Research led by movement disorders specialist Dr. Un Kang searches for clues to help diagnose and treat Parkinson鈥檚 disease in its earliest stages, well before symptom onset.
Photo: 秘密研究所 Langone Staff
As research elucidates the origins and mechanisms of Parkinson鈥檚 disease, a multidisciplinary team of 秘密研究所 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鈥檚 Disease
Two National Institutes of Health (NIH)鈥揻unded studies led by Un J. Kang, MD, the Founders Professor of Neurology, professor in the , and director of translational research in the and Fresco Institute for Parkinson鈥檚 and Movement Disorders, seek to reveal the dynamic between therapeutic dopamine鈥攖he standard of care for patients with the condition鈥攁nd the brain circuitry behind motor dysfunction.
In the first study, Dr. Kang is mapping cell types in the brain鈥檚 striatum to investigate how this circuitry influences so-called motor learning, which may underlie the long-duration therapeutic response seen in dopamine-treated patients. 鈥淲e鈥檙e discovering that dopamine not only helps patients move better, but also contributes to sustained functional improvement,鈥 he says. 鈥淲e鈥檙e trying to understand what鈥檚 behind this gradual buildup of benefit and how long it lasts.鈥
Paradoxically, Dr. Kang and his team are also investigating how brain compensation can interfere with dopamine鈥檚 therapeutic effects. When treatment begins, some patients鈥 brain circuitry, having rewired itself to adapt to dopamine loss, leads to hypersensitive response. 鈥淭hey go from movements that are too slow to uncontrolled movements that interfere with mobility for the opposite reason,鈥 notes Dr. Kang. 鈥淭he rewired brain no longer knows what to do with the dopamine.鈥
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鈥檚 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. 鈥淭hese symptoms are becoming more troublesome, but we鈥檙e learning they often begin decades before patients are diagnosed,鈥 Dr. Kang says.
One such symptom is rapid eye movement (REM) sleep behavioral disorder (RBD), a condition in which patients鈥 muscle control does not temporarily shut down during REM sleep. Dreams become 鈥渆nacted,鈥 accompanied by movements such as talking or kicking. The disorder itself may not be bothersome unless severe movements injure patients or their bed partners. 鈥淗owever we鈥檙e learning that RBD almost always leads to more extensive neurodegeneration, such as Parkinson鈥檚 disease, Lewy body dementia, or multiple system atrophy,鈥 notes Dr. Kang. Similarly, autonomic nervous system abnormalities that manifest as dizziness upon standing, urination problems, or constipation may also foretell Parkinson鈥檚 disease and related disorders.
The prevalence of gastrointestinal (GI) symptoms in patients with Parkinson鈥檚 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鈥檚 disease. He is examining the immunological state and neuro-immune interactions in the gut to understand how immune changes there may contribute to Parkinson鈥檚 disease, multiple system atrophy, and other disorders. Since the gut microbiome has been shown to differ in patients with Parkinson鈥檚 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.
鈥淲e鈥檙e trying to get different disciplines to look at this together to uncover how non-central nervous system鈥搑elated symptoms might have similar underlying mechanisms to what are traditionally thought to be hallmarks of these neurological disorders,鈥 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鈥檚 disease, enabling earlier diagnosis of the disease. Today, diagnosis is based on clinical presentation and examination鈥攚hen irreversible disease progression has already occurred. Dr. Kang鈥檚 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鈥檚 disease in more than 90 percent of cases and may predict eventual development of neurodegeneration at the prodromal stages.
鈥淭he idea is that we can eventually test everyone with certain symptoms for this biomarker, treat them early, and suddenly Parkinson鈥檚 disease is a much more manageable condition.鈥濃擴n Kang, MD
鈥淭he idea is that we can eventually test everyone with certain symptoms for this biomarker, treat them early, and suddenly Parkinson鈥檚 disease is a much more manageable condition,鈥 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鈥檚 disease. 鈥淲e 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,鈥 adds Dr. Kang.
A Clearer Disease Picture, Developed with Collaboration
Collectively, the research relies on specialists across the clinical spectrum working to understand Parkinson鈥檚 disease from every angle. Dr. Kang works with 秘密研究所 Langone sleep specialists, gastroenterologists, dysautonomia specialists, cognitive neurologists, and movement disorder specialists鈥攃ombining 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鈥檚 disease.
鈥淭oday, once patients become 鈥榯ypical鈥 in presenting with Parkinson鈥檚, our options for them are the same,鈥 concludes Dr. Kang. 鈥淏ut if we can paint a unique picture of how the disease manifests in each patient, that will unlock new possibilities for future treatment.鈥
