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Original Investigation |

Cerebrospinal Fluid Patterns and the Risk of Future Dementia in Early, Incident Parkinson Disease

David C. Bäckström, MD1; Magdalena Eriksson Domellöf, PhD1; Jan Linder, MD, PhD1; Bob Olsson, PhD2; Annika Öhrfelt, PhD2; Miles Trupp, PhD1; Henrik Zetterberg, MD, PhD2,3; Kaj Blennow, MD, PhD2; Lars Forsgren, MD, PhD1
[+] Author Affiliations
1Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden
2Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden
3University College London Institute of Neurology, Queen Square, London, England
JAMA Neurol. 2015;72(10):1175-1182. doi:10.1001/jamaneurol.2015.1449.
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Importance  Alterations in cerebrospinal fluid (CSF) have been found in Parkinson disease (PD) and in PD dementia (PDD), but the prognostic importance of such changes is not well known. In vivo biomarkers for disease processes in PD are important for future development of disease-modifying therapies.

Objective  To assess the diagnostic and prognostic value of a panel of CSF biomarkers in patients with early PD and related disorders.

Design, Setting, and Participants  Regional population-based, prospective cohort study of idiopathic parkinsonism that included patients diagnosed between January 1, 2004, and April 30, 2009, by a movement disorder team at a university hospital that represented the only neurology clinic in the region. Participants were 128 nondemented patients with new-onset parkinsonism (104 with PD, 11 with multiple system atrophy, and 13 with progressive supranuclear palsy) who were followed up for 5 to 9 years. At baseline, CSF from 30 healthy control participants was obtained for comparison.

Main Outcomes and Measures  Cerebrospinal fluid concentrations of neurofilament light chain protein, Aβ1-42, total tau, phosphorylated tau, α-synuclein, and heart fatty acid–binding protein were quantified by 2 blinded measurements (at baseline and after 1 year). Follow-up included an extensive neuropsychological assessment. As PD outcome variables, mild cognitive impairment and incident PDD were diagnosed based on published criteria.

Results  Among the 128 study participants, the 104 patients with early PD had a different CSF pattern compared with the 13 patients with progressive supranuclear palsy (baseline area under the receiver operating characteristic curve, 0.87; P < .0001) and the 30 control participants (baseline area under the receiver operating characteristic curve, 0.69; P = .0021). A CSF biomarker pattern associated with the development of PDD was observed. In PD, high neurofilament light chain protein, low Aβ1-42, and high heart fatty acid–binding protein at baseline were related to future PDD as analyzed by Cox proportional hazards regression models. Combined, these early biomarkers predicted PDD with high accuracy (hazard ratio, 11.8; 95% CI, 3.3-42.1; P = .0001) after adjusting for possible confounders.

Conclusions and Relevance  The analyzed CSF biomarkers have potential usefulness as a diagnostic tool in patients with parkinsonism. In PD, high neurofilament light chain protein, low Aβ1-42, and high heart fatty acid–binding protein were related to future PDD, providing new insights into the etiology of PDD.

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Figure 1.
Flow of Participants Through the 9-Year Study Period

CSF indicates cerebrospinal fluid; MSA, multiple system atrophy; PD, Parkinson disease; PDD, Parkinson disease dementia; and PSP, progressive supranuclear palsy.

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Figure 2.
Characteristics of Early Cerebrospinal Fluid Biomarkers for Etiological Diagnosis

Shown is the area under the receiving operating characteristic curve (AUROC) for differentiating patients with Parkinson disease (PD) from healthy control subjects (HCs) (A) and patients with progressive supranuclear palsy (PSP) from patients with PD (B and C). NFL indicates neurofilament light chain protein.

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Figure 3.
Cerebrospinal Fluid (CSF) Biomarkers in Relation to Clinical Outcome in Parkinson Disease

A-C, E, and F, Kaplan-Meier plots show outcome (dementia or disease progression) in 99 patients having Parkinson disease with baseline CSF biomarkers above and below cutoff levels. D, Age ranges are shown for patients having Parkinson disease with baseline ratios of NFL to Aβ1-42 above and below 1.0. P values are by log-rank test. HFABP indicates heart fatty acid–binding protein; H&Y, Modified Hoehn and Yahr Scale stage; and NFL, neurofilament light chain protein.

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