Cerebrospinal Fluid Biomarkers in Idiopathic Normal Pressure Hydrocephalus versus Alzheimer’s Disease and Subcortical Ischemic Vascular Disease: A Systematic Review

Background:The diagnostic workup of idiopathic normal pressure hydrocephalus (iNPH) can be challenging due to an overlap in symptoms and neuroimaging features with other disorders. Despite a growing interest, a cerebrospinal fluid (CSF) biomarker profile in iNPH has not yet been identified. Objecti ve:To determine the CSF biomarkers with the greatest evidence for differentiating iNPH from the most common differential diagnoses, Alzheimer's disease (AD) and subcortical ischemic vascular disease (SIVD). Methods:A systematic literature search was conducted in PubMed to identify relevant articles up to July 2018 using the following MESH-terms: "Cerebrospinal fluid", "diagnos*", "hydrocephalus, normal pressure". Relevant data were extracted to assess the risk of bias in the included studies. Results:Twenty-five studies including 664 patients with iNPH, 502 with AD, 57 with SIVD, 81 with other disorders, and 338 healthy controls (HC) were included. They investigated the diagnostic value of 92 CSF biomarkers. Most evidence existed for amyloid-β 42 (Aβ42), phosphorylated tau (p-tau), and total tau (t-tau) in iNPH versus AD and HC: Aβ42 did not differ between iNPH and AD, but was lower than in HC subjects. T-tau and p-tau were lower in iNPH versus AD on a level comparable to HC subjects. There was moderate or limited evidence for 62 and 88 biomarkers, respectively. Several plausible biases characterize the literature including small sample sizes and inconsistent diagnostic criteria. Conclusion:T-tau and p-tau may differentiate iNPH from AD and Aβ42 from HC. A combination of these biomarkers may improve the diagnostic accuracy in iNPH.