Cerebellar Pathology in Early Onset and Late Onset Essential Tremor

Kuo, Sheng‐Han; Wang, Jie; Tate, William J.; Pan, Ming‐Kai; Kelly, Geoffrey C.; Gutierrez, Jesús; Cortés, Etty; Vonsattel, Jean Paul; Louis, Elan D.; Faust, Phyllis L.

doi:10.1007/s12311-016-0826-5

Cited by 42 publications

(48 citation statements)

References 48 publications

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“…The mean age of onset for ET is most commonly reported to be between 45 and 55 years, with a bimodal distribution [21–23]. Of the ET cases in the ETCBR, there were 133 cases with clear documentation of age of tremor onset.…”

Section: Methodsmentioning

confidence: 99%

“…Therefore, we chose the age of onset of 50 to divide the early vs. late onset ET cases. Using data from our previous publications on the PC pathology in subgroups of ET cases and controls [21,24,25], we determined that with each ET group and control group composed of 30 subjects, we would be powered at 90% to detect differences of the magnitude previously detected [21,24,25]. Accordingly, we randomly selected 30 early onset ET cases, 30 late onset ET cases, and 30 controls in the current study.…”

Section: Methodsmentioning

confidence: 99%

“…Accordingly, we randomly selected 30 early onset ET cases, 30 late onset ET cases, and 30 controls in the current study. Of the selected cases for this study, data from 14 of 30 controls and 15 of 60 ET cases were reported in prior publications [21,24,25]. …”

Section: Methodsmentioning

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: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

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

Self Cite

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“…Even the authors who suggested this term have defined "late-onset" differently in various papers (e.g., defining it as ≥46 years in another paper) [69]. Finally, postmortem studies of humans suggest that the same degenerative pathology is found in both younger onset and older onset ET cases to the same extent [70]. In summary, there is little current evidence to support the notion that age of onset is the basis for distinct and separable subtypes of ET or that cases whose disease begins after a certain age cutoff do not have ET [68].…”

Section: Additional Biological Considerations: Aging and Etmentioning

confidence: 99%

The Roles of Age and Aging in Essential Tremor: An Epidemiological Perspective

Louis

2019

Neuroepidemiology

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Background: With an aging population, it behooves physicians and scientists to gain an understanding of the intersections between aging and human disease. Here, the author reviews the intersections between age, aging, and essential tremor (ET), particularly as these relate to disease epidemiology. Summary: The prevalence and incidence of ET both increase with age, and the former, in an exponential fashion with advanced aging. There is evidence that age may independently drive several features of the natural history of ET (e.g., the increase in tremor severity with time, the appearance of head tremor with time). Epidemiological studies clearly show that ET is associated with several conditions of advanced age, including Parkinson’s disease, mild cognitive impairment and dementia. Aside from age, age of onset has several important clinical correlates – familial forms of ET are more likely to have younger ages of onset, and older ages of onset are associated with more rapid disease progression. Key Messages: Overall, there are several important intersection points between age, aging, and ET. Potential biological explanations for these observations are discussed. Further knowledge about the basis for these observations will enhance our understanding of this disease and inform our care of patients.

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“…ET brains were from the Essential Tremor Centralized Brain Repository (ETCBR), a joint effort between investigators at Yale and Columbia Universities [33; 34]. ET diagnoses were all carefully assigned using three sequential methods, as described at length [14].…”

Section: Methodsmentioning

confidence: 99%

Cerebellar pathology in childhood-onset vs. adult-onset essential tremor

Louis

Kuo

Tate

et al. 2017

Neuroscience Letters

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Although the incidence of ET increases with advancing age, the disease may begin at any age, including childhood. The question arises as to whether childhood-onset ET cases manifest the same sets of pathological changes in the cerebellum as those whose onset is during adult life. We quantified a broad range of postmortem features (Purkinje cell [PC] counts, PC axonal torpedoes, a host of associated axonal changes [PC axonal recurrent collateral count, PC thickened axonal profile count, PC axonal branching count], heterotopic PCs, and basket cell rating) in 60 ET cases (11 childhood-onset and 49 adult-onset) and 30 controls. Compared to controls, childhood-onset ET cases had lower PC counts, higher torpedo counts, higher heterotopic PC counts, higher basket cell plexus rating, and marginally higher PC axonal recurrent collateral counts. The median PC thickened axonal profile count and median PC axonal branching count were two to five times higher in childhood-onset ET than controls, but the differences did not reach statistical significance. Childhood-onset and adult-onset ET had similar PC counts, torpedo counts, heterotopic PC counts, basket cell plexus rating, PC axonal recurrent collateral counts, PC thickened axonal profile count and PC axonal branching count. In conclusion, we found that childhood-onset and adult-onset ET shared similar pathological changes in the cerebellum. The data suggest that pathological changes we have observed in the cerebellum in ET are a part of the pathophysiological cascade of events in both forms of the disease and that both groups seem to reach the same pathological endpoints at a similar age of death.

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Cerebellar Pathology in Early Onset and Late Onset Essential Tremor

Cited by 42 publications

References 48 publications

Climbing fiber-Purkinje cell synaptic pathology across essential tremor subtypes

Climbing fiber-Purkinje cell synaptic pathology across essential tremor subtypes

The Roles of Age and Aging in Essential Tremor: An Epidemiological Perspective

Cerebellar pathology in childhood-onset vs. adult-onset essential tremor

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