Linking Essential Tremor to the Cerebellum: Neuropathological Evidence

Abstract

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.

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

“…In addition to these changes we have reported PC loss [13; 18], a finding that has been variably reproduced [19; 20; 21]. These pathological changes support the concept that the cerebellum is of mechanistic importance in ET [4; 22; 23]. They also support the concept that ET may be a neurodegenerative disease [4; 22; 23; 24].…”

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

“…One possible explanation for the increase in disease incidence with age as well as the reported increase in tremor severity with age may be neuronal attrition [23,24]. The pathophysiology of ET is not completely understood, although there is considerable evidence that it involves a mild form of cerebellar degeneration centered on and around the Purkinje cell population [17,[60][61][62]. It is well known that aging is associated with progressive Purkinje cell loss [63,64].…”

Genetics of essential tremor

“…Recent neuropathological evidence mostly point to the abnormalities in the cerebellum and in particular on the GABAergic Purkinje cells and their surrounding neuronal populations, resulting in hypertrophy in the basket cell axonal processes and hence likely to affect cerebellar cortical circuits and cerebellar output (reviewed in Ref. [7]). …”

“…This and the fact that the effect of harmaline wears off merely 2 h after its administration do not reflect the physiological condition of the disease [22]. Clinical data have indicated a possible role of GABA in the pathophysiology of ET [7,8]. Knock-out of GABA(A) receptor alpha1 subunit in mice has been reported to produce locomotor impairment and tremor [23], both of which are characteristics of ET.…”