Date Published: July 28, 2017
Publisher: BioMed Central
Author(s): Davide Chiasserini, Leonardo Biscetti, Paolo Eusebi, Nicola Salvadori, Giulia Frattini, Simone Simoni, Naomi De Roeck, Nicola Tambasco, Erik Stoops, Hugo Vanderstichele, Sebastiaan Engelborghs, Brit Mollenhauer, Paolo Calabresi, Lucilla Parnetti.
Neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease with dementia (PDD), and dementia with Lewy bodies (DLB) share clinical and molecular features. Cerebrospinal fluid (CSF) biomarkers may help the characterization of these diseases, improving the differential diagnosis. We evaluated the diagnostic performance of five CSF biomarkers across a well-characterized cohort of patients diagnosed with AD, DLB, PDD, and Parkinson’s disease (PD).
A total of 208 patients were enrolled in 3 European centers. The diagnostic groups (AD, n = 48; DLB, n = 40; PDD, n = 20; PD, n = 54) were compared with cognitively healthy neurological control subjects (patients with other neurological diseases [OND], n = 46). CSF levels of fatty acid binding protein 3, heart type (FABP3), α-synuclein (α-syn), amyloid-β peptide 1–42, total tau (t-tau), and phosphorylated tau 181 (p-tau) were assessed with immunoassays. Univariate and multivariate statistical analyses were applied to calculate the diagnostic value of the biomarkers as well as their association with clinical scores.
FABP3 levels were significantly increased in patients with AD and DLB compared with those with PD and OND (p < 0.001). CSF t-tau, p-tau, and α-syn were significantly higher in patients with AD than in patients with PDD, DLB, PD, and OND. Combination of FABP3 with p-tau showed high accuracy for the differential diagnosis between AD and DLB (AUC 0.92), whereas patients with AD were separated from those with PDD using a combination of p-tau, FABP3, and α-syn (AUC 0.96). CSF FABP3 was inversely associated with Mini Mental State Examination score in the whole cohort (r = −0.42, p < 0.001). The combination of CSF biomarkers linked to different aspects of neurodegeneration, such as FABP3, α-syn, and AD biomarkers, improves the biochemical characterization of AD and Lewy body disorders. The online version of this article (doi:10.1186/s13195-017-0276-4) contains supplementary material, which is available to authorized users.
Neurodegenerative disorders (NDDs) such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and dementia with Lewy bodies (DLB) share a central pathogenic theme: the accumulation, in extra- or intracellular deposits, of aggregated and misfolded proteins . The type of protein, as well as the size, shape, and location of the deposits, is quite typical of each disorder and is used in the pathological examination for characterizing each disease. However, NDDs show remarkable similarities from the clinicopathological point of view, making accurate diagnosis difficult, especially at early stages of the disease [2, 3]. For instance, the clinical presentation of AD and DLB, two diseases considered the most common neurodegenerative forms of dementia, may overlap significantly, leading to low accuracy of the differential diagnosis . Cognitive impairment can occur also in patients initially diagnosed with a prototypical movement disorder such as PD, generally at later stages of disease, and often leading to Parkinson’s disease with dementia (PDD). Apart from the temporal difference in the onset of cognitive deficits, PDD is remarkably similar to DLB in clinical terms, showing, beyond extrapyramidal signs, multidomain impairment and visual hallucinations .
In this study, we show that the combination of CSF biomarkers linked to different aspects of neurodegeneration may improve the characterization of NDDs, namely AD, DLB, PDD, and PD. In particular, we report the following findings:Tau protein and α-syn levels were significantly increased in patients with AD compared with the other diagnostic groups.FABP3 CSF levels were increased in the AD and DLB groups compared with the OND and PD groups.Combination of FABP3 with p-tau showed excellent performance in the discrimination between AD and DLB, whereas the inclusion of α-syn in the logistic models improved the discrimination of PDD and DLB from PD.FABP3 showed a significant inverse correlation with MMSE score in the whole cohort.
Our results show that the inclusion of FABP3 and α-syn in the core panel of AD CSF biomarkers can improve the molecular characterization of NDDs encompassing AD dementia and Lewy body disorders. Researchers in other studies have investigated the combination of different biomarkers for the differential diagnosis of dementia and parkinsonism, highlighting how measuring panels of proteins linked to different facets of neurodegeneration will be essential for the biochemical characterization of NDDs and to support clinical diagnosis [19, 67, 68]. Further longitudinal studies including different cohorts of patients with NDDs are necessary to verify the role of this biomarker panel across the neurodegeneration spectrum.