Purkinje cell loss is a characteristic of essential tremor

doi:10.1016/j.parkreldis.2011.05.004

Parkinsonism & Related Disorders

Volume 17, Issue 6, July 2011, Pages 406-409

https://doi.org/10.1016/j.parkreldis.2011.05.004 Get rights and content

Abstract

This paper began as a letter to the editor, commenting on several methodological and conceptual problems with the paper by Rajput et al. [1]. We were asked by the editors to expand the paper to include a more general discussion of the role of the cerebellum in essential tremor (ET). The study of the neuropathological underpinnings of essential tremor (ET) is a relatively new undertaking. The purpose of this paper is three-fold. The first is to comment on methodological problems in a recently-published paper by Rajput et al., the major one being the small sample size of that study, which resulted in a Type II statistical error. Hence, one cannot conclude based on their data that there is no Purkinje cell (PC) loss in ET. Secondly, we comment on conceptual problems with that study, which suggested that PC loss might not be a featured characteristic of ET because it is also found in other disease states. We discuss why this is an erroneous conclusion. Our third purpose is to more broadly discuss the role of the cerebellum in ET, giving consideration to the wealth of clinical and postmortem data that have accumulated over recent years. In this discussion, we make the following points: (1) it is now generally recognized that ET is a disease of cerebellar systems dysfunction, (2) given the nature of the postmortem work, revealing the presence of several types of structural-anatomical changes within the cerebellum and absence of detectable changes in other brain regions, the most empirically-based explanation is that the primary problem in ET is in the cerebellum itself, (3) that the collection of cellular changes in the cerebellum in ET are also present in other cerebellar degenerations should add to rather than detract from the notion that ET is a disease of cerebellar degeneration.

Section snippets

Comments on Rajput et al. [1]

We read with interest the paper by Rajput et al. [1] regarding Purkinje cell (PC) loss and ET and would like to comment on several issues.

First, they write: “The hypothesis that PC loss is pathognomonic of ET [here they cite papers by our group] is not supported by our data”. “Pathognomonic” implies that a particular feature is so specific to or distinctly characteristic of a disease that it makes the diagnosis. We have not put forth the hypothesis that PC loss is only found in the ET brain.

It is generally recognized that ET is a disease of cerebellar systems dysfunction

Given the sheer wealth of accumulating clinical, physiological, neuroimaging, surgical-therapeutic, and postmortem data (far too numerous to cite here) [6], [7], it would be difficult to argue that ET is anything other than a disease (or a set of related diseases) primarily of cerebellar system dysfunction. This is important to recognize as it provides both a physiological and a loose anatomical framework with which to begin to conceptualize ET as well as a focus through which to advance our

References (12)

A.H. Rajput et al.
Cerebellar purkinje cell loss is not pathognomonic of essential tremor
Parkinsonism Relat Disord
(2010)
E.D. Louis et al.
Neuropathological changes in essential tremor: 33 cases compared with 21 controls
Brain
(2007)
J.E. Axelrad et al.
Reduced purkinje cell number in essential tremor: a postmortem study
Arch Neurol
(2008)
R.E. Burke et al.
A critical evaluation of the braak staging scheme for parkinson’s disease
Ann Neurol
(2008)
W. Samuel et al.
Clinical correlates of cortical and nucleus basalis pathology in alzheimer dementia
Arch Neurol
(1994)
Louis ED. Essential tremor: evolving clinicopathological concepts in an era of intensive post-mortem enquiry. Lancet...

There are more references available in the full text version of this article.

Cited by (39)

Açaí juice (Euterpe oleraceae) prevents ethanol-induced motor impairments in adolescent female rats
2023, Journal of Functional Foods
Açaí (Euterpe oleracea), a natural species frequent in the Amazon biome is widely consumed by the inhabitants of the Amazon. Açaí juice presents high levels of antioxidant compounds, especially anthocyanins, which confer several pharmacological properties. According to the World Health Organization, the consumption of alcohol by adolescents occurs in early adolescence in an intense, intermittent, and episodic manner, also called binge drinking. The binge-like standard induces several hazardous effects on the central nervous system. The present work investigated the effects of clarified açaí juice on a model of binge alcohol-induced motor impairment in adolescents. Female rats received açaí juice (10 µL/g) or distilled water by gavage from the 30th to 58th postnatal day (PND). On the 35th to 58th PND, animals were exposed to four cycles of a binge-like paradigm (ethanol 3 g/kg/day by gavage, 3 days on–4 days off) or distilled water. On the 59th PND, all tested groups were submitted to motor behavioral assays on the open field, pole test, beam walking, and rotarod tests. Our results demonstrated that alcohol-exposed animals reduced the spontaneous locomotor activity, elicited bradykinesia-like behavior, as well as motor incoordination and imbalance on the behavioral tasks. The chronic açaí juice administration prevented the spontaneous locomotor activity alteration, bradykinesia, and incoordination induced by alcohol exposure in all behavioral tests, suggesting a protective effect on motor function. We concluded that açaí juice exerts a protective effect against alcohol-induced motor impairments in a binge ethanol-exposed adolescent model.
Is essential tremor a family of diseases or a syndrome? A syndrome
2022, International Review of Neurobiology
Citation Excerpt :
The notion that ET is a neurodegenerative disease linked to the cerebellum, has gained increasing momentum in recent years (Louis, 2010). The strongest argument for neurodegeneration is PC loss and increase in the number of torpedoes (rounded swellings of the proximal portion of the PC axon) as well as other degenerative changes in PC and neighboring neuronal populations (Louis & Faust, 2020; Louis, Faust, & Vonsattel, 2011, 2012; Louis et al., 2019). Gionco and colleagues recently reported a detailed postmortem study of 50 ET cases (24 ET and 26 ET plus) using a set of 14 quantitative metrics of cerebellar pathology including histologic and immunohistochemical methods (Gionco et al., 2021).
In a consensus statement, a task force of the “International Parkinson and Movement Disorder Society” (IPMDS) has recently proposed a two axes classification for tremor: axis I (clinical manifestations) and axis II (etiology). In the axis, I, the clinical features of tremor in a given patient are specified in terms of medical history, tremor characteristics, associated signs, and laboratory tests for some tremors leading to the discovery of axis 2 etiologies. Based on axis I sign and symptoms a specific clinical syndrome is diagnosed which have been categorized as isolated tremor syndrome (a syndrome consisting only of tremor) and combined tremor syndrome (consisting of tremor and other systemic or neurological signs). The IPMDS task force defined essential tremor as an isolated tremor syndrome of bilateral upper limb action tremor of at least 3 years duration with or without a tremor in other locations (e.g., head, voice or lower limbs) in absence of other neurological signs, such as dystonia, ataxia, or parkinsonism. Patients with neurological signs of uncertain significance (such as impaired tandem gait, questionable dystonic posturing, or memory impairment) are classified as essential tremor plus.
In this paper, the author will make the argument that essential tremor is a syndrome with multiple causes.
Principles and Practice of Movement Disorders
2021, Principles and Practice of Movement Disorders
An optimized surgical approach for obtaining stable extracellular single-unit recordings from the cerebellum of head-fixed behaving mice
2016, Journal of Neuroscience Methods
Citation Excerpt :
The cerebellum is essential for diverse functions, including motor coordination and learning, posture, and balance. Therefore, damage to its circuits causes a number of motor disorders, such as ataxia, dystonia, and tremor (Orr, 2012; LeDoux and Lorden, 2002; Wilson and Hess, 2013; Louis et al., 2011). Cerebellar function in both normal and abnormal states has been intensely studied.
Electrophysiological recording approaches are essential for understanding brain function. Among these approaches are various methods of performing single-unit recordings. However, a major hurdle to overcome when recording single units in vivo is stability. Poor stability results in a low signal-to-noise ratio, which makes it challenging to isolate neuronal signals. Proper isolation is needed for differentiating a signal from neighboring cells or the noise inherent to electrophysiology. Insufficient isolation makes it impossible to analyze full action potential waveforms. A common source of instability is an inadequate surgery. Problems during surgery cause blood loss, tissue damage and poor healing of the surrounding tissue, limited access to the target brain region, and, importantly, unreliable fixation points for holding the mouse's head.
We describe an optimized surgical procedure that ensures limited tissue damage and delineate a method for implanting head plates to hold the animal firmly in place.
Using the cerebellum as a model, we implement an extracellular recording technique to acquire single units from Purkinje cells and cerebellar nuclear neurons in behaving mice. We validate the stability of our method by holding single units after injecting the powerful tremorgenic drug harmaline. We performed multiple structural analyses after recording.
Our approach is ideal for studying neuronal function in active mice and valuable for recording single-neuron activity when considerable motion is unavoidable.
The surgical principles we present for accessing the cerebellum can be easily adapted to examine the function of neurons in other brain regions.
Pathogenesis of severe ataxia and tremor without the typical signs of neurodegeneration
2016, Neurobiology of Disease
Citation Excerpt :
Here, we used the cerebellum as a model to uncover how an intact circuit can still impact disease outcome. The cerebellum is involved in a number of motor disorders including ataxia, dystonia, and tremor (Louis et al., 2011; Orr, 2012; Wilson and Hess, 2013). Purkinje cells are the presumed source of these disorders, and they often degenerate (Unno et al., 2012; Orr, 2012; Prudente et al., 2013; Louis, 2014).
Neurological diseases are especially devastating when they involve neurodegeneration. Neuronal destruction is widespread in cognitive disorders such as Alzheimer's and regionally localized in motor disorders such as Parkinson's, Huntington's, and ataxia. But, surprisingly, the onset and progression of these diseases can occur without neurodegeneration. To understand the origins of diseases that do not have an obvious neuropathology, we tested how loss of CAR8, a regulator of IP3R1-mediated Ca^2 +-signaling, influences cerebellar circuit formation and neural function as movement deteriorates. We found that faulty molecular patterning, which shapes functional circuits called zones, leads to alterations in cerebellar wiring and Purkinje cell activity, but not to degeneration. Rescuing Purkinje cell function improved movement and reducing their Ca^2 + influx eliminated ectopic zones. Our findings in Car8^wdl mutant mice unveil a pathophysiological mechanism that may operate broadly to impact motor and non-motor conditions that do not involve degeneration.
Neuroanatomical correlates of dystonic tremor: A cross-sectional study
2014, Parkinsonism and Related Disorders
Citation Excerpt :
In the last few years, advances have been reached in the definition of the pathophysiological mechanisms underlying ET and DT. Evidences support the hypothesis that ET is a progressive disease sustained by neurodegenerative processes [2–5]. Neuroimaging [3,4] and post-mortem [5] studies in patients with ET demonstrated the presence of pathological changes mainly involving the cerebellum [6].
This study is aimed at investigating the neuroanatomical patterns characterizing dystonic tremor in comparison with essential tremor.
Voxel-based morphometry and cortical thickness data of 12 patients with dystonic tremor, 14 patients with essential tremor and 23 age- and sex-matched healthy control subjects were analyzed.
Patients with dystonic tremor showed a thickening and increased gray matter volume (surviving whole-brain correction for multiple comparisons) of the left sensorimotor cortex when compared to other groups. Otherwise, patients with essential tremor were characterized by a subtle atrophy of the anterior cerebellar cortex.
Our multimodal structural neuroimaging study demonstrated that patients with dystonic tremor and essential tremor are characterized by different neuroanatomical abnormalities. The involvement of the sensorimotor cortex in patients with dystonic tremor suggests that this disorder may share some pathophysiological mechanisms with focal dystonia.

View all citing articles on Scopus

^☆: The review of this paper was entirely handled by an Associate Editor, Dr. R.L. Rodnitzkyi.

View full text

Point of viewPurkinje cell loss is a characteristic of essential tremor☆

Abstract

Section snippets

Comments on Rajput et al. [1]

It is generally recognized that ET is a disease of cerebellar systems dysfunction

Cerebellar purkinje cell loss is not pathognomonic of essential tremor

Parkinsonism Relat Disord

Neuropathological changes in essential tremor: 33 cases compared with 21 controls

Brain

Reduced purkinje cell number in essential tremor: a postmortem study

Arch Neurol

A critical evaluation of the braak staging scheme for parkinson’s disease

Ann Neurol

Clinical correlates of cortical and nucleus basalis pathology in alzheimer dementia

Arch Neurol

Point of view
Purkinje cell loss is a characteristic of essential tremor☆