TY - JOUR

T1 - Increased TDP-43 protein in cerebrospinal fluid of patients with amyotrophic lateral sclerosis

AU - Kasai, Takashi

AU - Tokuda, Takahiko

AU - Ishigami, Noriko

AU - Sasayama, Hiroshi

AU - Foulds, Penelope

AU - Mitchell, Douglas J

AU - Mann, David M A

AU - Allsop, David

AU - Nakagawa, Masanori

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Amyotrophic Lateral Sclerosis

KW - Biological Markers

KW - DNA-Binding Proteins

KW - Enzyme-Linked Immunosorbent Assay

KW - Female

KW - Humans

KW - Male

KW - Middle Aged

KW - Severity of Illness Index

KW - Time Factors

U2 - 10.1007/s00401-008-0456-1

DO - 10.1007/s00401-008-0456-1

M3 - Journal article

C2 - 18989684

VL - 117

SP - 55

EP - 62

JO - Acta Neuropathologica

JF - Acta Neuropathologica

SN - 0001-6322

IS - 1

ER -