Phosphorylated tau/amyloid beta 1-42 ratio in ventricular cerebrospinal fluid reflects outcome in idiopathic normal pressure hydrocephalus

Sunil Patel,Edward B Lee,Leslie M Shaw,John Q Trojanowski,Steven E Arnold,M Sean Grady,Roy H Hamilton,Eric M Jackson,Christopher M Clark,Sharon X Xie,Anica Law

doi:10.1186/2045-8118-9-7

Abstract

BackgroundIdiopathic normal pressure hydrocephalus (iNPH) is a potentially reversible cause of dementia and gait disturbance that is typically treated by operative placement of a ventriculoperitoneal shunt. The outcome from shunting is variable, and some evidence suggests that the presence of comorbid Alzheimer's disease (AD) may impact shunt outcome. Evidence also suggests that AD biomarkers in cerebrospinal fluid (CSF) may predict the presence of AD. The aim of this study was to investigate the relationship between the phosphorylated tau/amyloid beta 1-42 (ptau/Aβ1-42) ratio in ventricular CSF and shunt outcome in patients with iNPH.MethodsWe conducted a prospective trial with a cohort of 39 patients with suspected iNPH. Patients were clinically and psychometrically assessed prior to and approximately 4 months after ventriculoperitoneal shunting. Lumbar and ventricular CSF obtained intraoperatively, and tissue from intraoperative cortical biopsies were analyzed for AD biomarkers. Outcome measures included performance on clinical symptom scales, supplementary gait measures, and standard psychometric tests. We investigated relationships between the ptau/Aβ1-42 ratio in ventricular CSF and cortical AD pathology, initial clinical features, shunt outcome, and lumbar CSF ptau/Aβ1-42 ratios in the patients in our cohort.ResultsWe found that high ptau/Aβ1-42 ratios in ventricular CSF correlated with the presence of cortical AD pathology. At baseline, iNPH patients with ratio values most suggestive of AD presented with better gait performance but poorer cognitive performance. Patients with high ptau/Aβ1-42 ratios also showed a less robust response to shunting on both gait and cognitive measures. Finally, in a subset of 18 patients who also underwent lumbar puncture, ventricular CSF ratios were significantly correlated with lumbar CSF ratios.ConclusionsLevels of AD biomarkers in CSF correlate with the presence of cortical AD pathology and predict aspects of clinical presentation in iNPH. Moreover, preliminary evidence suggests that CSF biomarkers of AD may prove useful for stratifying shunt prognosis in patients being evaluated and treated for this condition.

Highlights

Idiopathic normal pressure hydrocephalus is a potentially reversible cause of dementia and gait disturbance that is typically treated by operative placement of a ventriculoperitoneal shunt
We recently reported data indicating that the presence of amyloid beta 1-42 (Ab1-42) and tau–the pathologic hallmarks of Alzheimer’s disease (AD)–in cortical biopsies obtained at the time of shunt placement is associated with poorer response to shunting in patients with suspected Idiopathic normal pressure hydrocephalus (iNPH) [1]
We investigated the relationships between the ptau/Ab1-42 ratio in ventricular cerebrospinal fluid (CSF) and cortical AD pathology, baseline presentation, and postsurgical outcome of patients with suspected iNPH

Summary

Introduction

Idiopathic normal pressure hydrocephalus (iNPH) is a potentially reversible cause of dementia and gait disturbance that is typically treated by operative placement of a ventriculoperitoneal shunt. Evidence suggests that AD biomarkers in cerebrospinal fluid (CSF) may predict the presence of AD. We recently reported data indicating that the presence of amyloid beta 1-42 (Ab1-42) and tau–the pathologic hallmarks of AD–in cortical biopsies obtained at the time of shunt placement is associated with poorer response to shunting in patients with suspected iNPH [1]. Mounting evidence suggests that levels of amyloid beta and tau obtained from cerebrospinal fluid (CSF) samples may be used to identify patients with pathological changes indicative of AD at autopsy [5,6]. Based on our prior observation of the relationship between cortical AD pathology and shunt unresponsiveness, we predicted that levels of these biomarkers in CSF may differentiate iNPH patients who respond well to shunting from those who do not

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