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Accuracy of a Panel of 5 Cerebrospinal Fluid Biomarkers in the Differential Diagnosis of Patients With Dementia and/or Parkinsonian Disorders

Sara Hall, MD; Annika Öhrfelt, PhD; Radu Constantinescu, MD; Ulf Andreasson, PhD; Yulia Surova, MD; Fredrik Bostrom, MD; Christer Nilsson, MD, PhD; Håkan Widner, MD, PhD; Hilde Decraemer; Katarina Nägga, MD, PhD; Lennart Minthon, MD, PhD; Elisabet Londos, MD, PhD; Eugeen Vanmechelen, PhD; Björn Holmberg, MD, PhD; Henrik Zetterberg, MD, PhD; Kaj Blennow, MD, PhD; Oskar Hansson, MD, PhD
Arch Neurol. 2012;69(11):1445-1452. doi:10.1001/archneurol.2012.1654.
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Objective  To assess the ability of 5 cerebrospinal fluid (CSF) biomarkers to differentiate between common dementia and parkinsonian disorders.

Design  A cross-sectional, clinic-based study.

Participants  Cerebrospinal fluid samples (N = 453) were obtained from healthy individuals serving as controls and from patients with Parkinson disease (PD), PD with dementia (PDD), dementia with Lewy bodies (DLB), Alzheimer disease (AD), progressive supranuclear palsy (PSP), multiple system atrophy (MSA), or corticobasal degeneration (CBD).

Setting  Neurology and memory disorder clinics.

Main Outcome Measures  Cerebrospinal fluid biomarker levels in relation to clinical diagnosis.

Results  Cerebrospinal fluid levels of α-synuclein were decreased in patients with PD, PDD, DLB, and MSA but increased in patients with AD. Cerebrospinal fluid levels of β-amyloid 1-42 were decreased in DLB and even further decreased in AD. Cerebrospinal fluid levels of total tau and hyperphosphorylated tau were increased in AD. Multivariate analysis revealed that these biomarkers could differentiate AD from DLB and PDD with an area under the curve of 0.90, with α-synuclein and total tau contributing most to the model. Cerebrospinal fluid levels of neurofilament light chain were substantially increased in atypical parkinsonian disorders (ie, PSP, MSA, and CBD), and multivariate analysis revealed that the level of neurofilament light chain alone could differentiate PD from atypical parkinsonian disorders, with an area under the curve of 0.93.

Conclusions  Ascertainment of the α-synuclein level in CSF somewhat improves the differential diagnosis of AD vs DLB and PDD when combined with established AD biomarkers. The level of neurofilament light chain alone may differentiate PD from atypical parkinsonian disorders.

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Figures

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Figure 1. Levels of cerebrospinal fluid (CSF) biomarkers in the different diagnostic groups. Box plots of α-synuclein (αSyn) (A), β-amyloid 1-42 (Aβ1-42) (B), total tau (T-tau) (C), phosphorylated tau (P-tau; P-tau181 indicates that phosphorylation occurred at the 181 position; in this case, at threonine) (D), and neurofilament light chain (NF-L) (E) in CSF samples from controls (n = 107) and patients with Parkinson disease (PD) (n = 90), PD with dementia (PDD) (n = 33), dementia with Lewy bodies (DLB) (n = 70), Alzheimer disease (AD) (n = 48), progressive supranuclear palsy (PSP) (n = 45), multiple system atrophy (MSA) (n = 48), and corticobasal degeneration (CBD) (n = 12). The lower, upper, and middle lines of boxes correspond to the 25th percentile, 75th percentile, and median, respectively. The whiskers at the top and bottom extend from the 95th and 5th percentiles, respectively, and the circles represent outliers. The significant differences between groups according to the analysis of covariance models described in the “Results” section of the article are visualized in the figure.

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Figure 2. Diagnostic accuracy of cerebrospinal fluid (CSF) biomarkers in patients with dementia or parkinsonism. Multivariate discriminant analysis (DA) was performed using the orthogonal projections to latent structures (OPLS) algorithm. Receiver operating characteristic curves were calculated for both OPLS-DA and for each analyte, including α-synuclein (αSyn), β-amyloid 1-42 (Aβ1-42), total tau (T-tau), phosphorylated tau (P-tau), and neurofilament light chain (NF-L). The areas under the curve (AUC) are given. A, Patients with Alzheimer disease (AD) (n = 48) were compared with patients with dementia with Lewy bodies (DLB) and those with Parkinson disease with dementia (PDD) (n = 103). B, Corresponding variable importance in projection (VIP) plot illustrates the relative contributions of T-tau, αSyn, P-tau, Aβ1-42, and NF-L to the separation between patients with AD vs patients with DLB or PDD. C, Patients with Parkinson disease (PD) (n = 90) were compared with patients with atypical parkinsonism, ie, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and multiple system atrophy (MSA) (n = 105). D, Corresponding VIP plot illustrates the relative contributions of NF-L, P-tau, αSyn, T-tau, and Aβ1-42 to the separation between patients with PD vs patients with PSP, MSA, and CBD. Error bars represent the 95% CI.

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