Clinical trial NCT05910944: European Study of Prodromal iNPH
Official title: European Study of Prodromal iNPH
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Normal Pressure Hydrocephalus
Hydrocephalus
Keywords: natural history
cerebrospinal fluid
biomarkers
long term follow-up
Lead sponsor: Uppsala University Hospital
Sponsor class: OTHER
Collaborators: name: Swedish Society for Medical Research
First posted: 2023-06-20
Enrollment: 140
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients in Group 1 can be included from patients referred to a tertiary hydrocephalus center after investigations/work-up have shown too mild symptoms to motivate shunt surgery.

Healthy age-matched controls (Group 2) can be included by advertising and by asking relatives to patients in Group 1 and Group 3.

For each included individual in Group 1 (prodromal iNPH), two patients are included in Group 3 (symptomatic iNPH). These patients are consecutively included at each center from routine patients that are planned for shunt surgery. They should be age matched with the individual in Group 1 (+/- 3 years).

Brief summary: To investigate if progression from prodromal into symptomatic NPH can be predicted from advanced neuroimaging, biomarkers in cerebrospinal fluid (CSF) and plasma and investigate the unknown mechanisms causing deterioration by investigating longitudinal changes in the above-mentioned variables. Three different cohorts with both asymptomatic and symptomatic patients as well as healthy controls will be investigated over time, both without intervention and before and after shunt surgery.

Detailed description: Three prospective cohorts will be included during five years from seven European centers.

Group 1 - Prodromal NPH. Patients with imaging features associated with iNPH and no symptoms, or to little symptoms to motivate shunt surgery, will be included prospectively. At baseline, an MRI of the brain will be performed and a lumbar puncture to collect CSF as well as blood samples. The patients will be followed with a standardized scheme that will go on for as long as the patient chose to remain in the study or until the patient develops symptoms and are referred for shunt surgery. The study scheme includes repeated assessments of symptoms, MRI of the brain, CSF samples and blood samples. The following study visits are planned before surgery: baseline, 6 months, 1st year, 2nd year, 4th year, 6th year. After shunt surgery, clinical evaluations and blood samples will be collected at four assessments during five years post-operative.

Group 2 - Healthy controls - For every patient in Group 1, one patient can be included in Group 2. They will be investigated with the same protocol as Group 1 but only follow the protocol for one cycle (Baseline to year 4).

Group 3 - Symptomatic NPH - For each included individual in Group 1 (prodromal NPH), two patients are included in Group 3 (symptomatic NPH). These patients are consecutively included at each centre from routine patients that are planned for shunt surgery. They should be age matched with the individual in Group 1 (+/- 3 years). Their investigations will be identical with the post-operative routine for five years as Group 1.

Eligibility criteria: Inclusion criteria - Group 1 - prodromal iNPH

* Brain imaging with both:

  * Evans index \> 0.3
  * Callosal angle ≤ 90 º or:
  * Disproportionately enlarged subarachnoid space hydrocephalus (DESH) - defined as: enlarged ventricles, dilated sylvian fissures and tight sulci at the high convexity.
* Absence of symptoms or too mild symptoms to motivate shunt surgery according to local routine, and all of the following:

  * Normal gait pattern, or slight disturbance of the gait pattern that is not considered to be caused by a disease in the central nervous system (CNS).
  * Gait velocity (maximum gait speed), men ≥ 1.4 m/s; women ≥ 1.25 m/s.
  * Rombergs test with eyes open \> 60 seconds
  * Mini Mental State Examination (MMSE) ≥ 27 or Montreal Cognitive Assessment (MoCA) ≥ 23
* Informed consent

Exclusion criteria - Group 1 - prodromal iNPH

* Contraindication for MRI
* Other serious disease with expected survival less than three years
* Other type of hydrocephalus:

  * non-communicating hydrocephalus
  * secondary communicating hydrocephalus
  * suspected congenital hydrocephalus (severely enlarged ventricles, narrow sylvian fissures and normal non-compressed sulci at the high convexity or morphological findings consistent with PaVM18)
* Anticoagulants in a dose that hinders lumbar puncture

Inclusion criteria - Group 2 - healthy controls

• Age \> 65 years

Exclusion criteria - Group 2 - healthy controls:

* Imaging findings meet inclusion criteria of Group 1
* Previously known relevant neurological disease
* Pathological gait pattern with unknown reason.
* MMSE \< 27 or MoCA \< 26.
* Anticoagulants in a dose that hinders lumbar puncture

Inclusion criteria Group 3 symptomatic iNPH

* iNPH diagnosis according to international guidelines.19
* Age matched with the individual in Group 1 (+/- 3 years)

Exclusion criteria Group 3 symptomatic iNPH

* Previous stroke (clinical stroke, not only radiologically verified)
* Other serious disease with expected survival less than three years

Primary outcomes:
measure: Frequency of patients with prodromal iNPH that requires shunt surgery within 6 years from inclusion.
timeFrame: From date of inclusion until decision of shunt surgery, assessed up to 72 months
measure: Frequency of patients with prodromal iNPH that progress to symptomatic iNPH
timeFrame: From date of inclusion until 20 points reduction in total iNPH-scale score or 20% reduction in gait speed, assessed up to 72 months
measure: Post operative improvement in iNPH-scale score in patients with mild, moderate and severe preoperative symptoms
timeFrame: Change from preoperative (last visit before surgery) iNPH scale at 3 months, 12 months, 36 months and 60 months follow-up.
Secondary outcomes:
measure: Change in white matter hyperintensities (WMH)
timeFrame: Change from baseline at 24 months, at 48 months and at time of decision of shunt surgery, assessed up to 72 months
measure: Change in brain morphology
timeFrame: Change from baseline at 24 months, at 48 months and at time of decision of shunt surgery, assessed up to 72 months
measure: Change in ventricular volume
timeFrame: Change from baseline at 24 months, at 48 months and at time of decision of shunt surgery, assessed up to 72 months
measure: Change in parenchymal water content
timeFrame: Change from baseline at 24 months, at 48 months and at time of decision of shunt surgery, assessed up to 72 months
measure: Change in cerebral myelin volume
timeFrame: Change from baseline at 24 months, at 48 months and at time of decision of shunt surgery, assessed up to 72 months
measure: Changes in plasma biomarkers
timeFrame: Change from baseline at 6 months, 12 months, 24 months, 48 months and at time of decision of shunt surgery, assessed up to 72 months
measure: Changes in cerebrospinal fluid (CSF) biomarkers
timeFrame: Change from baseline at 6 months, 12 months, 24 months, 48 months and at time of decision of shunt surgery, assessed up to 72 months
measure: Changes in plasma and cerebrospinal fluid (CSF) proteins
timeFrame: Change from baseline at 6 months, 12 months, 24 months, 48 months and at time of decision of shunt surgery, assessed up to 72 months
measure: Change in quality of life
timeFrame: Change from baseline at 6 months, 12 months, 24 months, 48 months and at time of decision of shunt surgery, assessed up to 72 months
Other outcomes:
Locations:
city: Kuopio
country: Finland
facility: Kuopio University Hospital
city: Bologna
country: Italy
facility: Bellaria Hospital
city: Gothenburg
country: Sweden
facility: Sahlgrenska University Hospital
city: Linköping
country: Sweden
facility: Linköping University Hospital
city: Stockholm
country: Sweden
facility: Karolinska University Hospital
city: Umeå
country: Sweden
facility: Umeå University Hospital
city: Uppsala
country: Sweden
facility: Uppsala University Hospital
Study officials:
affiliation: Uppsala University Hospital
name: Johan Virhammar, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: