Awards for Parkinson’s Disease Recognize Pioneering Treatments

The Albert and Mary Lasker Foundation announced September 8 that Alim Louis Benabid of Joseph Fournier University in Grenoble, France, and Mahlon DeLong of Emory University School of Medicine in Atlanta will receive the 2014 Lasker-DeBakey Clinical Medicine Research Award for their development of deep brain stimulation (DBS) to treat tremors and dyskinesia in people with Parkinson’s disease. The pair will split a $250,000 honorarium, to be awarded at a ceremony on September 19 in New York City. On October 2, another major figure in the Parkinson’s field will share in the $250,000 2014 Warren Alpert Foundation Prize, to be awarded at a ceremony at Harvard Medical School. Honoree Oleh Hornykiewicz of the Medical University of Vienna discovered treatment with L-dopa, which has been used as a first-line therapy for PD since the 1960s. Benabid and DeLong described their breakthroughs in the September 8 JAMA online.

In the late 1980s, when DeLong and Benabid performed their groundbreaking research, people with Parkinson’s were already benefiting from L-dopa, which was available in pill form. However, it was apparent that over time, the drug could cause unpleasant side effects, including involuntary movements called dyskinesias. “Better treatments were needed,” DeLong and Benabid noted in their article.

Alim Louis Benabid (left) and Mahlon R. DeLong. [Images courtesy of Pierre Jayet (left) and Albert and Mary Lasker Foundation.]

To better understand the root of the dyskenisea and come up with new therapeutics, DeLong studied the basal ganglia. He focused on this part of the brain because its activity is abnormal in people with movement disorders such as Parkinson’s. By stimulating the brains of monkeys with microelectrodes and observing their movements, DeLong defined a basal ganglia “motor circuit” that includes two key parts, the globus pallidus and subthalamic nucleus. The subthalamic nucleus receives input from the cortex, while the globus pallidus sends signals out of the basal ganglia to the thalamus and brainstem. 

A monkey model for Parkinson’s disease, based on the neurotoxin MPTP that damages dopaminergic neurons, proved crucial for DeLong’s work (Langston et al., 1984). In those animals, he saw that neurons were overactive in both the globus pallidus and subthalamic nucleus. If those hyperactive neurons created the movement symptoms, then shutting them down should alleviate the problems, DeLong hypothesized. In 1990, he tested his prediction, using a second neurotoxin to create a lesion in the subthalamic nucleus. Within minutes the monkeys moved better, with less rigidity and trembling in their limbs (Bergman et al., 1990). 

This work inspired DeLong and other surgeons to take a similar approach in people with Parkinson’s, though in humans they preferred to target the globus pallidus. Destroying the subthalamic nucleus carried a risk of creating a different movement disorder, chorea, which causes flailing of limbs. Surgeons typically used radio signals, instead of a toxin, to destroy the globus pallidus in a procedure called pallidotomy. It improved parkinsonism and eliminated the dyskinesia associated with L-dopa therapy, but surgeons worried about irreversible side effects from a permanent procedure.

Benabid came up with a safer method. He discovered it during surgery for essential tremor, a movement disorder distinct from PD. Before creating a permanent lesion in the thalamus to stop essential tremor, standard practice was to pinpoint the surgical site using electrical stimulation.  Fifty Hertz was sufficient, but during one such exploration, Benabid wondered what might happen at higher frequencies and boosted it to 100 Hertz. The person’s hand tremor stopped (Benabid et al., 1987). The patient—who was awake for the procedure—was delighted with the result.

This finding was “paradoxical,” DeLong and Benabid noted; stimulating the neurons had the same effect as shutting them down. Benabid hypothesized the current “jammed” the neural signals, overriding their normal activity. Scientists still do not fully understand the mechanism of DBS (see May 2010 news story). 

Regardless of the mechanism, the stimulation clearly worked. Benabid realized he could stop tremors by using continuous electric stimulation rather than permanently destroying part of the brain. The treatment, unlike lesions, would be reversible—if anything went wrong, he could simply turn off the juice. DBS electrodes were already available for pain treatment. Inspired by DeLong’s monkey study, Benabid tried implanting them in the subthalamic nucleus of three people with PD (Limousin et al., 1995). 

Those were the first to receive this life-changing treatment, which was approved by the Food and Drug Administration in 2002. More than 100,000 people with PD have since seen their tremors stilled thanks to DBS (see Jan 2013 news story). People who get DBS can often reduce the dosage of L-dopa and other PD medications, limiting side effects of the medications. Moreover, neurosurgeons are currently testing DBS in different brain regions, for a variety of conditions, including Alzheimer’s, Tourette’s syndrome, and depression (see May 2010 news story). 

Oleh Hornykiewicz. [Image courtesy of Peter Lackner.]

Despite its drawbacks, L-dopa remains a life-altering therapeutic. Benabid and DeLong share the same accolade as the late George Cotzias of Brookhaven National Laboratory in Upton, New York, who received the Albert Lasker Clinical Medical Research Award in 1969 to honor his work developing oral L-dopa. The Nobel Prize committee later recognized L-dopa treatment when they awarded the 2000 Physiology or Medicine prize to Arvid Carlsson, Paul Greengard and Eric Kandel. Carlsson discovered that dopamine is a neurotransmitter, and Greengard figured out how it and other neurotransmitters work, while Kandel received his share for research on signal transduction. However, dozens of neuroscientists publicly objected to the Nobel committee’s decision, arguing that Hornykiewicz had been unfairly left out (Rajput, 2001). Cotzias had died in 1977, and Nobel Prizes are not awarded posthumously.

Hornykiewicz discovered that dopamine levels are normally higher in the basal ganglia than other parts of the brain, and that people with PD have unusually low dopamine concentrations in the globus pallidus, subthalamic nucleus, substantia nigra and other parts of the brain. He then injected L-dopa, a precursor to dopamine, intravenously into patients in what were to be the first clinical trials for this treatment beginning in 1961. Decades later, the drug stands as the top choice for first-line treatment (see Jun 2014 news story). Hornykiewicz shares the 2014 Warren Alpert Foundation Prize with Roger Nicoll of the University of California, San Francisco, for his work on synapses, and Solomon Snyder of Johns Hopkins University in Baltimore for developing methods to study neural receptors.—Amber Dance

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References

News Citations

  1. Deep-Brain Stimulation: Decade of Surgical Relief, Not Just for PD
  2. A Day in the OR: Surgeons Zap Neurons for Parkinson’s, AD
  3. Deep-Brain Stimulation: An Electrode for All Occasions?
  4. Tried and True: Levodopa Still Best First-Line Parkinson’s Medication

Paper Citations

  1. Langston JW, Langston EB, Irwin I. MPTP-induced parkinsonism in human and non-human primates--clinical and experimental aspects. Acta Neurol Scand Suppl. 1984;100:49-54. PubMed.
  2. Bergman H, Wichmann T, Delong MR. Reversal of experimental parkinsonism by lesions of the subthalamic nucleus. Science. 1990 Sep 21;249(4975):1436-8. PubMed.
  3. Benabid AL, Pollak P, Louveau A, Henry S, de Rougemont J. Combined (thalamotomy and stimulation) stereotactic surgery of the VIM thalamic nucleus for bilateral Parkinson disease. Appl Neurophysiol. 1987;50(1-6):344-6. PubMed.
  4. Limousin P, Pollak P, Benazzouz A, Hoffmann D, Le Bas JF, Broussolle E, Perret JE, Benabid AL. Effect of parkinsonian signs and symptoms of bilateral subthalamic nucleus stimulation. Lancet. 1995 Jan 14;345(8942):91-5. PubMed.
  5. Rajput AH. An open letter to the Committee on The Nobel Prize in Medicine. Parkinsonism Relat Disord. 2001 Apr;7(2):149-55. PubMed.

Further Reading

Papers

  1. Laxton AW, Tang-Wai DF, McAndrews MP, Zumsteg D, Wennberg R, Keren R, Wherrett J, Naglie G, Hamani C, Smith GS, Lozano AM. A phase I trial of deep brain stimulation of memory circuits in Alzheimer's disease. Ann Neurol. 2010 Oct;68(4):521-34. PubMed.
  2. Okun MS, Fernandez HH, Wu SS, Kirsch-Darrow L, Bowers D, Bova F, Suelter M, Jacobson CE, Wang X, Gordon CW, Zeilman P, Romrell J, Martin P, Ward H, Rodriguez RL, Foote KD. Cognition and mood in Parkinson's disease in subthalamic nucleus versus globus pallidus interna deep brain stimulation: the COMPARE trial. Ann Neurol. 2009 May;65(5):586-95. PubMed.
  3. Bronstein JM, Tagliati M, Alterman RL, Lozano AM, Volkmann J, Stefani A, Horak FB, Okun MS, Foote KD, Krack P, Pahwa R, Henderson JM, Hariz MI, Bakay RA, Rezai A, Marks WJ, Moro E, Vitek JL, Weaver FM, Gross RE, Delong MR. Deep brain stimulation for Parkinson disease: an expert consensus and review of key issues. Arch Neurol. 2011 Feb;68(2):165. PubMed.
  4. Castrioto A, Lozano AM, Poon YY, Lang AE, Fallis M, Moro E. Ten-year outcome of subthalamic stimulation in Parkinson disease: a blinded evaluation. Arch Neurol. 2011 Dec;68(12):1550-6. PubMed.

Primary Papers

  1. DeLong MR, Benabid AL. Discovery of High-Frequency Deep Brain Stimulation for Treatment of Parkinson Disease: 2014 Lasker Award. JAMA. 2014 Sep 8; PubMed.

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