Essential tremor with ubiquitinated intranuclear inclusions and cerebellar degeneration

Louis, Elan D.; Mazzoni, Pietro; Karén, Jakob; Moskowitz, Carol; Lawton, Arlene; Garber, Anthony T.; Vonsattel, Jean Paul

doi:10.5414/np300414

Cited by 14 publications

(5 citation statements)

References 32 publications

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“…For example, some of the ET cases have more pronounced changes in the cerebellum (e.g., involving damage in the deep cerebellar nuclei), perhaps indicative of a more destructive process [65]. Yet others have ubiquitin positive inclusions in the Purkinje cells and elsewhere [66]. Even within the bulk of ET cases with the standard set of cerebellar degenerative changes described in previous sections, there is considerable variance with respect to these changes, and it is highly likely that within this broad category are several subtypes characterized by differences in the cascade of pathological changes.…”

Section: Et Is Likely a Heterogeneous Set Of Diseasesmentioning

confidence: 95%

Linking Essential Tremor to the Cerebellum: Neuropathological Evidence

Louis

2015

Cerebellum

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A fundamental question about essential tremor (ET) is whether its associated pathological changes and disease mechanisms are linkable to a specific brain region. To that end, recent tissue-based studies have made significant strides in elucidating changes in the ET brain. Emerging from these studies is increasing neuropathological evidence linking ET to the cerebellum. These studies have systematically identified a broad range of structural, degenerative changes in the ET cerebellum, spanning across all Purkinje cell compartments. These include the dendritic compartment (where there is an increase in number of Purkinje cell dendritic swellings, a pruning of the dendritic arbor, and a reduction in spine density), the cell body (where, aside from reductions in Purkinje cell linear density in some studies, there is an increase in the number of heterotopic Purkinje cell soma), and the axonal compartment (where a plethora of changes in axonal morphology have been observed, including an increase in the number of thickened axonal profiles, torpedoes, axonal recurrent collaterals, axonal branching, and terminal axonal sprouting). Additional changes, possibly due to secondary remodeling, have been observed in neighboring neuronal populations. These include a hypertrophy of basket cell axonal processes and changes in the distribution of climbing fiber-Purkinje cell synapses. These changes all distinguish ET from normal control brains. Initial studies further indicate that the profile (i.e., constellation) of these changes may separate ET from other diseases of the cerebellum, thereby serving as a disease signature. With the discovery of these changes, a new model of ET has arisen, which posits that it may be a neurodegenerative disorder centered in the cerebellar cortex. These newly emerging neuropathological studies pave the way for anatomically focused, hypothesis-driven, molecular mechanistic studies of disease pathogenesis.

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Section: Et Is Likely a Heterogeneous Set Of Diseasesmentioning

confidence: 95%

Linking Essential Tremor to the Cerebellum: Neuropathological Evidence

Louis

2015

Cerebellum

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“…In this way, postmortem findings reflect the clinical findings in this disorder, and both serve to support the notion that ET itself is likely to be a family of diseases (Louis 2014b). Thus, a small number of ET cases exhibit ubiquitin-positive intranuclear inclusions in the PCs and elsewhere (Louis and others 2010; Louis and others 2012b) and others exhibit pronounced changes in the cerebellar dentate nucleus, as noted above (Louis and others 2006a). Some also exhibit Lewy bodies in the brainstem and, particularly, in the locus ceruleus (Louis and others 2005; Louis and others 2007), a structure whose neurons synapse directly with PCs.…”

Section: Heterogeneity Of Postmortem Findings In the Et Cerebellummentioning

confidence: 70%

Essential Tremor

Louis

2015

Neuroscientist

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Essential tremor (ET) is one of the most common neurological diseases, with an estimated 7 million affected individuals in the United States. Postmortem studies in the past few years have resulted in new knowledge as well as a new formulation of disease pathophysiology. This new formulation centers on the notion that ET might be a disease of the cerebellum and, more specifically, the Purkinje cell (PC) population. Indeed, several investigators have proposed that ET may be a “Purkinjopathy.” Supporting this formulation are data from controlled postmortem studies demonstrating (1) a range of morphological changes in the PC axon, (2) abnormalities in the position and orientation of PC bodies, (3) reduction in the number of PCs in some studies, (4) morphological changes in and pruning of the PC dendritic arbor with loss of dendritic spines, and (5) alterations in both the PC-basket cell interface and the PC-climbing fiber interface in ET cases. This new formulation has engendered some controversy and raised additional questions. Whether the constellation of changes observed in ET differs from that seen in other degenerative disorders of the cerebellum remains to be determined, although initial studies suggest the likely presence of a distinct profile of changes in ET.

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“…Purkinje cells receive projections from LC. Another postmortem study showed intranuclear inclusions in cerebellum [21]. These findings point toward cerebellum as the potential site of neurodegeneration in ET patients.…”

Section: Check For Updatesmentioning

confidence: 82%

Recent Updates on Essential Tremor

Jamal¹

2019

Int J Neurol Neurother

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Essential Tremor is the most common movement disorder, but many aspects of this common condition are unclear. There have been multiple updates in the field of Essential Tremor in last few years, that has improved our understanding to some extent. Recently, consensus criteria for classifying tremor disorders was published. Special emphasis was on Essential Tremor, to facilitate better phenotyping and understanding of underlying etiology. Purpose was to identify homogenous population of different tremor syndromes. In addition, recent work focused on developing non-motor neuropsychological tests that can be used for Essential Tremor patients. A study used these tests to identify MCI subtypes associated with Essential Tremor. Further studies have been conducted to study gait and mood difficulties in Essential Tremor patients. Concept of early and late onset Essential Tremor as distinct clinical entities was not endorsed by recent neuropathological study. MRI guided focused ultrasound thalamotomy was FDA approved for patients with refractory Essential Tremor. This review summarizes the recent advances in the field of Essential Tremor.

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Essential tremor with ubiquitinated intranuclear inclusions and cerebellar degeneration

Cited by 14 publications

References 32 publications

Linking Essential Tremor to the Cerebellum: Neuropathological Evidence

Linking Essential Tremor to the Cerebellum: Neuropathological Evidence

Essential Tremor

Recent Updates on Essential Tremor

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