title: Increased TDP-43 protein in cerebrospinal fluid of patients with amyotrophic lateral sclerosis.
abstract: There is mounting pathological, biochemical and genetic evidence that the metabolism and aggregation of the 43-kDa transactive response (TAR)-DNA-binding protein (TDP-43) play a crucial role in the pathogenesis of sporadic and some forms of familial amyotrophic lateral sclerosis (ALS). Recently, it was reported using an ELISA system that elevated levels of TDP-43 were detected in plasma samples from patients with Alzheimer's disease and frontotemporal dementia, compared to healthy controls. To determine whether quantification of TDP-43 in cerebrospinal fluid (CSF) is potentially informative in the diagnosis of ALS, we measured the concentration, by a similar ELISA method, of TDP-43 in CSF from 30 patients with ALS (diagnosed according to the revised El Escorial criteria) and 29 age-matched control patients without any neurodegenerative disease. We found that, as a group, the ALS patients had significantly higher levels of TDP-43 in their CSF than the age-matched controls (6.92 +/- 3.71 ng/ml in ALS versus 5.31 +/- 0.94 ng/ml in controls, p < 0.05), with levels of TDP-43 in CSF elevated beyond 95% upper confidence level for the control group in six (20%) of the patients with sporadic ALS. All the six patients with higher levels of CSF TDP-43 were examined within 10 months of the onset of illness. The patients examined within 10 months of onset showed significantly higher levels of CSF TDP-43 (8.24 +/- 4.72 ng/ml) than those examined after 11 months or more of onset (5.41 +/- 0.66 ng/ml, p < 0.05). These results suggest that the levels of TDP-43 in CSF may increase in the early stage of ALS. We also confirmed the existence of the TDP-43 protein in CSF from some patients with ALS, and a control subject, by western blotting of proteins immunocaptured from the CSF samples. Raised TDP-43 levels in the CSF may preempt the formation of TDP-43 pathology in the central nervous system, or correlate with early-stage TDP-43 pathology, and accordingly be a biomarker for the early stage of ALS.
authors.affiliation: Department of Neurology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-0841, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kasai
authors.forename: Takahiko
authors.initials: T
authors.lastname: Tokuda
authors.forename: Noriko
authors.initials: N
authors.lastname: Ishigami
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sasayama
authors.forename: Penelope
authors.initials: P
authors.lastname: Foulds
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Mitchell
authors.forename: David M A
authors.initials: DM
authors.lastname: Mann
authors.forename: David
authors.initials: D
authors.lastname: Allsop
authors.forename: Masanori
authors.initials: M
authors.lastname: Nakagawa
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000134:cerebrospinal fluid* / Q000175:diagnosis; D015415:Biomarkers / Q000134:cerebrospinal fluid*; D004268:DNA-Binding Proteins / Q000134:cerebrospinal fluid*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012720:Severity of Illness Index; D013997:Time Factors
chemical_list: D015415:Biomarkers; D004268:DNA-Binding Proteins