Increased TDP-43 protein in cerebrospinal fluid of patients with amyotrophic lateral sclerosis.
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.
Kasai
Takashi
T
Department of Neurology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-0841, Japan.
Tokuda
Takahiko
T
Ishigami
Noriko
N
Sasayama
Hiroshi
H
Foulds
Penelope
P
Mitchell
Douglas J
DJ
Mann
David M A
DM
Allsop
David
D
Nakagawa
Masanori
M
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
D015415:Biomarkers; D004268:DNA-Binding Proteins