Normal Pressure Hydrocephalus Biomarkers Investigation

Cognitive Impairment Clinical Trial

— NORPHY  

Official title:

Liquor Oxysterols Concentrations as Biomarkers in Idiopathic Normal Pressure Hydrocephalus

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05562596
• Other study ID #: Hydro2022
• Status: Not yet recruiting
• Start date: October 30, 2022
• Est. completion date: July 1, 2024

Study information

• Verified date: September 2022
• Source: University of Roma La Sapienza
• Contact: Luigi Iuliano, M.D.
• Phone: +393406462332
• Email: luigi.iuliano[@]uniroma1.it
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Normal Pressure Hydrocephalus (NPH) is a clinical condition that induces cognitive deterioration that can be reverted, at least in part, by introducing ventricular-peritoneal diversion controlled by a miniaturized valve system.

Mechanisms involved in such an improvement of cognitive function after liquor diversion are unknown.

Oxysterols are a family of cholesterol-related compounds having diverse biological functions. Among others, they are involved in cholesterol homeostasis in the brain and are detectable in liquor, potentially impacting neurodegeneration.

NPH is an ideal clinical model to study oxysterol distribution in liquor before and after ventricular-peritoneal diversion.

Description:

Normal-pressure hydrocephalus (NPH) is a progressive, chronic, and extremely complex syndrome, firstly described in 1957, which represents the most common form of reversible dementia in the elderly.

The onset of NPH is on average in the seventh decade of life, with a slightly higher prevalence in males, and the Adam-Hakim triad, which includes dementia, urinary incontinence, and gait deviations, constitutes its clinical mainstay.

Clinical manifestations of NPH are hard to notice, especially at the onset, and the patient itself may not grasp the presence of early signs of NPH until a major event - a fall, for example, occurs.

Diagnosis of NPH is made upon clinical and radiological data and on the effectiveness of cerebrospinal fluid (CSF) shunting by ventricular diversion.

Mechanisms involved in the development of NPH are mainly unknown. Oxysterols are sterol compounds congeners of cholesterol with diverse biological properties. Some of them are linked to cholesterol trafficking in the brain - e.g. 24S-hydroxycholesterol (24S-HC) that allows the transport of cholesterol from the brain to the liver, and are supposedly implicated in neurodegenerative diseases. Evaluation of CSF oxysterols concentration in patients diagnosed with NPH constitutes the primary objective of this study.

CSF levels of oxysterols will be evaluated at two key time points: during the diagnostic work-up, via a spinal tap, and during the surgical treatment of NPH, via ventricular diversion.

In particular, within one month of recruitment, patients are evaluated clinically -including brain MR, cognitive function by MMSE, urinary incontinence, and gait deviation, and are subjected to the spinal tap test to meet the criteria of NPH.

Patients eligible for surgery are then subjected, within one month of diagnosis, to ventricular-peritoneal diversion controlled by a miniaturized valve system. This procedure is known to induce impressive amelioration of symptoms, including cognitive ones.

Oxysterol levels are correlated with the degree of cognitive function, i.e. MMSE score before and after surgery. A second sample of oxysterols is collected at the time of surgery from ventricular drainage to look at any potential difference between regional brain oxysterolome, I.,e. peripheral (spinal and central) nervous system.

Oxysterols are quantitatively measured by isotope dilution gas chromatography mass spectrometry. The first objective is to compare oxysterol levels between two different areas of the circulating liquor, i.e. peripheral (spinal site) and central (ventricular site). In this context, the time frame of the two sample collection is set to two months, i.e. surgery is carried out within one month of the diagnostic spinal tap. The second objective is to assess the correlation between oxysterol levels and minimental status examination score.

This study is designed to cast a light on the pathogenesis of NPH and to evaluate the possible correlation between CSF oxysterols concentration and clinical symptoms severity, with a focus on dementia, assessed via cognitive screening tests such as Mini-Mental State Evaluation (MMSE).

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 30
• Est. completion date: July 1, 2024
• Est. primary completion date: April 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 60 Years to 85 Years

Eligibility

Inclusion Criteria:

• Patients with a diagnosis of NPH

Exclusion Criteria:

• Patients with a non-performing ASA score to the intervention

Related Conditions & MeSH terms

• Cognitive Dysfunction
• Cognitive Impairment
• Hydrocephalus
• Hydrocephalus, Normal Pressure
• Normal Pressure Hydrocephalus

Intervention

Diagnostic Test:
• Measurement of oxysterol profile, including 20 molecules, in liquor before and after surgery
Samples are quantitated by deuterium-labeled mass-spectrometry amalysis.

Locations

Country	Name	City	State
Italy	Goretti Hospital	Latina	LT

Sponsors (2)

Lead Sponsor	Collaborator
University of Roma La Sapienza	AUSL Latina

Country where clinical trial is conducted

Italy, 

References & Publications (9)

ADAMS RD, FISHER CM, HAKIM S, OJEMANN RG, SWEET WH. SYMPTOMATIC OCCULT HYDROCEPHALUS WITH "NORMAL" CEREBROSPINAL-FLUID PRESSURE.A TREATABLE SYNDROME. N Engl J Med. 1965 Jul 15;273:117-26. — View Citation

Crick PJ, William Bentley T, Abdel-Khalik J, Matthews I, Clayton PT, Morris AA, Bigger BW, Zerbinati C, Tritapepe L, Iuliano L, Wang Y, Griffiths WJ. Quantitative charge-tags for sterol and oxysterol analysis. Clin Chem. 2015 Feb;61(2):400-11. doi: 10.1373/clinchem.2014.231332. Epub 2014 Dec 15. — View Citation

Forner Giner J, Sanz-Requena R, Flórez N, Alberich-Bayarri A, García-Martí G, Ponz A, Martí-Bonmatí L. Quantitative phase-contrast MRI study of cerebrospinal fluid flow: a method for identifying patients with normal-pressure hydrocephalus. Neurologia. 2014 Mar;29(2):68-75. doi: 10.1016/j.nrl.2013.02.016. Epub 2013 May 3. English, Spanish. — View Citation

Hakim S, Adams RD. The special clinical problem of symptomatic hydrocephalus with normal cerebrospinal fluid pressure. Observations on cerebrospinal fluid hydrodynamics. J Neurol Sci. 1965 Jul-Aug;2(4):307-27. — View Citation

Hashimoto M, Ishikawa M, Mori E, Kuwana N; Study of INPH on neurological improvement (SINPHONI). Diagnosis of idiopathic normal pressure hydrocephalus is supported by MRI-based scheme: a prospective cohort study. Cerebrospinal Fluid Res. 2010 Oct 31;7:18. doi: 10.1186/1743-8454-7-18. — View Citation

Iuliano L, Crick PJ, Zerbinati C, Tritapepe L, Abdel-Khalik J, Poirot M, Wang Y, Griffiths WJ. Cholesterol metabolites exported from human brain. Steroids. 2015 Jul;99(Pt B):189-93. doi: 10.1016/j.steroids.2015.01.026. Epub 2015 Feb 7. — View Citation

Mori E, Ishikawa M, Kato T, Kazui H, Miyake H, Miyajima M, Nakajima M, Hashimoto M, Kuriyama N, Tokuda T, Ishii K, Kaijima M, Hirata Y, Saito M, Arai H; Japanese Society of Normal Pressure Hydrocephalus. Guidelines for management of idiopathic normal pressure hydrocephalus: second edition. Neurol Med Chir (Tokyo). 2012;52(11):775-809. — View Citation

Testa G, Staurenghi E, Zerbinati C, Gargiulo S, Iuliano L, Giaccone G, Fantò F, Poli G, Leonarduzzi G, Gamba P. Changes in brain oxysterols at different stages of Alzheimer's disease: Their involvement in neuroinflammation. Redox Biol. 2016 Dec;10:24-33. doi: 10.1016/j.redox.2016.09.001. Epub 2016 Sep 16. — View Citation

Williams MA, Relkin NR. Diagnosis and management of idiopathic normal-pressure hydrocephalus. Neurol Clin Pract. 2013 Oct;3(5):375-385. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Oxysterol levels in peripheral and central brain liquor	Comparison between values of quantitative analysis of oxysterols in liquor collected at time of spinal and central liquor obtained at spinal tap and ventricular drainage	2 months
Primary	Correlation between oxysterol levels in the peripheral and central liquor and MMSE score	Evaluation of potential correlation between oxysterol levels and mini-mental status examination score.	2 months