White Matter Distortion and Dementia Biomarkers in Normal Pressure Hydrocephalus (NPH) (OWN-NPH)

Observational Study to Investigate the Effect of White Matter Tract Distortion and Neurodegenerative Biomarkers on Shunt-responsiveness in Idiopathic Normal Pressure Hydrocephalus (iNPH)

Idiopathic Normal Pressure Hydrocephalus (iNPH) is a progressive condition of the elderly that results in severe disability. iNPH can dramatically respond to Cerebral spinal fluid(CSF)-shunting where excess ventricular fluid is diverted from the brain. Not all patients with iNPH respond to CSF-shunting however. The reasons for this are uncertain.

Aim 1: To understand if specific nerve pathways (white matter tracts) that are near ventricles are damaged in patients that respond to shunting as opposed to those that do not.

Aim 2: Can we explain shunt non-responsiveness by screening for dementia like illnesses (neurodegeneration) using a large array of methods.

Aim 3: To understand whether wearable activity and bed sleep monitors are palatable in a NPH population and to understand if these metrics relate to quality of life.

Aim 4: To see whether self-administered digital cognitive assessments can measure improvements pre and post surgery.

Study Overview

• Status: Recruiting
• Conditions: Normal Pressure Hydrocephalus
• Intervention / Treatment: Procedure: Ventriculoperitoneal Shunt (VP); Procedure: Brain and Skin Biopsy; Diagnostic test: MRI Brain

Detailed Description

This single-centre observational cohort study will follow 50 patients diagnosed with symptomatic Normal Pressure Hydrocephalus (NPH) (idiopathic or late presenting congenital hydrocephalus and not secondary hydrocephalus) through their clinical journey, from initial assessment to post-CSF shunt surgery or a time when surgery is decided against. Separate groups of 50 asymptomatic individuals with chronic hydrocephalus and non-hydrocephalus individuals will act as controls.

Participants will undergo comprehensive clinical assessments including gait, cognitive and urinary evaluations, quality of life measures, serum and CSF degenerative biomarker analysis, diffusion-weighted Magnetic Resonance Imaging (MRI) and optional brain and skin biopsies. Data collection will focus on capturing changes in clinical presentation and imaging findings before and after shunting. REDCap will be utilised as the primary tool for data storage.

Primary outcome measures assess pre and post-shunting imaging changes in shunt-responders and non-responders. Shunt response will be defined as 10% improvement in gait speed. Secondary outcomes evaluate the relationship between biomarkers and clinical outcomes. Longitudinal data will help identify factors distinguishing responders from non-responders, with descriptive and inferential statistics used.

• Study Type: Observational
• Enrollment (Estimated): 100

Contacts and Locations

• Study Contact: Name: Chris Carswell; Phone Number: +44 20311 1234; Email: NPH@imperial.ac.uk
• Study Contact Backup: Name: Harvey G Burns; Phone Number: +44 20311 1234; Email: NPH@imperial.ac.uk

Study Locations

• United Kingdom
  • London, United Kingdom, W6 8RF
    • Recruiting
    • Imperial College Healthcare NHS Trust
    • Contact: Harvey G Burns; Phone Number: +44 20311 1234; Email: NPH@imperial.ac.uk
    • Contact: Chris Carswell, PHD, FRCP; Phone Number: +44 20311 1234; Email: NPH@imperial.ac.uk
    • Principal Investigator: Chris Carswell, PHD, FRCP
    • Sub-Investigator: Harvey Burns, BSc, MRes
    • Sub-Investigator: Josephine Schena, BSc, MSc
    • Sub-Investigator: Alex Hayes, MBBS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Patients with hydrocephalus, neurodegenerative disease and healthy controls will be recruited by Dr Chris Carswell at Imperial College Hospital NHS Trust.

Description

Group 1 (communicating hydrocephalus):

Inclusion Criteria:

• Adult patients >60
• With gait apraxia
• With or without cognitive impairment
• Urinary dysfunction
• Communicating Hydrocephalus

Exclusion Criteria:

• Asymptomatic hydrocephalus
• High pressure-hydrocephalus
• Serious head injury within 5 years of presentation or a clear secondary cause (e.g. brain infection)
• History of childhood gait disturbance
• Clear alternative explanation for symptoms (e.g. Parkinson's disease with limb rigidity, peripheral neuropathy with sensory ataxia, cervical myelopathy).
• Too frail for shunt surgery
• Medically unstable (e.g. active angina, respiratory disease, recurrent delirium, active epilepsy).
• Unable to tolerate MRI brain imaging
• Unable to have a lumbar puncture
• Immobile
• Unable to attend the hospital for study visits

Group 2 (asymptomatic and non-hydrocepahlus dementia and healthy controls):

Inclusion Criteria (Any of the following):

• Healthy Carers
• Members of the Public
• Staff of Imperial College/ICHT
• Non-NPH Dementias (including Alzheimer's disease or vascular dementia)
• Asymptomatic Hydrocephalus

Exclusion Criteria:

- Unable to attend the hospital for study visits

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Group 1; Group 1 includes adults over 60 years old diagnosed with late-onset communicating hydrocephalus, characterised by gait apraxia, with or without cognitive impairment and urinary dysfunction. Eligibility is confirmed through clinical imaging showing an Evan's index >0.3 and an iNPH Radscale score >4. Individuals with recent severe head trauma, high-pressure hydrocephalus, or alternative causes for similar symptoms are excluded. This criteria for group 1 ensures a distinct group for studying the late-onset, communicating form of the condition.	Procedure: Ventriculoperitoneal Shunt (VP); VP Shunt surgery involves surgical insertion of a catheter (tube) to divert brain fluid from the cerebral ventricles to the abdominal peritoneum. This will be performed in Group 1 patients as clinically indicated.; Other Names: VP Shunt; Procedure: Brain and Skin Biopsy; Brain and skin biopsy's may be taken during the VP shunt to assist in histological analysis for neurodegenerative changes.; Diagnostic test: MRI Brain; MRI brain with diffusion imagining will be performed before and after shunt surgery.
Group 2; Group 2 will include 30 adult patients with asymptomatic chronic hydrocephalus, non-hydrocephalus dementia and healthy controls.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
White Matter Pathway Diffusion Metrics	Change from baseline in diffusion tensor imaging (DTI) metrics of white matter pathways (e.g. FA, AD, RD) before and after shunt surgery. The following tracts will be studied: corpus collosum, internal capsule, corona radiata and anterior thalamic radiation.	Perioperative

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neurodegenerative Biomarkers and CSF-shunt responsiveness	Composite degenerative index (plasma abeta, GFAP, Ptau217, NfL, CSF synuclein RT QuIC and brain and skin histology) will be generated and compared between CSF shunt-responsive and CSF non-responsive groups.	Perioperative
Serum Neurodegenerative Biomarkers	The serum biomarkers will measure a-beta (pg/ml), G-FAB (pg/ml), NfL (pg/ml) and p-tau217 (pg/ml).	From enrolment, at periprocedural and up to 27 weeks
Sleep Monitoring	The Withings' Sleep mats are devices designed to track sleep patterns. Participants will be offered under mattress sleep monitors capable of showing time spent in bed and analyse sleep cycles.	From enrolment and through study completion, an average of 1 year
Activity Monitoring	The Withings' Activity Monitors are devices designed to track physical activity and heart rate. Participants will be offered wrist activity monitors which capture data on steps taken, calories burned and overall movement throughout the day, providing insights into daily activity levels.	From enrolment and through study completion, an average of 1 year
Tinetti Performance Oriented Mobility Assessment Score (balance)	Total scores range from 0 to 16, with higher scores indicating better outcomes of balance performance.	From enrolment, at periprocedural and up to 27 weeks
Tinetti Performance Oriented Mobility Assessment Score (Gait)	Total scores range from 0 to 12, with higher scores indicating better outcomes of gait performance.	From enrolment, at periprocedural and up to 27 weeks
International Consultation on Incontinence Questionnaire for Urinary Incontinence Short Form (ICIQ UI SF)	The assessment measures the frequency and severity of urinary incontinence. The total scores range from 0-21. Higher scores indicate worse bladder symptoms.	From enrolment, at periprocedural and up to 27 weeks.
International Consultation on Incontinence Questionnaire for Bowels (ICIQ-B)	The assessment measures the pattern and control of bowel incontinence. The total scores for bowel pattern ranges from 1-21 and bowel control ranges from 0-28. Higher scores indicate worse bowel symptoms.	From enrolment, at periprocedural and up to 27 weeks.
International Consultation of Incontinence Questionnaire for Sexual Function	The assessment measures the severity and bother of sexual function. The scores for sexual function range from 1-5 and are assessed on an individual basis. Higher scores indicate worse sexual function.	From enrolment, at periprocedural and up to 27 weeks.
International Consultation of Incontinence Questionnaire for Quality of Life	The assessment measures the quality of life bladder, bowels and sexual function has on the individual. The scores suggest how much they bother the participant and it ranges from 0-10. Higher bother scores indicate lower quality of life.	From enrolment, at periprocedural and up to 27 weeks.
Overactive Bladder Symptoms (OAB)	The total score ranges from 0 to 15, with higher scores indicating worse bladder severity symptoms.	From enrolment, at periprocedural, and up to 27 weeks.
Kubo scale	Assesses gait disturbance, cognitive impairment and urinary disturbance. Total scores range from 0 to 12, with higher scores indicating better outcomes.	From enrolment, at periprocedural and up to 27 weeks.
Patient Health Questionnaire-9 (PHQ-9)	Assesses the severity of depression. Total score ranges from 0 to 27, with higher scores indicating more severe depressive symptoms.	From enrolment, at periprocedural and up to 27 weeks.
Generalised Anxiety Disorder-7 (GAD-7)	Assesses the severity of anxiety symptoms. Total scores range from 0 to 21, with higher scores indicating more severe anxiety.	From enrolment, at periprocedural and up to 27 weeks.
Sintonen 15D	Overall score adds 15 metrics of quality of life. Total scores range from 75-15 with lower scores indicating better quality of life.	From enrolment, at periprocedural and up to 27 weeks.
PSP QoL	Overall score adds 45 metrics of quality of life using a Likert scale to score from 0-5. Total scores range from 0-225 with lower scores indicating better quality of life.	From enrolment, at periprocedural and up to 27 weeks.
Rockwood Clinical Frailty Scale Score	Frailty rating score in older adults. Total scores range from 1 to 9 with higher indicating greater frailty.	From enrolment, at periprocedural and up to 27 weeks.
Addenbrooke's Cognitive Examination ||| (ACE-|||)	Total score evaluates cognitive functions including memory, language, visuospatial, attention and language. Total scores range from 0 to 100, with higher scores indicating better cognitive function.	From enrolment, at periprocedural and up to 27 weeks.
Cognitron Cognitive Assessment Platform	Includes a total score of a collection of cognitive tests to assess various cognitive domains in those with NPH pre and post surgery. There are specific domain specific scores.	From enrolment, at periprocedural and up to 27 weeks.
PKMAS Gait Analysis Software	Objective gait metric data is taken from the Protokinetics gait mat to analyse gait parameters of those with NPH. These metrics include, all aspects of gait (e.g. foot length, gait velocity, stride length)	From enrolment, at periprocedural and up to 27 weeks.

Collaborators and Investigators

• Sponsor: Imperial College London
• Collaborators: King's College London; University College, London; Medical Research Council; University of Edinburgh; Michael J. Fox Foundation for Parkinson's Research

Study record dates

Study Major Dates

• Study Start (Actual): March 25, 2025
• Primary Completion (Estimated): February 1, 2028
• Study Completion (Estimated): February 1, 2029

Study Registration Dates

• First Submitted: March 3, 2025
• First Submitted That Met QC Criteria: August 1, 2025
• First Posted (Actual): August 5, 2025

Study Record Updates

• Last Update Posted (Actual): March 27, 2026
• Last Update Submitted That Met QC Criteria: March 24, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: diffusion tensor imaging; hydrocephalus; activity monitors; NPH; normal pressure hydrocephalus; shunt surgery; neurodegenerative; gait impairment; protokinetic; shunt-responsiveness; white matter tractography
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Hydrocephalus; Hydrocephalus, Normal Pressure; Surgical Procedures, Operative; Neurosurgical Procedures; Anastomosis, Surgical; Cerebrospinal Fluid Shunts; Ventriculoperitoneal Shunt
• Other Study ID Numbers: 311620; W0300981 (Other Grant/Funding Number: Medical Research Council (MRC))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: IPD may be shared with collaborators if it is within the remit of the ethics approval and depending on the nature of the collaboration.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes