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Original Investigation |

Association of Cerebrospinal Fluid β-Amyloid 1-42, T-tau, P-tau181, and α-Synuclein Levels With Clinical Features of Drug-Naive Patients With Early Parkinson Disease

Ju-Hee Kang, MD1,2; David J. Irwin, MD3,4; Alice S. Chen-Plotkin, MD3,4; Andrew Siderowf, MD5; Chelsea Caspell, MS6; Christopher S. Coffey, PhD6; Teresa Waligórska, MS1; Peggy Taylor, ScD7; Sarah Pan, MPH1; Mark Frasier, PhD8; Kenneth Marek, MD9; Karl Kieburtz, MD, MPH10,11; Danna Jennings, MD9; Tanya Simuni, MD12; Caroline M. Tanner, MD, PhD13; Andrew Singleton, PhD14; Arthur W. Toga, PhD15; Sohini Chowdhury, MA8; Brit Mollenhauer, MD16,17; John Q. Trojanowski, MD, PhD1,4,18; Leslie M. Shaw, PhD1 ; and the Parkinson’s Progression Markers Initiative
[+] Author Affiliations
1Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia
2Department of Pharmacology, Inha University School of Medicine, Incheon, Republic of Korea
3Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia
4Morris K. Udall Center of Excellence for Parkinson’s Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia
5Avid Radiopharmaceuticals, Philadelphia, Pennsylvania
6Department of Biostatistics, College of Public Health, University of Iowa, Iowa City
7Covance Inc, Dedham, Massachusetts
8The Michael J. Fox Foundation for Parkinson’s Research, New York, New York
9Institute for Neurodegenerative Disorders, New Haven, Connecticut
10Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, New York
11Clinical Trials Coordination Center, University of Rochester, Rochester, New York
12Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
13Parkinson’s Institute, Sunnyvale, California
14Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland
15Laboratory of Neuro Imaging, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles
16Paracelsus-Elena-Klinik, Kassel, Germany
17Department of Neurosurgery and Neuropathology, University of Goettingen, Goettingen, Germany
18Institute on Aging, Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia
JAMA Neurol. 2013;70(10):1277-1287. doi:10.1001/jamaneurol.2013.3861.
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Importance  We observed a significant correlation between cerebrospinal fluid (CSF) levels of tau proteins and α-synuclein, but not β-amyloid 1-42 (Aβ1-42), and lower concentration of CSF biomarkers, as compared with healthy controls, in a cohort of entirely untreated patients with Parkinson disease (PD) at the earliest stage of the disease studied so far.

Objective  To evaluate the baseline characteristics and relationship to clinical features of CSF biomarkers (Aβ1-42, total tau [T-tau], tau phosphorylated at threonine 181 [P-tau181], and α-synuclein) in drug-naive patients with early PD and demographically matched healthy controls enrolled in the Parkinson’s Progression Markers Initiative (PPMI) study.

Design, Setting, and Participants  Cross-sectional study of the initial 102 research volunteers (63 patients with PD and 39 healthy controls) of the PPMI cohort.

Main Outcomes and Measures  The CSF biomarkers were measured by INNO-BIA AlzBio3 immunoassay (Aβ1-42, T-tau, and P-tau181; Innogenetics Inc) or by enzyme-linked immunosorbent assay (α-synuclein). Clinical features including diagnosis, demographic characteristics, motor, neuropsychiatric, and cognitive assessments, and DaTscan were systematically assessed according to the PPMI study protocol.

Results  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. Using multivariate regression analysis, we found that lower Aβ1-42 and P-tau181 levels were associated with PD diagnosis and that decreased CSF 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. Finally, we found a significant correlation of the levels of α-synuclein with the levels of T-tau and P-tau181.

Conclusions and Relevance  In this first report of CSF biomarkers in PPMI study subjects, we found that measures of CSF Aβ1-42, T-tau, P-tau181, and α-synuclein have prognostic and diagnostic potential in early-stage PD. Further investigations using the entire PPMI cohort will test the predictive performance of CSF biomarkers for PD progression.

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Figure 1.
Scatterplots of Cerebrospinal Fluid α-Synuclein Concentrations in Healthy Controls and Patients With Parkinson Disease

Each group was differentiated according to their cerebrospinal fluid hemoglobin concentration to total subjects (A), subjects with a cerebrospinal fluid hemoglobin concentration less than 500 ng/mL (B), and subjects with a cerebrospinal fluid hemoglobin concentration less than 200 ng/mL (C). P values were assessed by Mann-Whitney U test. α-Syn indicates α-synuclein; HCs, healthy controls; and PD, Parkinson disease.

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Figure 2.
Scatterplots of Alzheimer Disease Cerebrospinal Fluid Biomarkers and Their Ratios in Healthy Controls and Patients With Parkinson Disease

Scatterplots of β-amyloid 1-42 (Aβ1-42) (A), total tau (T-tau) (B), and tau phosphorylated at threonine 181 (P-tau181) (C) and ratios of T-tau/Aβ1-42 (D), P-tau181/Aβ1-42 (E), and P-tau181/T-tau (F) are shown. P values were assessed by Mann-Whitney U test. HCs indicates healthy controls; PD, Parkinson disease.

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Figure 3.
Correlation of Cerebrospinal Fluid α-Synuclein Levels With Total Tau, Tau Phosphorylated at Threonine 181, and β-Amyloid 1-42

Correlations of cerebrospinal fluid α-synuclein (α-syn) levels with total tau (T-tau) (A), tau phosphorylated at threonine 181 (P-tau181) (B), and β-amyloid 1-42 (Aβ1-42) (C) in all 102 subjects, with T-tau (D), P-tau181 (E), and Aβ1-42 (F) in 63 patients with Parkinson disease, and with T-tau (G), P-tau181 (H), and Aβ1-42 (I) in 39 healthy controls are shown. Solid lines indicate linear regression; dotted lines, 95% CIs. P values were assessed by Pearson correlation.

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