Cerebrospinal Fluid Biomarkers in the Evaluation and Treatment of Normal Pressure Hydrocephalus

Abstract

Normal pressure hydrocephalus (NPH) is characterized by slowly progressive gait disturbance, cognitive impairment and urinary incontinence. It is a well-known potentially reversible cause of dementia by the shunt operation. However, it is not simple to select candidates for the shunt operation due to combined pathology and poor general medical conditions in the aged population and the high complication rate of the procedure. In PART I, a retrospective study, we reported patients with NPH whose symptomatic response to repetitive lumbar puncture (LP) was maintained for longer than one year without the need for the shunt operation and analyzed the predictor for the prolonged symptomatic response to repetitive LP in patients with NPH. In PART II, a prospective study, we investigated levels of the β-amyloid 1-42 (Aβ42), total tau protein (T-tau) and tau phosphorylated at position threonine 181 (P-tau) in cerebrospinal fluid (CSF) of NPH patients and tried to find their clinical implications in the evaluation and treatment of NPH.

PART I: A retrospective study

Thirty-one NPH patients were retrospectively evaluated. Gait disturbance, urinary incontinence, and cognitive impairment were semi-quantified. We divided the patients into three groups (non-responders, temporary responders, and prolonged responders) according to their responses after LP. We analyzed the characteristics of the groups. Gait disturbance (p= 0.046) and urinary incontinence (p= 0.040) scores and total NPH symptom score (p= 0.007) immediate after CSF drainage were more significantly improved in prolonged responders than in temporary responders. On multiple logistic regression analysis, total NPH score improvement immediate after LP was the only predictor of the prolonged responders (p= 0.038, odds ratio= 9.718). Our study showed that some NPH patients could maintain favorable courses for at least one year after LP without the shunt operation. Repetitive LP could be an alternative treatment in selected NPH patients.

PART II: A prospective study

Twenty-five possible NPH patients were prospectively enrolled and their CSF were collected to analyze levels of Aβ42, T-tau and P-tau using ELISA method. Gait disturbance, urinary incontinence, and cognitive impairment were semi-quantified and detailed neuropsychological test was performed. The CSF of 17 Alzheimer's disease (AD) patients and 10 normal control subjects were tested to determine a cutoff level of the possible coexistence of AD pathology in NPH patients. Eight NPH patients were classified into NPH with lower CSF Aβ42 group and 17 patients were classified into NPH with higher CSF Aβ42 group (cutoff value = 490.13 pg/ml, Aβ42). There was no difference in the NPH grading score and improvement rate after LP between the two groups. In the evaluation of 18 patients who underwent the detailed neuropsychological tests (7 with lower CSF Aβ42 and 11 with high), the NPH with lower CSF Aβ42 group had more deficit in attention (p=0.018), visuospatial function (p=0.043) and verbal memory (p=0.009). In the evaluation of 10 patients who underwent NP test twice before and after LPs, with lower CSF Aβ42 group showed less improvement in phonemic categorical naming (p=0.008) and frontal inhibitory function (p=0.018) after LP compared to NPH with higher CSF Aβ42 group. Our study suggested that the incidence of Aβ42 pathology in NPH patients was not different from normal elderly population and the coexistence of Aβ42 pathology in NPH patients might be a contributing factor for lumbar puncture or shunt unresponsiveness especially in the field of cognitive dysfunction.