DENVER —Essential tremor may be as much as 20 times more common than Parkinson’s disease. Yet, its underlying cause and disease mechanisms remain unknown. With the aid of new imaging data gained from measuring metabolite levels in the cerebellum, however, neurologists may be closer than ever to explaining the pathophysiology of this disorder.

“No one has ever demonstrated what the pathology is in essential tremor. No one has ever demonstrated cell death,” said principal investigator Elan D. Louis, MD, MS, Assistant Professor of Neurology at Columbia University in New York City. “This imaging technique allows us to indirectly assess the viability of the brain cells and, specifically, the neurons. It seems like a perfect method to approach this question other than doing postmortem examinations.” Dr. Louis presented the results of his study at the 54th Annual Meeting of the American Academy of Neurology.

Essential tremor affects up to 6% of the general population. Even when it is mild, essential tremor can be disabling; when it is severe, patients often cannot feed or dress themselves, write, or work. Currently available therapies are less than optimal. If researchers could pinpoint whether neuronal damage is occurring in a specific region of the brain or establish that essential tremor is neurodegenerative in origin, then they might be able to develop more effective symptomatic treatments. The prospect of a pathophysiologic breakthrough also has neurologists envisioning the design of neuroprotective strategies to prevent the disease from progressing before the onset of major symptoms.

Dr. Louis and colleagues used a scanning technique, 1H magnetic resonance spectroscopic imaging, to measure levels of intracellular metabolites such as N-acetylaspartate (NAA), total choline, and total creatine (tCR) in several brain regions in patients with essential tremor. Because NAA is a marker of neuronal viability, the researchers believed that any reductions observed in this particular metabolite would indicate neuronal damage or death.

In comparing 14 cases of essential tremor with nine controls of similar mean age (mid-50s to early 60s), the investigators found that cerebellar cortical levels of NAA, expressed as a ratio with tCR, were reduced by about 20% in patients with essential tremor versus the control subjects. Furthermore, there was a significant inverse association between these same cerebellar cortical levels and the age of patients in the essential tremor cases. Although the reductions in NAA/tCR levels in the cerebellum suggest that neuronal loss or damage is occurring in this region of the brain, it is the accelerated decline in such levels observed with increasing age that led the investigators to conclude that essential tremor may indeed be a neurodegenerative disease.

Essential tremor affects people of all age-groups, although its prevalence increases substantially with age. In some cases, it runs in families in an autosomal dominant fashion; in other instances, there is no familial predisposition, suggesting that the causes are likely to be environmental factors. Hands, head, and voice are most often affected, and the symptoms often begin as mild tremors that become more severe and disabling over time.

Regarding its relationship to other disorders, essential tremor appears to be its own distinct—if idiopathic—disease, or perhaps a family of diseases lumped together. Although some patients with essential tremor develop Parkinson’s disease and some patients with other neurologic disorders, such as dystonia, also have essential tremor, the majority of patients with essential tremor are not affected by similar comorbidities.

Parkinson’s disease remains an important model, however. According to Dr. Louis, it was “a huge leap” when researchers first determined that the cells dying in patients with Parkinson’s disease were those containing dopamine, because the next aim was to devise therapies that would replace that loss of dopamine. This revolutionized the treatment of Parkinson’s disease, he added. “With essential tremor, we need to establish that cells are dying,” he said. And in that respect, “I think this study helps,” he added. “Secondly, [the next goal is] to identify more specifically which cells are dying, what the neurochemical defect is, and therefore what is the most rational pharmacotherapy one can devise based on that.”

In addition to further delineating which cells are dying in which specific brain regions, the next steps include developing a large brain bank for more accurate pathologic research—all in the interest of describing an pathophysiology that has remained unexplained for some time, Dr. Louis noted.

NR

Return to table of contents