After nearly 150 years of failed therapies for Parkinson’s disease, the introduction of dopamine for patient treatment began in the late 1960s, and its transformative effect on patient movement, function and speech was immediately embraced. Since that time, dopamine-based therapies have formed the backbone of Parkinson’s therapy and have informed the basis of scientific understanding regarding the cause of this common neurodegenerative condition.

In the past decade or two, however, a few key facts have caused some Parkinson’s researchers to question the focus on dopamine alone: First, patients initially respond well to dopamine therapy but inevitably progress. Second, there are numerous nonmotor symptoms that patients experience even very early in the course of the disease that are not resolved by dopamine therapy. An entire field of research has emerged to look into these factors outside of the dopamine pathway.

One such team in this field is that of Michele Tagliati, MD, the Caron and Steven D. Broidy Chair in Movement Disorders, director of the Movement Disorders Program, and vice chair of the Department of Neurology at Cedars-Sinai. After a clinical trial using an approved drug for Type 2 diabetes (liraglutide) to target insulin resistance in the brain of Parkinson’s patients resulted in significant improvement in nonmotor symptoms, he has set his sights on another potential target in this population: dysregulation of the noradrenergic system.

“This area of research is fascinating, because you can easily imagine how looking at the disease before it manifests as neurological symptoms would open a window of opportunity to treat or modify its progression,” Tagliati said.

Many of the pre-diagnostic and nonmotor symptoms of Parkinson’s—including fatigue, bowel and bladder problems, restlessness, sleep disruption, and problems with swallowing, saliva control, and sweating—are also major contributors to reduced quality of life for patients with the condition.

The Noradrenergic System and Its Possible Role in Parkinson’s

The noradrenergic system serves as a key neuromodulator. It produces and transmits a hormone called noradrenaline, also known as norepinephrine, to control the body’s fight-or-flight response as well as to regulate arousal, attention and reactions to stress. Symptoms associated with potential noradrenergic dysregulation include REM sleep behavior disorder, depression and anxiety, hypertension, attention deficit hyperactivity disorder, sweating, shaking, fatigue, and muscle tension—most of which overlap with symptoms experienced by patients with Parkinson’s before and after diagnosis.

Noradrenaline is produced in large part in the locus coeruleus—an area of the brain that undergoes significant and early deterioration in patients with Parkinson’s disease. An increasing appreciation for these connections between symptoms and disease physiology has made the noradrenergic system ripe for exploration in the world of Parkinson’s therapeutics.

After recognizing the potential importance of this link several years ago, Tagliati’s clinical research group launched an investigator-initiated pilot study in collaboration with Roy Artal, MD, medical director of Tower Sleep Medicine at Cedars-Sinai. Together, they are exploring the potential to prevent or delay the development of Parkinson’s disease among high-risk individuals via early detection and treatment with drugs that help normalize the effects of an overactive noradrenergic system.

The study’s patients are typically identified based on a diagnosis of REM sleep behavior disorder—a common precursor of Parkinson’s—and referred to Tagliati for inclusion in the study. Many participants also have other common pre-diagnostic symptoms, such as loss of smell, depression or constipation.

Early findings from participant biomarker analysis, MRI studies of neuromelanin (a marker of noradrenaline production), MIBG cardiac imaging and heart rate variability tests suggest many of these high-risk patients have abnormally increased sympathetic tone—an overactive noradrenergic system. Participants in the pilot study who have these findings are offered the option to take alpha and beta blockers to lower sympathetic tone and potentially reduce their risk of progression to neurodegeneration.

“If our hypothesis about blocking adrenaline excess in presymptomatic individuals is correct, it would completely change the way we look at Parkinson’s disease,” said Tagliati.

A Part of the Whole

In addition to pioneering exploration into the world of preventive therapy or disease-modifying treatment, it is possible that combining noradrenergic therapies with dopamine-based regimens could offer extended or enhanced symptom management among patients with active disease.

When combined with other areas of research, such as the metabolism and insulin drug-repurposing studies initiated by Tagliati, the field of Parkinson’s research has exploded into numerous promising areas.

“We have entered a new era of opportunity for Parkinson’s treatment, and the coming years are likely to see a long-awaited improvement in our ability to manage this disease in its motor and nonmotor complexity,” Tagliati said. “Even better, our findings may open an important conceptual doorway for the way we think about intervening with other neurodegenerative and neurological conditions.”

References

1.       Wu T, Bresee J, Wertheimer E, et al. Liraglutide once daily versus placebo in Parkinson’s disease: a randomized, double-blind, placebo-controlled trial [abstract]. Mov Disord. 2022; 37 (suppl 1). 
2.       Hogg E, Wu T, Bresee C, Wertheimer J, et al. A phase II, randomized, double-blinded, placebo-controlled trial of liraglutide in Parkinson's disease. Pre-print available at http://dx.doi.org/10.2139/ssrn.4212371.