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

Imperial College London100 enrolled

Overview

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.

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

100

Interventions

Ventriculoperitoneal Shunt (VP)PROCEDURE

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.

Brain and Skin BiopsyPROCEDURE

Brain and skin biopsy's may be taken during the VP shunt to assist in histological analysis for neurodegenerative changes.

MRI BrainDIAGNOSTIC_TEST

MRI brain with diffusion imagining will be performed before and after shunt surgery.

Eligibility

Sex: ALLMin age: 60 YearsHealthy volunteers:

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

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.

Time frame: Perioperative

Secondary Outcomes

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.

Time frame: 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).

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.