Biomarkers for Parkinson's Diagnostic, Prognostic
Susan Jeffrey
A new study suggests that a constellation of 4 biomarkers has both diagnostic and prognostic potential for patients with Parkinson's disease (PD).
Specifically, investigators are reporting that the combination of the Alzheimer's biomarkers β-amyloid 1-42 (Aβ1-42), total tau (T-tau), tau phosphorylated at threonine 181 (P-tau181), and α-synuclein, all measured in the cerebrospinal fluid (CSF), are lower in drug-naive patients with early-stage PD than among healthy controls. Aβ1-42 and P-tau181 were significant predictors of Parkinson's disease, and T-tau and α-synuclein were associated with the severity of motor dysfunction.
The findings, published online August 26 in JAMA Neurology, are the first report from the Parkinson's Progression Markers Initiative (PPMI), an international study that aims to identify biomarkers of progression in PD and define subsets of patients by clinical and biomarker "signatures."
"Although further study using the full PPMI data set is necessary to validate the current results, patients with PD who have lower CSF Aβ1-42, P-tau181, and α-synuclein levels are more likely to have the PIGD [postural instability–gait disturbance]-dominant motor phenotype, which has been associated with more rapid disease progression," the researchers, with lead author Ju-Hee Kang, MD, and corresponding author Leslie M. Shaw, PhD, both from the Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, conclude in their report.
"Biomarkers for Parkinson's disease such as these could help us diagnose patients earlier, and we've now shown that the simultaneous measurement of a variety of neurodegenerative disease proteins is valuable," Dr. Shaw said in a statement from the university.
Biomarkers Project
The PPMI aims to identify PD progression biomarkers and define subsets of patients using clinical and biomarker signatures, the authors write, particularly subgroups whose disease progression rates are likely to differ. The 5-year observational study includes 400 drug-naive patients with early-stage idiopathic PD and 200 healthy controls from 24 carefully selected clinical sites in the United States, Europe, and Australia.
For this analysis, they looked at these CSF biomarkers in 102 participants enrolled at 15 of these sites.
PD progresses to dementia in approximately 80% of patients, although the rates of progression to dementia vary widely, they note. PIGD is a motor phenotype that has been associated with more rapid cognitive decline compared with the tremor-dominant type of PD.
Measures of Aβ1-42, T-tau, and Ptau181 are already used to distinguish patients with Alzheimer's disease (AD) from cognitively normal individuals, progression from mild cognitive impairment to AD, and AD from non-AD dementia types. In addition, α-synuclein levels have been shown to be reduced in PD, but to their knowledge, the authors note, no report has looked at AD-related biomarkers and α-synuclein in living patients with PD.
"We hypothesized that measurement of Aβ1-42, T-tau, P-tau181, and α-syn in CSF can differentiate patients with early-stage PD from demographically matched HCs [healthy controls] and can reflect the heterogeneity of clinical features of PD. To test our hypothesis, we report the CSF profile of Aβ1-42, T-tau, P-tau181, and α-syn in the initial 102 PPMI subjects and assess whether specific clinical features of PD are associated with distinct biomarker signatures for Aβ1-42, T-tau, P-tau181, and α-syn in untreated patients with PD at the earliest stage of the disease studied so far," they write.
In this report, the AD-related CSF biomarkers were measured by INNO-BIA AlzBio3 immunoassay (Innogenetics Inc) and α-synuclein by enzyme-linked immunosorbent assay. Clinical features studied included diagnosis, demographic characteristics, motor, neuropsychiatric, and cognitive assessments and DaTscan.
"Slightly, but significantly, lower levels of Aβ1-42, T-tau, P-tau181, α-synuclein, and T-tau/Aβ1-42 were seen in subjects with PD compared with healthy controls but with a marked overlap between groups," the authors write.
Multivariate regression analysis showed lower Aβ1-42 and P-tau181 levels were associated with PD diagnosis, and that decreased T-tau and α-synuclein were associated with increased motor severity.
"Notably, when we classified patients with PD by their motor phenotypes, lower CSF Aβ1-42 and P-tau181 concentrations were associated with the postural instability–gait disturbance–dominant phenotype but not with the tremor-dominant or intermediate phenotype," they note.
There was also a significant correlation of α-synuclein levels with those of T-tau and P-tau181.
"These results provide evidence for the potential value of these CSF biomarkers for the diagnosis and assessment of heterogeneous disease progression in early-stage PD and suggest biomarker strategies for the possible recognition of prodromal PD similar to what is being pursued with AD biomarkers," the authors write.
The Future of PD
Asked for comment on these findings, Michael S. Okun, MD, professor of neurology at the University of Florida Center for Movement Disorders and Neurorestoration in Gainesville, National Medical Director for the National Parkinson Foundation, and chair of the Movement Disorders Society's scientific issues committee, said the use of biomarkers to track disease progression is a very important area that will likely affect the future of PD research.
"This current study was unique, especially since the cohort was drawn from untreated early Parkinson's disease patients which are traditionally a population hard for researchers to tap into," Dr. Okun told Medscape Medical News. "In the future, the use of cerebrospinal fluid along with imaging and perhaps other biomarkers could help guide drug development and other advances."
David E. Vaillancourt, PhD, professor of applied physiology and kinesiology, neurology and biomedical engineering, also at the University of Florida, with a particular interest in biomarkers, agreed.
"Imaging, CSF, and blood biomarkers all provide unique approaches for identifying PD," Dr. Vaillancourt told Medscape Medical News. "The current study using CSF demonstrates some of the strengths and limitations of this approach.
"Future studies comparing biomarkers and combining data across biomarkers will be important for the field, and may possibly influence patient care," he added.
This work was supported by The Michael J. Fox Foundation for Parkinson's Research, Abbott, Avid Radiopharmaceuticals, Biogen Idec, Covance, Elan, Eli Lilly and Co, F. Hoffman–La Roche Ltd, GE Healthcare, Genentech, GlaxoSmithKline, Merck & Co, Pfizer Inc, and UCB Pharma SA. Dr. Shaw was previously a consultant for Innogenetics and collaborates on quality assessment activities as part of the Parkinson's Progression Markers Initiative and as part of the Alzheimer's Disease Neuroimaging Initiative.
