We read with great interest the study by Destrebecq et. al.1 on impaired predictive coding in the somatosensory mismatch detection network in essential tremor (ET), and wish to congratulate the authors on their elegant and informative study. Studies of the role of the cerebellum the pathophysiology of this enigmatic disease are vitally important.
We would like to respectfully draw attention to the following set of sentences in their Introduction: “Pathology studies inconsistently [our italics] showed in patients with ET a loss of Purkinje cells (PC), heterotopic PCs, axonal swelling, redistribution of climbing fiber synapses, or morphological abnormalities in both the DN and afferent/efferent tracts of cortico-cerebellar loops.” In particular, we draw the reader’s attention to the word “inconsistently”. Here we would like to distinguish PC loss, which is one degenerative feature of ET, from a host of 20 additional degenerative changes that have been observed and catalogued in the ET brain (three of which are specified above by the authors).2
Although numerous studies have demonstrated the presence of PC loss in ET,3 there is one study that was properly powered which did not.4 Critique of the methodology of that study has been discussed in detail (especially see extensive discussion in “PC death” section of Louis and Faust5),3, 5 thereby calling into question whether there are any valid data which do not show PC loss in ET. Indeed, a recently published study of 215 ET brains collected over a 21-year period continues to demonstrate a significant reduction in PC counts in ET vs control brains and discussed the numerous other means that have been employed to successfully quantify, either directly or indirectly (e.g., through studies of empty baskets or through nearest neighbor analyses), the extent of PC loss in ET.6
In contrast to PC loss, numerous additional degenerative changes in the ET brain have not inconsistently [our italics] been reported, and these place ET within the spectrum of cerebellar degenerative disorders.2 These changes, which involve both the PC and neighboring neuronal populations and connections, have been grouped into 8 broad categories: PC loss, heterotopic PCs, PC dendritic changes, PC axonal changes (torpedoes), PC axonal changes (other than torpedoes), PC axonal changes (torpedo-associated), basket cell axonal hypertrophy, and climbing fiber-PC synaptic changes.2 A recent analysis that used data from only a small number of these degenerative cerebellar changes demonstrated that it was possible to distinguish ET and control brains with approximately 95% sensitivity and specificity and, as such, took a clear step towards tissue-based diagnostic criteria for ET.7
Studies of ET brains, either in vivo, as conducted by Destrebecq et. al.1 or at the time of postmortem,7 help to shed light on the mechanisms whereby cerebellar dysfunction and degeneration result in a disease that is devastating for millions of Americans.
Funding Sources:
This work was supported by the National Institutes of Health (NIH) Award #R01 NS086736 and #R01 NS117745. NIH played no role in the design, collection, analysis, or interpretation of the data, or in the writing of this manuscript.
Financial Disclosure of all authors (for the preceding 12 months):
Dr. Louis has received research support from the National Institutes of Health: NINDS #R01 NS117745 (principal investigator), NINDS #R01 NS086736 (principal investigator), 1R01NS137042–01A1 (principal investigator), NINDS #UE5 NS098987 (principal investigator), and 5R01NS124854–03 (co-investigator). Dr Louis receives publishing royalties for Merritt’s Textbook of Neurology. Dr. Louis provides consultancy related to topics in neuroepidemiology. Dr. Faust has received research support from the National Institutes of Health: NINDS #R01 NS117745 (principal investigator), NINDS #R01 NS086736 (co-investigator), NINDS #R01 NS124854 (principal investigator), NINDS #R01 NS136686 (co-investigator), NINDS #1R01 NS137042 (co-investigator).
Footnotes
Financial Disclosure/Conflict of Interest Related to Research Covered in This Article: Dr. Louis has not financial disclosures or conflicts of interest. Dr. Faust has not financial disclosures or conflicts of interest.
Data Sharing:
This paper does not report original data.
References
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Data Availability Statement
This paper does not report original data.