Amyloid mis-metabolism in idiopathic normal pressure hydrocephalus.

ABSTRACT

BACKGROUND: Patients with idiopathic normal pressure hydrocephalus (iNPH) have reduced cerebrospinal fluid (CSF) concentrations of amyloid-ß (Aß) and α- and ß-cleaved soluble forms of amyloid precursor protein (sAPPα and sAPPß). The aims of this study were to examine if changes could also be seen in the CSF for secreted metabolites of APP-like protein 1 (APLP1) and to explore the prognostic value of amyloid-related CSF biomarkers, as well as markers of neuronal injury and astroglial activation, as regards to clinical outcome after shunt surgery. METHODS: Twenty patients diagnosed with iNPH, 10 improved and 10 unchanged by shunt surgery, and 20 neurologically healthy controls were included. All patients were examined clinically prior to surgery and at 6-month follow-up after surgery using the iNPH scale. Lumbar puncture was performed pre-operatively. CSF samples were analyzed for neurofilament light (NFL), Aß isoforms Aß38, Aß40 and Aß42, sAPPα, sAPPß, APLP1 ß-derived peptides APL1ß25, APL1ß 27 and APL1ß 28 and YKL40 by immunochemical methods. RESULTS: The concentrations of all soluble forms of APP, all Aß isoforms and APL1ß28 were lower, whilst APL1ß25 and APL1ß27 were higher in the CSF of iNPH patients compared to controls. There was no difference in biomarker concentrations between patients who improved after surgery and those who remained unchanged. CONCLUSIONS: The reduced CSF concentrations of Aß38, Aß40, Aß42, sAPPα and sAPPß suggest that APP expression could be downregulated in iNPH. In contrast, APLP1 concentration in the CSF seems relatively unchanged. The increase of APL1ß25 and APL1ß27 in combination with a slight decreased APL1ß28 could be caused by more available γ-secretase due to reduced availability of its primary substrate, APP. The data did not support the use of these markers as indicators of shunt responsiveness.