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Abstract
Objective To isolate and identify a new, as yet unknown molecule in CSF that could serve as marker for Alzheimer disease.
Methods We immunized mice with human CSF and fused hybridomas for monoclonal antibodies and screened these antibodies for their capacity to discriminate CSF of patients with Alzheimer disease from CSF of controls. We then chromatographically isolated the antigen to the best discriminating antibody and identified the antigen using mass spectrometric methods. Thereafter, we quantified the CSF concentration of the antigen in a new cohort of patients with Alzheimer disease and controls and performed immunohistochemistry of postmortem brain tissue derived from patients with Alzheimer disease and controls.
Results We generated >200 hybridomas and selected 1 antibody that discriminated CSF from patients with Alzheimer disease from that of controls. We identified golgin A4 as the antigen detected by this antibody. Golgin A4 concentration was significantly higher in CSF from patients with Alzheimer disease than in CSF of controls (145 [interquartile range 125–155] vs 115 [ 99–128] pg/mL, p < 0.001) and demonstrated a substantial discriminative power (area under the receiver operating characteristic curve 0.80, 95% confidence interval 0.67–0.94). Immunohistochemistry of postmortem brain sections from patients with Alzheimer disease revealed a significant accumulation of golgin A4 in granulovacuolar degeneration bodies (GVBs).
Conclusions These results support the notion that golgin A4 could serve as a diagnostic marker in Alzheimer disease. For validation of this notion, prospective multicenter diagnostic studies will evaluate golgin A4 as diagnostic marker for Alzheimer disease. Furthermore, it has to be determined whether the association of golgin A4 with GVBs is an epiphenomenon or whether golgin A4 plays a more direct role in Alzheimer disease, allowing it to serve as a target in therapeutic treatment strategies.
Classification of evidence This study provides Class III evidence that elevated CSF golgin A4 levels identify patients with Alzheimer disease.
Glossary
- Aβ=
- β-amyloid;
- ALS-FTD=
- amyotrophic lateral sclerosis with frontotemporal dementia;
- CK1δ=
- casein kinase 1 delta;
- DSM-IV=
- Diagnostic and Statistical Manual of Mental Disorders, 4th edition;
- ELISA=
- enzyme-linked immunosorbent assay;
- Fc=
- fragment crystallizable;
- FUS=
- fused in sarcoma;
- GVB=
- granulovacuolar degeneration body;
- GVD=
- granulovacuolar degeneration;
- IQR=
- interquartile range;
- MALDI=
- matrix-assisted laser desorption/ionization;
- MS=
- mass spectrometry;
- ROC=
- receiver operator characteristic;
- TOF=
- time of flight
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Class of Evidence: NPub.org/coe
- Received September 20, 2017.
- Accepted in final form July 26, 2018.
- © 2018 American Academy of Neurology
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