Parkinson’s disease (PD), a movement disorder and leading cause of disability worldwide, causes tremor, slowness, stiffness, and walking and balance problems, plus other issues such as constipation, depression, and memory loss. Most PD patients are diagnosed after age 60, and many develop cognitive changes, including dementia. Currently, diagnosing PD is difficult because patients often present at advanced stages, with vastly different symptoms. With no definitive tests, clinicians rely on clinical exams, imaging, and assays that rule out other diseases. Meanwhile, treatment is limited to alleviating symptoms. Researchers are searching for reliable biomarkers to help clinicians diagnose PD, track its progression, and develop effective targeted therapies.
An ideal biomarker would be objective, available without invasive procedures or expensive exams, and identify PD as early as possible—ideally before symptoms develop—and paired with appropriate prevention strategies, said Mark Frasier, PhD, senior vice president of research programs at The Michael J. Fox Foundation for Parkinson’s Research (MJFF). MJFF’s $900 million in research funding includes sponsorship of the Parkinson’s Progression Markers Initiative (PPMI), an international study that aims to identify and validate clinical, imaging, genetic, and protein PD biomarkers. PPMI makes its data available to the research community in real time and takes applications for biosample use.
An Uncertain Pathophysiology
PD’s cause remains unknown. Historically, scientists have seen PD as the result of lost dopamine neurons in brain regions that control movement, Frasier said. But in the last 15 years, research has pointed to misfolded alpha-synuclein proteins (α-syn)—which clump and form Lewy bodies in the brain—as a culprit. Patients with Alzheimer’s disease (AD) and other neurologic conditions also have Lewy bodies.
More recent evidence suggests that PD may begin outside of the brain, perhaps in the gut, Frasier added. It might travel along neurons to the brain (Neuron 2019;103:627–41). This theory jives with the digestive problems that many PD patients notice up to 10 years before they develop tremors, researchers have noted.
On the Horizon
In recent years, the PD research field “has transformed from one with no biomarker activity to one with many emerging biomarkers that might translate into clinical labs,” Frasier said. The MJFF research portfolio includes support of studies into 100 biomarker candidates, half of which are molecular. Frasier identified several as especially intriguing.
The first is the radiopharmaceutical imaging agent DaTscan, approved by the Food and Drug Administration in 2018. DaTscan helps provide images that show evidence of degeneration in the brain’s nigrostriatal region, based on a reduced density of dopamine transporters. Frasier said DaTscan could have sufficient sensitivity to show if an intervention slows cell loss. But it cannot be used on its own and isn’t useful for all patients, according to MJFF.
Studies show that α-syn consistently occurs at lower concentrations in PD patients’ cerebrospinal fluid (CSF), compared with controls, Frasier noted. Most recently, PPMI data have shown that α-syn that originates in the brain and is present in CSF decreases early in PD, before motor symptoms develop (Mov Disord 2019;34:1354-64). Response of α-syn in blood plasma to peripheral changes in PD patients has also attracted interest. A recent proof-of-concept study shows that α-syn in blood cells reliably differentiated between Parkinson’s patients with motor symptoms and healthy controls (Ann Clin Transl Neurol 2019;6:2426-36).
Neurofilament light chain (NfL) is an attractive biomarker because it’s found in blood plasma, so testing is noninvasive. This protein marks neuronal cell loss, which is a feature of PD and other diseases. NfL appears to be changed in PD patients, compared with controls, Frasier noted. Research has focused mostly on NfL in CSF and has noted a good correlation between NfL levels in mouse CSF and serum (Neuron 2016;91:494–6). A recent study in humans suggests that an NfL blood test might track PD progression (Neurology 2019;93:e1104–11).
Accessible in urine, the lipid bis(monoacylglycero)phosphate (BMP) increases with lysosomal dysfunction in PD and other neurodegenerative diseases. Research has shown an association between BMP and LRRK2 mutations, a common cause of inherited PD (Mov Disord 2019; doi:10.1002/mds.27818). More phase 1 trials are looking at BMP.
The Role of Epigenetics
Research has also found epigenetic changes—especially abnormal DNA methylation—in blood samples from PD patients. These DNA methylation patterns might provide insights into the molecular mechanisms driving PD and serve as biomarkers, said Travis Dunckley, PhD, and Paula Desplats, PhD. Many studies show that neurotoxins—especially those in pesticides—interfere with epigenetic processes in PD (Acta Neuropathol 2016;132:515–30). “Genetic studies don’t explain most of PD risk, so the rest of it is probably environmental, including these types of toxins,” said Dunckley, an assistant research professor at the Arizona State University-Banner Neurodegenerative Disease Research Center in Tempe.
To determine whether DNA methylation signatures in blood might be useful PD biomarkers, Dunckley and Desplats, an associate professor of neurosciences and pathology at University of California San Diego School of Medicine, are studying 2,500 samples from the PPMI cohort that were collected longitudinally over 3 years. The researchers will analyze methylation profiles from patients with unknown causes of PD, PD patients and asymptomatic participants with LRRK2 mutations, at-risk people with sleep disorders and smell loss, and healthy controls.
The researchers intend to describe participants’ methylation profiles for use in future research, to determine if genetic variants modify profiles and assess whether methylation influences when people with sleep and smell problems develop PD. They would also like to find 10-12 methylation markers that could be used as part of a lab panel, said Desplats.
A Link to Alzheimer’s Disease
PPMI Steering Committee members Leslie Shaw, PhD, and John Trojanowski, MD, PhD, both professors of pathology and laboratory medicine at the University of Pennsylvania Perelman School of Medicine, emphasized a connection between PD and AD. Cognitive impairment is very common in PD patients, and about two-thirds eventually develop AD. Trojanowski’s non-PPMI research also suggests that AD biomarkers may be useful in assessing prognosis for PD and in developing potential treatments for the disease (Lancet Neurol 2017;16:55-65).
Unpublished findings from neuropathology exams on deceased patients who participated in PPMI and the Alzheimer’s Disease Neuroimaging Initiative (ADNI) show that about 90% of PD patients have AD pathology, Trojanowski added. “This finding isn’t widely known or appreciated, especially among drug companies,” he said.
Trojanowski and Shaw have shown that types of tau proteins (especially tau Aβ42) that are part of Lewy body protein tangle are also seen in AD patients and have potential as PD prognostic markers. Low levels of tau and Aβ42 are correlated with severe motor function loss in PD patients, compared with controls (JAMA Neurol 2013;70:1277-87; Acta Neuropathol 2016;131:935–49).
Trojanowski and Shaw also noted the importance of PPMI’s and ADNI’s longitudinal designs, focus on consistent exams, and collection of data over a long period of time. It takes several years for many participants to show changes, but their experiences will lay the groundwork for studies of new medicines. Ideally, PD biomarker studies would last 10-15 years so that researchers can see whether markers detect disease early enough for interventions to have meaningful effects, said Shaw and Trojanowski.
Visions of the Future
Because PD has a varied presentation, researchers and clinicians need information about several aspects of its pathophysiology. Probably several biomarkers will be useful and necessary, said Ronit Sharon, PhD, an associate professor of biochemistry and molecular biology at Hebrew University-Hadassah Medical School in Israel, who is developing an α-syn blood test.
Dunckley thinks PD might have dozens of risk genes and envisions a future test that would detect causative mutations in several, provide information about gene expression measured in RNA (which PPMI sequences), and produce an epigenetics profile to establish an overall PD molecular risk profile.
Frasier is optimistic about this possibility. “Molecular profiling technologies have advanced such in the last five years that they are cost-effective and generate incredible amounts of molecular data,” he said. PPMI samples are enabling whole genome sequencing, RNA, and proteomic data to help distinguish specific PD subtypes, he noted.
These methods have allowed cancer researchers to identify subtypes based on molecular signature and led to targeted therapies, said Frasier. He’s excited to see how the PPMI data drive similar advances in PD.
Deborah Levenson is a freelance writer in College Park, Maryland. +Email: [email protected]