The pathophysiology of normal pressure hydrocephalus (NPH) is not clear, and various prognostic factors are currently being investigated that could facilitate the selection of patients who would benefit from surgical treatment. This research aimed to examine for the first time whether changes in cranial and spinal volume of cerebrospinal fluid (CSF) influence intracranial hydrodynamics and biomarker concentrations, as well as intracranial pressure while improving the patient's clinical condition, which justifies surgical placement of permanent drainage. Twenty patients with clinical and euroradiological signs of NPH underwent external lumbar drainage during a period of 72 h. During this period we monitored changes in the concentration of biomarkers in the CSF and intracranial pressure, and also measured the volume of CSF in the craniospinal space before and after drainage. Clinical improvement was observed in 10 patients. The results showed that the ability to regulate CSF pressure with volume changes was significantly reduced in patients with negative clinical response. MRI volumetry showed that intracranial CSF accounts for 20% of the total intracranial volume, and that this CSF volume, as well as the total craniospinal volume, is greater in patients who have a positive clinical response (responders) to extended lumbar drainage. The sum of the total volume of the CSF in the cranium and in the spinal space indicates that this volume is about 466 ml in adults, which is significantly higher than previously thought, even when the volume is reduced by 150 ml, which represents the average increase in the ventricles in NPH patients. Changes in the concentration of selected biomarkers (amyloid β, total, and phosphorylated tau proteins) from CSF samples at three-time points (0, 36, and 72 h) during drainage are associated with changes in the clinical condition. The gradual increase in Aβ1-42 concentration that occurs during the three-day CSF drainage represents a possible positive prognostic factor for the placement of permanent CSF drainage in patients with NPH.