortem features. These data do not support the notion that these age-of-onset related forms of ET represent distinct clinical-pathological entities.

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Section: Discussionmentioning

confidence: 99%

Cerebellar Pathology in Early Onset and Late Onset Essential Tremor

et al. 2016

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“…In general, CF-PC synapses are highly plastic and are dynamically regulated in response to their synaptic activity; 3,4 therefore, it is conceivable that DBS could disrupt abnormal brain oscillatory networks and affect the organization of CF-PC synapses in ET. In the current study, we evaluated whether the inverse correlation between tremor severity and abnormal CF-PC synapses, recently observed in ET cases without DBS treatment 1,2 (see above), would be altered in age-matched ET cases who had undergone DBS treatment.…”

Section: Introductionmentioning

confidence: 99%

“…We recently observed an increase in CF synapses on the thin, distal PC dendritic branchlets in ET vs. control cerebella (i.e., the abnormal presence of CF extension into the PF-PC synaptic territory). 1 Interestingly, the percentage of CF-PC synapses on thin PC dendritic branchlets was inversely correlated with tremor severity, 1,2 suggesting that these abnormal CF-PC synapses may be linked in some way to the mechanism of tremor.…”

Section: Introductionmentioning

confidence: 99%

Deep brain stimulation and climbing fiber synaptic pathology in essential tremor

Kuo

Lin

Wang

et al. 2016

Annals of Neurology

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Essential tremor (ET) patients have abnormal climbing fiber (CF) synapses in the parallel fiber territory in the cerebellum, and these abnormal CF synapses are inversely correlated with tremor severity. We therefore examined CF synaptic pathology in ET cases with and without thalamic DBS and assessed the association with tremor severity. We found that CF synaptic pathology was inversely correlated with tremor severity in ET cases without DBS, and this correlation disappeared in ET cases with DBS. Our data suggest that DBS might have effects in modulating excitatory synapses in ET cerebellum, in addition to its symptomatic effects on tremor.

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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%

“…Defective CF-PC synaptic connections can also occur in the setting of PC degeneration in various forms of spinocerebellar ataxias (SCAs) [25]. Specifically, CFs regressed and only formed excitatory synaptic connections in the very proximal PC dendritic region in mouse models of SCAs [3, 13, 19], which is quite different from the pattern observed in the human disease ET, in which there is an extension of CFs to the distal PC dendritic branchlets [31, 41]. To our knowledge, there are no systematic comparisons of CF and PC pathologies in the postmortem human cerebellum across a range of degenerative movement disorders.…”

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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Climbing fiber synaptic changes correlate with clinical features in essential tremor

Cited by 21 publications

References 7 publications

Cerebellar Pathology in Early Onset and Late Onset Essential Tremor

Cerebellar Pathology in Early Onset and Late Onset Essential Tremor

Deep brain stimulation and climbing fiber synaptic pathology in essential tremor

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

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