About Tremor

AboutTremor

Decade of the Brain

The 41st President of the United States proclaimed 1990 to the end of 1999 as the Decade of the Brain. The President’s proclamation included, “The need for continued study of the brain is compelling: millions of Americans are affected each year by disorders of the brain ranging from neurogenetic diseases to degenerative disorders.”

Post Decade of the Brain

More than ten million Americans live with essential tremor, ten times the number of people afflicted with Parkinson’s Disease. The noticeable difference is not in the number of people afflicted, but in the lack of sufficient scientific interest in essential tremor. Although common and known for centuries, essential tremor is like a new disease, in that little is known about the exact cause. Initial attempts at understanding essential tremor have had mixed success.

Finding the Abnormal Cell

Progress in understanding Alzheimer’s Disease began with finding abnormal cells and deposits in the cerebral cortex. A large step in understanding Parkinson’s Disease came about with the finding of selective dopamine cell loss in the substantia nigra.

In essential tremor, no specific pathologic signature has been identified. The initial negative findings in essential tremor patient brains were found before modern techniques were developed. Interestingly, a small sample was shown to be characterized by high levels of the neurotransmitter norepinephrine in the cerebellum. In order to take another look for abnormal cells in essential tremor, Dr. Elan Louis of Columbia University is conducting a study in which participants videotape their tremor and donate their brain after death. Through the use of modern microscopic techniques, it is hoped to find a structural or neurochemical anomaly that will provide an important clue to the cause of essential tremor.

Postscript

Dr. Louis and his colleagues believe they have found an identifiable pathology. The findings show “that the disease is likely to be a pathologically heterogeneous family of diseases, and that there is a link between ET and Lewy body disease.” The pathological material has identified two groups: “cases with mild cerebellar degenerative changes versus those with a focal presence of Lewy bodies in the locus ceruleus.” Dr. Louis has authored a paper with Hiral LaRoia suggesting an association between ET and Parkinson’s and Alzheimer’s.

Finding Essential Tremor Genes

Many persons with essential tremor have inherited tremor from a mother or father, who in turn inherited tremor from a father or mother. Essential tremor is likely caused by more than one gene, but it is probable that many genes related to tremor have related functional roles, like parts of an engine. By finding these genes, one at a time from a family with that gene, molecular biologists will eventually understand what the essential tremor gene-protein products do. This general approach is the same as that applied in the past for other conditions, such as Huntington’s Disease. Eventually, this knowledge could lead to treatments. If you belong to a family with ten or more living members with essential tremor, please contact Tremor Action Network.

Postscript

Despite the familial risk for ET no high-risk gene has been identified, with the exception of LINGO1.

Mouse Model of Tremor

Researchers in most neurological diseases employ rodents, especially mice, in models of the human disease. “Chemical” models use a drug to simulate the human condition being studied, while “genetic” models use either spontaneous rodent mutations that are similar to human disease, or a transgenic mouse, which contains the human gene causing the disease. Chemical models have been useful to search for new medications for human disease. Genetic models have been generally used to study the mechanism of disease. To give examples, there are genetic models of epilepsy, Alzheimer’s, “Lou Gehrig’s disease” (ALS) and Parkinson’s; and, chemical models of epilepsy and Parkinson’s. Because an essential tremor gene has not yet been found, no transgenic essential tremor mouse has yet been generated. For many years, the drug harmaline was known to produce tremor in rodents. Dr. Fredricka Martin and Dr. Adrian Handforth have refined this model so that it can be used to screen for potential therapies in essential tremor. Candidate medications are regarded as promising if they suppress tremor to a high degree without causing sedation or clumsiness, and do so in doses compatible with doses achievable in humans. This approach may also provide clues about the cause of tremor, by indicating what classes of drugs with known mechanisms are effective.

Clinical Trials

Numerous clinicians in North America, Europe and around the world are interested in finding new therapies for essential tremor. Each year trials are reported that were started after anecdotal favorable reports or “educated guesses.” Although much progress has been made through this empirical approach in identifying therapies, much more progress is needed. Eventually, we may anticipate essential tremor-specific therapies based on knowledge of the abnormal cell and the abnormal genes.

Relatively few centers are conducting clinical trials of therapies for essential tremor on a regular basis. One such site is that of Adrian Handforth, M.D. at the VA Greater Los Angeles Healthcare System. These investigators are utilizing a mouse model to screen for potential effectiveness. If the medication passes the mouse test, it is then assessed in a small open-treatment pilot clinical trial. The final stage will be a controlled clinical trial. These trials require a series of outpatient visits. Interested participants should be within driving distance. Subjects do not have to be a veteran, but should be at least age eighteen. Email: charles.handforth@med.va.gov.

The Limiting Factor

Contrary to popular belief, the lack of ideas is not the most common factor holding up scientific progress. Instead it is the lack of funds that hamper progress. After a vigorous growth period of NIH research budgets, research funding has stabilized, so that new applicants will have a hard time obtaining funding. More than ever, essential tremor needs funding support from private donors.

Postscript

There is definitely a need for “open collaboration” with the knowledge of less NIH funding.

Acknowledgement

Tremor Action Network acknowledges Dr. Adrian Handforth, for providing the information on the various approaches investigators are beginning to employ to tackle this elusive disorder.

“Life is not merely to be alive, but to be well.”
— Marcus Valerius Martialis

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