New, Multisystem Insights Reveal Potential Treatment Pathways for Parkinson Disease

January 11, 2021
NeurologyLive Staff

Research led by movement disorders specialist Un Jung Kang, MD, searches for clues to help diagnose and treat Parkinson’s disease in its earliest stages, well before symptom onset.

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As research elucidates the origins and mechanisms of Parkinson’s disease, a multidisciplinary team of NYU Langone researchers is synthesizing those clues in order to diagnose and effectively treat the disease in its earliest stages, before traditional symptoms come to light. With new insights into motor and non-motor symptoms, earlier detection and individualized treatments hold greater promise.

Uncovering the Brain Circuitry Changes in Parkinson’s Disease

Two National Institutes of Health (NIH)–funded studies led by Un Jung Kang, MD, the Founders Professor of Neurology, professor in the Department of Neuroscience and Physiology, and director of translational research in the Department of Neurology and Fresco Institute for Parkinson’s and Movement Disorders, seek to reveal the dynamic between therapeutic dopamine—the standard of care for patients with the condition—and the brain circuitry behind motor dysfunction.

In the first study, Dr. Kang is mapping cell types in the brain’s striatum to investigate how this circuitry influences so-called motor learning, which may underlie the long-duration therapeutic response seen in dopamine-treated patients. “We’re discovering that dopamine not only helps patients move better, but also contributes to sustained functional improvement,” he says. “We’re trying to understand what’s behind this gradual buildup of benefit and how long it lasts.”

Paradoxically, Dr. Kang and his team are also investigating how brain compensation can interfere with dopamine’s therapeutic effects. When treatment begins, some patients’ brain circuitry, having rewired itself to adapt to dopamine loss, leads to hypersensitive response. “They go from movements that are too slow to uncontrolled movements that interfere with mobility for the opposite reason,” notes Dr. Kang. “The rewired brain no longer knows what to do with the dopamine.”

By understanding this effect and the cellular-level changes in brain biochemistry, Dr. Kang hopes to fine-tune therapies by combining cell-selective, neuroanatomical, and biochemical approaches to target neurotransmitters beyond dopamine, with greater specificity than surgical therapies such as deep brain stimulation.

Non-Motor Symptoms May Predict Disease Onset

Other research is targeting the effects of Parkinson’s disease beyond motor symptoms. Problems with sleep, blood pressure, constipation, and urination have become more prominent in a patient population living longer due to treatment advances. “These symptoms are becoming more troublesome, but we’re learning they often begin decades before patients are diagnosed,” Dr. Kang says.

One such symptom is rapid eye movement (REM) sleep behavioral disorder (RBD), a condition in which patients’ muscle control does not temporarily shut down during REM sleep. Dreams become “enacted,” accompanied by movements such as talking or kicking. The disorder itself may not be bothersome unless severe movements injure patients or their bed partners. “However we’re learning that RBD almost always leads to more extensive neurodegeneration, such as Parkinson’s disease, Lewy body dementia, or multiple system atrophy,” notes Dr. Kang. Similarly, autonomic nervous system abnormalities that manifest as dizziness upon standing, urination problems, or constipation may also foretell Parkinson’s disease and related disorders.

The prevalence of gastrointestinal (GI) symptoms in patients with Parkinson’s disease, along with recent interest in the initiation of synuclein pathology in the gut and transfer to the brain via the vagus nerve, has prompted Dr. Kang to study detailed GI physiology in patients with Parkinson’s disease. He is examining the immunological state and neuro-immune interactions in the gut to understand how immune changes there may contribute to Parkinson’s disease, multiple system atrophy, and other disorders. Since the gut microbiome has been shown to differ in patients with Parkinson’s disease and other neurological disorders, the team hopes to develop an integrated understanding of how these changes, GI immunity, and GI function collectively contribute to neurodegenerative pathogenesis.

“We’re trying to get different disciplines to look at this together to uncover how non-central nervous system–related symptoms might have similar underlying mechanisms to what are traditionally thought to be hallmarks of these neurological disorders,” says Dr. Kang.

Finding a Biomarker for Early Detection

A key aim of the research is to pinpoint a biomarker that could correlate with one of these peripheral precursors to Parkinson’s disease, enabling earlier diagnosis of the disease. Today, diagnosis is based on clinical presentation and examination—when irreversible disease progression has already occurred. Dr. Kang’s research seeks to enable diagnosis decades earlier so therapies can potentially slow the disease before severe symptoms present. One promising biomarker involves an abnormal form of alpha-synuclein, which can accurately identify patients with Parkinson’s disease in more than 90 percent of cases and may predict eventual development of neurodegeneration at the prodromal stages.

“The idea is that we can eventually test everyone with certain symptoms for this biomarker, treat them early, and suddenly Parkinson’s disease is a much more manageable condition.”—Un Jung Kang, MD

“The idea is that we can eventually test everyone with certain symptoms for this biomarker, treat them early, and suddenly Parkinson’s disease is a much more manageable condition,” Dr. Kang observes.

Better understanding of such biomarkers might also help better stratify patients according to their disease pathogenesis, eventually enabling targeting of interventions based on heterogeneous forms of Parkinson’s disease. “We may be able to start picking out those patients with higher risk, use a biomarker to narrow them into subtypes, and then intervene before the disease becomes obvious,” adds Dr. Kang.

A Clearer Disease Picture, Developed with Collaboration

Collectively, the research relies on specialists across the clinical spectrum working to understand Parkinson’s disease from every angle. Dr. Kang works with NYU Langone sleep specialists, gastroenterologists, dysautonomia specialists, cognitive neurologists, and movement disorder specialists—combining clinical expertise with basic neuroscience, genomics, and immunology. The multisystem approach is linking insights from cutting-edge research into a cohesive blueprint of the root causes and various expressions of Parkinson’s disease.

“Today, once patients become ‘typical’ in presenting with Parkinson’s, our options for them are the same,” concludes Dr. Kang. “But if we can paint a unique picture of how the disease manifests in each patient, that will unlock new possibilities for future treatment.”