Cerebrospinal fluid biomarkers in Parkinson disease

Clinica Neurologica, Università di Perugia, Ospedale Santa Maria della Misericordia, 06132 Santa Andrea delle Fratte, Perugia, Italy.
Nature Reviews Neurology (Impact Factor: 15.36). 03/2013; 9(3):131-40. DOI: 10.1038/nrneurol.2013.10
Source: PubMed


Clinical diagnosis of Parkinson disease (PD) is difficult in early stages of disease, with high risk of misdiagnosis. The long preclinical phase of PD provides the possibility for early therapeutic intervention once disease-modifying therapies have been developed, but lack of biomarkers for early diagnosis and monitoring of disease progression represents a major obstacle to achievement of this goal. Accordingly, research efforts aimed at identification of novel biomarkers have been increasing in the past 5 years. Cerebrospinal fluid (CSF) is an accessible source of brain-derived proteins, which mirror molecular changes that take place in the CNS. In this Review, we discuss evidence from numerous studies that have focused on identification of candidate CSF biomarkers for PD. Notably, molecular pathways related to α-synuclein, tau and β-amyloid peptides have received considerable attention. CSF levels of the protein DJ-1 are also of interest, although further investigation of this candidate marker is required. These studies support the usefulness of a combination of various CSF biomarkers of PD to increase diagnostic accuracy during early phases of the disease, and to differentiate PD from other neurodegenerative disorders.

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Available from: Lucilla Parnetti,
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    • "To date, the analysis of total α-synuclein (t-αsyn ) in cerebrospinal fluid (CSF) has been described in several publications [4] [5] [6] [7] [8] [9] [10] [11] [12] (see [13] for a review), while only single studies have dealt with the detection of disease-associated forms, including oligomers, in human plasma or CSF [7] [14]. However, there is no commercially available kit for the detection of d-α-syn in body fluids. "
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    ABSTRACT: With the aim to evaluate the significance and reliability of detecting disease-specific α-synuclein in the cerebrospinal fluid (CSF) we developed an ELISA and bead-assay. We used a commercial antibody (5G4) that does not bind to the physiological monomeric form of α-synuclein, but is highly specific for the disease-associated forms, including high molecular weight fraction of β-sheet rich oligomers. We applied both tests in CSF from a series of neuropathologically confirmed αsynucleinopathy cases, including Parkinson' disease dementia (PDD) and dementia with Lewy bodies (DLB) (n = 7), as well as Alzheimer' disease (n = 6), and control patients without neurodegenerative pathologies (n = 9). Disease-specific α-synuclein was detectable in the CSF in a subset of patients with α-synuclein pathology in the brain. When combined with the analysis of total α-synuclein, the bead-assay for disease-specific α-synuclein was highly specific for PDD/DLB. Detection of disease-associated αsynuclein combined with the total levels of α-synuclein is a promising tool for the in-vivo diagnosis of αsynucleinopathies, including PDD and LBD.
    Clinical neuropathology 09/2014; 33(5):329-34. DOI:10.5414/NP300796 · 1.53 Impact Factor
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    • "Snca is mainly a cytoplasmic protein, but it has been shown to be secreted by exocytosis and is also present in exosomes (Lee et al., 2005; Emmanouilidou et al., 2010; Jang et al., 2010; Pan-Montojo et al., 2012). Snca has been found in cerebrospinal fluid (CSF) and plasma and its concentration in these fluids has been suggested as a possible biomarker for PD (Parnetti et al., 2013), even though there are substantial discrepancies between the results reported in different studies (Lee et al., 2006; Li et al., 2007; Duran et al., 2010; Shi et al., 2010; Mollenhauer et al., 2011; Park et al., 2011; Foulds et al., 2012; Wennstrom et al., 2013). In this context, recent measurements of clearance of Snca in CSF under steady-state conditions in PD patients and PD animal models show that there is no change in the clearance of Snca in the CSF respect to the corresponding controls (Fanara et al., 2012). "
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    ABSTRACT: Alpha-synuclein (Snca) plays a major role in Parkinson disease (PD). Circulating anti-Snca antibodies has been described in PD patients and healthy controls, but they have been poorly characterized. This study was designed to assess the prevalence of anti-Snca reactivity in human subjects carrying the LRRK2 mutation, idiopathic PD (iPD) patients, and healthy controls and to map the epitopes of the anti-Snca antibodies. Antibodies to Snca were detected by ELISA and immunoblotting using purified recombinant Snca in plasma from individuals carrying LRRK2 mutations (104), iPD patients (59), and healthy controls (83). Epitopes of antibodies were mapped using recombinant protein constructs comprising different regions of Snca. Clear positive anti-Snca reactivity showed no correlation with age, sex, years of evolution, or the disability scores for PD patients and anti-Snca reactivity was not prevalent in human patients with other neurological or autoimmune diseases. Thirteen of the positive individuals were carriers of LRRK2 mutations either non-manifesting (8 out 49 screened) or manifesting (5 positive out 55), three positive (out of 59) were iPD patients, and five positive (out of 83) were healthy controls. Epitope mapping showed that antibodies against the N-terminal (a.a. 1-60) or C-terminal (a.a. 109-140) regions of Snca predominate in LRRK2 mutation carriers and iPD patients, being N122 a critical amino acid for recognition by the anti-C-terminal directed antibodies. Anti-Snca circulating antibodies seem to cluster within families carrying the LRRK2 mutation indicating possible genetic or common environmental factors in the generation of anti-Snca antibodies. These results suggest that case-controls' studies are insufficient and further studies in family cohorts of patients and healthy controls should be undertaken, to progress in the understanding of the possible relationship of anti-Snca antibodies and PD pathology.
    Frontiers in Aging Neuroscience 07/2014; 6:169. DOI:10.3389/fnagi.2014.00169 · 4.00 Impact Factor
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    • "The development of effective diagnostic methods, which could identify patients at risk and the early stages of these illnesses would be of major importance. The early diagnosis of ND diseases ideally should include central nervous system imaging and biomarkers from different sources, such as blood and cerebrospinal fluid (CSF), that could support the clinical diagnosis [18]. A biomarker is defined as a 'characteristic that is objectively measured and evaluated as an indicator of normal biology, pathological process, or pharmacologic responses to a therapeutic intervention' [19]. "
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    ABSTRACT: Alzheimer´s and Parkinson´s diseases are severe neurodegenerative conditions triggered by complex biochemical routes. Many groups are currently pursuing the search for valuable biomarkers to either perform early diagnostic or to follow the disease's progress. Several studies have reported relevant findings regarding environmental issues and the progression of such diseases. Here the etiology and mechanisms of these diseases are briefly reviewed. Approaches that might reveal candidate biomarkers and environmental stressors associated to the diseases were analyzed under a proteomic perspective. This article is part of a Special Issue entitled: Environmental and structural proteomics.
    Journal of proteomics 04/2014; 104. DOI:10.1016/j.jprot.2014.04.014 · 3.89 Impact Factor
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