title: Cerebrospinal fluid lysosomal enzymes and alpha-synuclein in Parkinson's disease.
abstract: To assess the discriminating power of multiple cerebrospinal fluid (CSF) biomarkers for Parkinson's disease (PD), we measured several proteins playing an important role in the disease pathogenesis. The activities of β-glucocerebrosidase and other lysosomal enzymes, together with total and oligomeric α-synuclein, and total and phosphorylated tau, were thus assessed in CSF of 71 PD patients and compared to 45 neurological controls. Activities of β-glucocerebrosidase, β-mannosidase, β-hexosaminidase, and β-galactosidase were measured with established enzymatic assays, while α-synuclein and tau biomarkers were evaluated with immunoassays. A subset of PD patients (n = 44) was also screened for mutations in the β-glucocerebrosidase-encoding gene (GBA1). In the PD group, β-glucocerebrosidase activity was reduced (P < 0.05) and patients at earlier stages showed lower enzymatic activity (P < 0.05); conversely, β-hexosaminidase activity was significantly increased (P < 0.05). Eight PD patients (18%) presented GBA1 sequence variations; 3 of them were heterozygous for the N370S mutation. Levels of total α-synuclein were significantly reduced (P < 0.05) in PD, in contrast to increased levels of α-synuclein oligomers, with a higher oligomeric/total α-synuclein ratio in PD patients when compared with controls (P < 0.001). A combination of β-glucocerebrosidase activity, oligomeric/total α-synuclein ratio, and age gave the best performance in discriminating PD from neurological controls (sensitivity 82%; specificity 71%, area under the receiver operating characteristic curve = 0.87). These results demonstrate the possibility of detecting lysosomal dysfunction in CSF and further support the need to combine different biomarkers for improving the diagnostic accuracy of PD.
authors.affiliation: Clinica Neurologica, Università degli Studi di Perugia, Perugia, Italy.
authors.forename: Lucilla
authors.initials: L
authors.lastname: Parnetti
authors.forename: Davide
authors.initials: D
authors.lastname: Chiasserini
authors.forename: Emanuele
authors.initials: E
authors.lastname: Persichetti
authors.forename: Paolo
authors.initials: P
authors.lastname: Eusebi
authors.forename: Shiji
authors.initials: S
authors.lastname: Varghese
authors.forename: Mohammad M
authors.initials: MM
authors.lastname: Qureshi
authors.forename: Andrea
authors.initials: A
authors.lastname: Dardis
authors.forename: Marta
authors.initials: M
authors.lastname: Deganuto
authors.forename: Claudia
authors.initials: C
authors.lastname: De Carlo
authors.forename: Anna
authors.initials: A
authors.lastname: Castrioto
authors.forename: Chiara
authors.initials: C
authors.lastname: Balducci
authors.forename: Silvia
authors.initials: S
authors.lastname: Paciotti
authors.forename: Nicola
authors.initials: N
authors.lastname: Tambasco
authors.forename: Bruno
authors.initials: B
authors.lastname: Bembi
authors.forename: Laura
authors.initials: L
authors.lastname: Bonanni
authors.forename: Marco
authors.initials: M
authors.lastname: Onofrj
authors.forename: Aroldo
authors.initials: A
authors.lastname: Rossi
authors.forename: Tommaso
authors.initials: T
authors.lastname: Beccari
authors.forename: Omar
authors.initials: O
authors.lastname: El-Agnaf
authors.forename: Paolo
authors.initials: P
authors.lastname: Calabresi
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D005838:Genotype; D005962:Glucosylceramidase / Q000134:cerebrospinal fluid / Q000235:genetics; D006026:Glycoside Hydrolases / Q000134:cerebrospinal fluid*; D006801:Humans; D007118:Immunoassay; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010300:Parkinson Disease / Q000134:cerebrospinal fluid* / Q000235:genetics; D011446:Prospective Studies; D051844:alpha-Synuclein / Q000134:cerebrospinal fluid*; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: D051844:alpha-Synuclein; D016875:tau Proteins; D006026:Glycoside Hydrolases; D005962:Glucosylceramidase
keywords: CSF biomarkers; Parkinson's disease; alpha-synuclein; beta-glucocerebrosidase; lysosomal enzymes