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Investigation of Brain Mechanisms Involved in the Urinary Continence Mechanism Associated With Aging

Primary Purpose

Urgency Urinary Incontinence

Status

Recruiting

Phase

Not Applicable

Locations

United States

Study Type

Interventional

Intervention

Brain functional MRI with simplified urodynamics

About this trial

This is an interventional other trial for Urgency Urinary Incontinence focused on measuring Urinary Incontinence, Urgency urinary incontinence

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleAccepts Healthy Volunteers

Inclusion Criteria:

'Old' (community-dwelling, mentally and functionally intact ambulatory women aged 65+ years) or 'Young' (equivalent women aged 18-45)
'Wet' (those who meet the International Continence Society definition of urgency urinary incontinence (urinary leakage accompanied by a sudden, strong urge to void which is difficult to defer) >5 times per week, for 3 months despite treatment for reversible causes (e.g., Urinary tract infection) and confirmed by a mean of one episode per day of UUI on 3-day bladder diary) or 'Dry' (women without current or past UUI or other lower urinary tract symptoms.) Infrequent stress incontinence of a small amount is acceptable.
Urge-predominant mixed incontinence is acceptable provided the subject is able to differentiate between stress incontinence (SUI - leakage that coincides instantaneously with cough, laugh, exercise) and urgency incontinence, i.e., leakage accompanied by a sudden strong urge to void that is difficult to defer.
Those with current or previous use of anticholinergic/beta-3 agonist medications will be considered for the study if they are willing to go through a washout period of at least 4 weeks of duration.

Exclusion Criteria:

Dry Groups

Current or prior treatment for UUI
Leakage on bladder diary not ascribed to minimal SUI (see bullet above)

All Groups: 'Wet' or 'Dry'; 'Young' or 'Old'

Cognitive impairment:
- MoCA<26
- inability to perform a voiding diary/pad test
- inability to reliably take daily medication
- inability to comply with fMRI testing
Impaired mobility
o Timed up and go test ≥ 12 secs
Medical instability:
- severe uncontrolled hypertension >180mmHg systolic or >100mmHg diastolic
- potential major changes in medical management over the course of the study period (i.e. upcoming surgery/treatment)
- frailty according to the Fried criteria
MRI incompatibility:
- contraindicated metal implants
- claustrophobia
- unidentified/untested compatibility of metal implants
Medication incompatibility:
- allergy to study medication (all prophylactic antibiotic choices)
- interaction of prophylactic antibiotic choices with current medications
- expected change in medication during the study
Neurological conditions:
- spinal cord injury;
- multiple sclerosis
- clinically apparent lesions (e.g. lacunae associated with stroke)
- prior stroke
- Parkinson's Disease/ALS/MSA
- any clinically apparent neurological condition
Lower urinary tract comorbidities/treatment:
- history of pelvic irradiation
- bladder or advanced uterine cancer
- possible urethral obstruction (advanced prolapse [POP-Q>II] or Qmax<12 ml/s on free flow)
- urinary retention (PVR >200 ml)
- Interstitial Cystitis/Bladder Pain Syndrome
- artificial sphincter implant
- Botox treatment for UUI within 1 year
- Neuromodulation treatment for UUI
Other comorbidities:
- uncontrolled depression (PHQ-9 ≥10)

Sites / Locations

University of PittsburghRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Brain functional MRI with simplified urodynamics

Arm Description

Females with urgency urinary incontinence

Outcomes

Primary Outcome Measures

BOLD (Blood oxygen level dependent) fMRI signal contrast

BOLD signal contrast - voxel-wise subtraction of normalized brain activity signal measure (BOLD response) during bladder fluid withdrawal from that during bladder infusion. Magnitude of BOLD contrast is then compared using ANOVA to compare the four groups (old dry/old wet/young dry/young wet). Differences are displayed as a map of t-values for each voxel of the brain, showing likelihood of statistical significance of differences. A priori regions of interest i.e. the bed nucleus of the stria terminalis (BST), pontine micturition center (PMC), periaqueductal grey (PAG), insula, medial prefrontal cortex (mPFC), dorsal anterior cingulate cortex/supplementary motor area (dACC/SMA) will be specified. Since BOLD signal represents the normalized contrast in fMRI signal between two states as a proxy for cerebral blood flow, it does not have a unit.

Secondary Outcome Measures

Changes in brain structural integrity

Difference in structural integrity of connective tracts will be compared using ANOVA to compare the four groups (old dry/old wet/young dry/young wet). Measure of structural integrity (normalized quantitative anisotropy, NQA), which describes the diffusion of water molecules around neuronal compartments (e.g., myelin, neurofilaments and microtubules) will be extracted from each individual and compared across groups.

Changes in brain structural integrity

Difference in structural integrity of connective tracts will be compared using ANOVA to compare the four groups (old dry/old wet/young dry/young wet). Measure of structural integrity (generalized fractional anisotropy, GFA), which describes the diffusion of water molecules around neuronal compartments (e.g., myelin, neurofilaments and microtubules) will be extracted from each individual and compared across groups.

Functional connectivity during infusion/withdrawal task

Functional connectivity calculated using generalized psychophysiological interaction (gPPI) analysis for each ROI (Eigenvariate time series; no units) will be extracted from the BOLD signal and a regression analysis performed, modeling the infusion/withdrawal blocks and the a priori ROI time series (mPFC, dACC/SMA, Insula) and its interactions with 'infuse' and 'withdraw' blocks.

Resting state analysis

Resting state connectivity will be calculated by extracting the eigenvariate (no units) of three a priori selected ROIs (mPFC, dACC/SMA, Insula) and calculate voxel-wise connectivity maps for each region. Regional homogeneity evaluates regional changes in connectedness corresponding to local activation (temporal and spatial) between groups.

Differences in volume of brain structures

Difference in grey matter volume (mm^3) on MRI as calculated by voxel based morphometry using ANOVA to compare the four groups (old dry/old wet/young dry/young wet). Grey matter volume of important brain structures will be compared.

Differences in white matter damage of brain structures

Difference in volume of white matter damage (mm^3) on MRI using ANOVA to compare the four groups (old dry/old wet/young dry/young wet). Global volume of white matter damage will be compared. along with damage location.

Full Information

NCT ID

NCT04599088

First Posted

October 1, 2020

Last Updated

June 7, 2023

Sponsor

University of Pittsburgh

Collaborators

National Institute on Aging (NIA)

1. Study Identification

Unique Protocol Identification Number

NCT04599088

Brief Title

Investigation of Brain Mechanisms Involved in the Urinary Continence Mechanism Associated With Aging

Official Title

Investigation of Brain Mechanisms Involved in the Urinary Continence Mechanism Associated With Aging

Study Type

Interventional

2. Study Status

Record Verification Date

June 2023

Overall Recruitment Status

Recruiting

Study Start Date

December 14, 2020 (Actual)

Primary Completion Date

May 2025 (Anticipated)

Study Completion Date

November 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of Pittsburgh

Collaborators

National Institute on Aging (NIA)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

Urge urinary incontinence (UUI) is a common problem in older people which vastly reduces quality of life, yet the cause and mechanism of disease are not well understood. This study will characterize brain control of the bladder in young and old continent individuals and age-matched incontinent counterparts. This will expand the investigators current knowledge of how the brain controls the bladder, how that control changes with age and disease, and suggest new targets to guide development of better treatment.

Detailed Description

Current data suggest that bladder control comprises 3 cerebral circuits that maintain continence by suppressing the voiding reflex in the midbrain. In the UUI phenotype that responded to BFB (Biofeedback assisted pelvic floor muscle therapy), the mechanism involved enhancing deactivation of the first brain circuit (medial prefrontal cortex, mPFC) which resulted in less activation of the second circuit (which includes the midcingulate cortex). In the phenotype that was resistant to BFB, no brain changes were seen. Although the investigators have an emerging picture of the brain's role in UUI, the investigators have only rudimentary understanding of what is 'normal', i.e. how the brain normally controls the bladder. Moreover, the investigators do not know whether this control mechanism is the same across the lifespan, or whether it changes owing to the impact of aging. Thus, the investigators aims are to characterize the brain's normal role in bladder control in both young and old people, to determine the changes in brain structure and function that lead to bladder control failure (UUI), and to examine how such changes differ between young and old individuals. To address the aims, the investigators will utilize detailed neuroimaging to evaluate 80 asymptomatic women and 80 women with UUI, each group divided into young (18-45) and old (65+ years) individuals. The study will enable the investigators to define the brain's key structures, functional activity, and mechanisms involved in normal bladder control, and to identify the differences in these elements among those with UUI, both young and old. By elucidating the mechanisms that mediate the brain's control (and loss of control) of bladder function, the proposed study should enhance the investigators working model, deepen the understanding of the impact of aging, and identify better targets for the treatment of UUI. It may thereby enable scientists to develop novel and more effective new therapies based on the revolution in neuroscience-and more hope for UUI sufferers.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Urgency Urinary Incontinence

Keywords

Urinary Incontinence, Urgency urinary incontinence

7. Study Design

Primary Purpose

Other

Study Phase

Not Applicable

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

190 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Brain functional MRI with simplified urodynamics

Arm Type

Experimental

Arm Description

Females with urgency urinary incontinence

Intervention Type

Other

Intervention Name(s)

Brain functional MRI with simplified urodynamics

Intervention Description

Structural: MPRAGE provides a structural image, which is used for coregistration of subjects. Structural scans are then performed including Diffusion Spectrum Imaging (DSI; microstructural), and Fluid-attenuated inversion recovery (FLAIR; white matter specific) scans. Functional: With about 50 ml in the bladder, resting state functional BOLD measurements are made, followed by functional whole-brain images while a small amount of saline is infused and withdrawn from the bladder, in 2 blocks of 4 repetitions each. Each repetition starts with a 12-scan pause, followed by infusion (6 scans = 12 s), pause (6 scans), and withdrawal (6 scans). Each block of 4 repetitions is completed by a 6 scan pause during which scanning continues. 24 ml is infused at 120 ml/min, and slightly less is withdrawn to avoid accommodation.This is repeated on an empty and full bladder along with a resting state image.

Primary Outcome Measure Information:

Title

BOLD (Blood oxygen level dependent) fMRI signal contrast

Description

Time Frame

20 minutes of a 1 hour MRI scan

Secondary Outcome Measure Information:

Title

Changes in brain structural integrity

Description

Time Frame

15 minutes of 1 hour MRI scan

Title

Changes in brain structural integrity

Description

Difference in structural integrity of connective tracts will be compared using ANOVA to compare the four groups (old dry/old wet/young dry/young wet). Measure of structural integrity (generalized fractional anisotropy, GFA), which describes the diffusion of water molecules around neuronal compartments (e.g., myelin, neurofilaments and microtubules) will be extracted from each individual and compared across groups.

Time Frame

15 minutes of 1 hour MRI scan

Title

Functional connectivity during infusion/withdrawal task

Description

Time Frame

20 minutes of 1 hour MRI scan

Title

Resting state analysis

Description

Time Frame

10 minutes of 1 hour MRI scan

Title

Differences in volume of brain structures

Description

Time Frame

10 minutes of 1 hour MRI scan

Title

Differences in white matter damage of brain structures

Description

Time Frame

10 minutes of 1 hour MRI scan

10. Eligibility

Sex

Female

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 'Old' (community-dwelling, mentally and functionally intact ambulatory women aged 65+ years) or 'Young' (equivalent women aged 18-45) 'Wet' (those who meet the International Continence Society definition of urgency urinary incontinence (urinary leakage accompanied by a sudden, strong urge to void which is difficult to defer) >5 times per week, for 3 months despite treatment for reversible causes (e.g., Urinary tract infection) and confirmed by a mean of one episode per day of UUI on 3-day bladder diary) or 'Dry' (women without current or past UUI or other lower urinary tract symptoms.) Infrequent stress incontinence of a small amount is acceptable. Urge-predominant mixed incontinence is acceptable provided the subject is able to differentiate between stress incontinence (SUI - leakage that coincides instantaneously with cough, laugh, exercise) and urgency incontinence, i.e., leakage accompanied by a sudden strong urge to void that is difficult to defer. Those with current or previous use of anticholinergic/beta-3 agonist medications will be considered for the study if they are willing to go through a washout period of at least 4 weeks of duration. Exclusion Criteria: Dry Groups Current or prior treatment for UUI Leakage on bladder diary not ascribed to minimal SUI (see bullet above) All Groups: 'Wet' or 'Dry'; 'Young' or 'Old' Cognitive impairment: MoCA<26 inability to perform a voiding diary/pad test inability to reliably take daily medication inability to comply with fMRI testing Impaired mobility o Timed up and go test ≥ 12 secs Medical instability: severe uncontrolled hypertension >180mmHg systolic or >100mmHg diastolic potential major changes in medical management over the course of the study period (i.e. upcoming surgery/treatment) frailty according to the Fried criteria MRI incompatibility: contraindicated metal implants claustrophobia unidentified/untested compatibility of metal implants Medication incompatibility: allergy to study medication (all prophylactic antibiotic choices) interaction of prophylactic antibiotic choices with current medications expected change in medication during the study Neurological conditions: spinal cord injury; multiple sclerosis clinically apparent lesions (e.g. lacunae associated with stroke) prior stroke Parkinson's Disease/ALS/MSA any clinically apparent neurological condition Lower urinary tract comorbidities/treatment: history of pelvic irradiation bladder or advanced uterine cancer possible urethral obstruction (advanced prolapse [POP-Q>II] or Qmax<12 ml/s on free flow) urinary retention (PVR >200 ml) Interstitial Cystitis/Bladder Pain Syndrome artificial sphincter implant Botox treatment for UUI within 1 year Neuromodulation treatment for UUI Other comorbidities: uncontrolled depression (PHQ-9 ≥10)

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Becky Clarkson, PhD

Phone

412-647-1270

bdc29@pitt.edu

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Neil M Resnick, MD

Organizational Affiliation

University of Pittsburgh

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Pittsburgh

City

Pittsburgh

State/Province

Pennsylvania

ZIP/Postal Code

15213

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Becky Clarkson, PhD

Phone

412-647-1270

bdc29@pitt.edu

First Name & Middle Initial & Last Name & Degree

Becky Clarkson, PhD

First Name & Middle Initial & Last Name & Degree

Layla Banihashemi, PhD

First Name & Middle Initial & Last Name & Degree

Christopher Chermansky, MD

First Name & Middle Initial & Last Name & Degree

Helmet Karim, PhD

First Name & Middle Initial & Last Name & Degree

Subashan Perera, PhD

First Name & Middle Initial & Last Name & Degree

Shachi Tyagi, MD

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

All of the individual participant data collected during the trial, after de-identification may be shared with other researchers.

IPD Sharing Time Frame

Following publication, no end date

IPD Sharing Access Criteria

Any purpose

Learn more about this trial

Investigation of Brain Mechanisms Involved in the Urinary Continence Mechanism Associated With Aging

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