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Locus coeruleus dysfunction: A feature of essential or senile tremor?

The origin of essential tremor (ET) has remained enigmatic since its first description despite considerable effort. It is clinically defined as a symmetric postural and action tremor mainly of the hands but also frequently of other extremities. It is generally acknowledged that the definition may lump many entities together, which adds to the difficulties in properly studying this disease. The neuropathologic basis of this condition is still unknown. While the first published series could not find a typical pathology, a recent cohort proposed 2 types of pathologies: a variant with Lewy body degeneration mainly in the locus coeruleus, and a cerebellar variant with reduced Purkinje cells. This has been challenged by 2 other recent studies that could confirm neither the finding of increased Lewy bodies nor the loss of Purkinje cells, and therefore we remain without certainty as to the pathologic nature of this frequent disease. A new approach to the problem comes from biochemical assessments of brain tissue in patients with ET. Shill et al. have for the first time systematically compared biochemical changes in the brain in a relatively large cohort of 23 ET patients with those in 37 controls. They quantitatively analyzed biochemical markers of neurotransmitter function and neuronal loss in regions of the brainstem and cerebellum believed to play a possible role in ET. In this cohort, striatal tyrosine hydroxylase, a marker of dopaminergic neurons, was not different from the controls. This is the strongest evidence so far arguing against the hypothesis that ET is due to nigrostriatal dopaminergic degeneration. The hypothesis that some ET patients have dopaminergic degeneration came from an autopsy study that found Lewy bodies in the brainstem and particularly in the locus coeruleus. Another line of arguments comes from the still disputed observation of a more frequent occurrence of Parkinson’s disease (PD) in patients with ET. The second result of this remarkable study shows that dopamine beta-hydroxylase is normal in the locus coeruleus, indicating that a major deficit of noradrenergic innervation is unlikely in ET. This would argue against the old hypothesis that a primary noradrenergic deficit might contribute to postural tremor. However, Shill et al. also found that parvalbumin, a marker of c-aminobutyric acid (GABA)ergic neurons, is significantly reduced in the locus coeruleus and the pons of ET cases. This might indirectly affect noradrenergic innervation and provides the first hint of a biochemical abnormality in ET. Interestingly, cerebellar parvalbumin was normal, suggesting that there is not a widespread loss of GABAergic neurons. How can a decrease of GABA in the locus coeruleus produce tremor? Dysfunction of the locus coeruleus has been considered when discussing the pathophysiology of tremors. This nucleus is the only source of cortical, thalamic, and cerebellar noradrenergic supply and has a major role in arousal and several other functions. The cells of the locus coeruleus can fire synchronously under experimental conditions and perhaps could promote tremorigenic oscillation in motor pathways, but such a hypothesis still needs to be substantiated. There is an even more interesting finding hidden in the data of this remarkable study, and the authors kindly allowed me to examine their original data. While for the whole group, the difference of locus coeruleus parvalbumin is statistically significant, this is due to a subgroup of patients with a shorter duration and therefore later onset of tremor. The patient group under investigation includes 2 subgroups: a larger group of 19 patients with a mean age at onset of 80 years of age (on average 6 years before death), and a small group of 4 patients with a mean tremor onset at 32 years of age, which is typical for classical ET. The group with lateonset ET led to the results of the study being statistically significant, while 3 of the 4 patients with early-onset tremor had normal parvalbumin. Assuming that reduced locus coeruleus GABA is a feature of ET, one would expect that those with the longest disease course should have the largest deficiency, but the opposite was found here. Certainly, the small group of early-onset -