Exercise Training and Cognitive Function in Kidney Disease

Study Overview
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Brief Summary
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Chronic kidney disease (CKD), affects over 45% of all individuals over 70 years of age. Patients with moderate CKD have more than a two-fold increased risk of cognitive impairment than those without CKD; furthermore, as many as 20-70% of patients with CKD have established cognitive impairment and overt dementia. The burden of cognitive impairment and dementia leads to functional decline and accelerated loss of independence, contributing to the tremendous individual, societal, and economic burden of CKD (i.e., 20% of Medicare expenditures in adults >65 years of age). There is no recommended treatment to prevent cognitive decline in CKD patients, and the few medications available for cognitive impairment have only short term modest effects. There is a critical need to evaluate therapies to forestall cognitive impairment, and maintain or improve cognitive functioning in older patients with CKD. To address this need, this study will test the hypothesis that older patients with moderate/severe CKD and pre-clinical cognitive impairment randomized to a 6-month home-based exercise program will improve cognitive function and MRI measured brain structure, compared to a usual care control group. This study will combine an assessment of cognition with MR imaging techniques to fully evaluate brain structure, blood flow, and behavior relationships at a level previously not conducted in this population

Official Title
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Exercise Training and Cognitive Function in Kidney Disease

Conditions
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Cognitive Function, Preclinical, Chronic Kidney Diseases, Older Adults

Intervention / Treatment
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* Behavioral: Partially supervised home-based walking exercise
* Behavioral: Control


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: English speaking men and women diagnosed stage 3-5 CKD (eGFR<60 to 15 ml/min); 60-80 years of age, self-experienced persistent decline in cognitive capacity determined as self-reported cognitive complaint (i.e., answering yes to the question: Do you feel like your memory or thinking skills have gotten worse recently? (before any clinical impairment of cognition has occurred) ability to undergo an MRI; no history of major head trauma. Exclusion Criteria: • current/past diagnosis of neurological/psychiatric disorders; any medications to improve cognition or mood; Diagnosed Dementia or a score of <2 on the mini-cog assessment Ischemic ulcerations or gangrene on the feet or legs; Participating in a supervised exercise program with intent to increase fitness levels 3 days/week, Requires assistive ambulation; Limited exercise capacity due to conditions other than claudication unstable angina, Claudication severe arthritis, extreme dyspnea on exertion, unstable coronary artery disease; Class III-IV heart failure; Current uncontrolled sustained arrhythmias, severe/symptomatic aortic or mitral stenosis, hypertrophic obstructive cardiomyopathy, severe pulmonary hypertension, active myocarditis/pericarditis, thrombophlebitis, recent systemic/pulmonary embolus (within 3 months); Resting systolic BP >200 mmHg or resting diastolic BP >110 mmHg; Revascularization procedures within the previous 6 months; Any unforeseen illness or disability that would preclude exercise testing or training based on patient provider opinion; Pregnancy No diagnosis of CKD One or more contraindication for MRI cardiac pacemaker, aneurysm clip, cochlear implants, shrapnel, history of metal fragments in eyes, neurostimulators, diagnosed claustrophobia.

Ages Eligible for Study
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Minimum Age: 60 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, controlled design with a 1:1 allocation
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Home-based walking exercise<br>Home-based exercise program: The exercise training group will participate in an educational session on exercise for CKD. Participants will receive a packet of information with an exercise prescription and a heart rate monitor that monitors the exercise. Participants will be asked to exercise (a brisk walk) at home, 3 times per week, for 30-60 minutes for 24 weeks. Participants will be contacted via phone biweekly or more frequently if they are behind the exercise routine, and the investigators will meet with them monthly to provide encouragement and progression of exercise, and to download the heart rate monitor. | Behavioral: Partially supervised home-based walking exercise<br>* Participants will be asked to exercise at home by walking at a moderate intensity. Each participant will receive an exercise prescription. Participants will receive a heart rate monitor. The heart rate monitors will be used to achieve a desired exercise intensity and to monitor adherence levels. The participants will receive biweekly to weekly phone calls, and monthly in person meetings will be used to address any barriers, provide encouragement, and progress the exercise.<br>|
| Active Comparator: Control<br>The control group will receive standard instructions on exercise for patients with kidney disease similar to what is commonly done in clinical practice. The control group will not receive an exercise prescription or heart rate monitor. Participants will be contacted via phone biweekly to answer any questions and ensure continued study participation. The control group will not meet with the investigators monthly. | Behavioral: Control<br>* Participants will be asked to exercise at home by walking at a moderate intensity. The participants will receive biweekly phone calls, but will not receive a heart rate monitor, individual exercise prescription, or meet with the investigators monthly.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite Global Cognitive Function | Determine the effect of a 6-month home-based exercise program on composite global cognitive functioning as determined by principal component analysis of immediate free recall of trials 1-5 on California verbal learning II, long-delay free recall and recognition, and memory discriminability, trail making test part A and part B, digit symbol substitution test, semantic and phonemic fluency, and Digit span subtest in older patients with kidney disease and preclinical cognitive impairment. A composite global cognitive score was created by converting the individual cognitive scores to standardized z scores and then averaging the standardized z scores. An increase in change from baseline to 6 months is considered an improvement. | Change from baseline in composite global cognitive function at 6 months | 
| Composite Executive Function | A composite executive functioning score was created by converting 4 individual executive cognitive scores (verbal fluency FAS and animal summary score, digit span backward subtest, and TMT-B) to standardized z scores and then averaging the standardized z scores. A larger change in Z score is considered an improvement. | Change from baseline in composite executive function at 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| White Matter Integrity | Whole brain white matter integrity was created by averaging the fractional anisotropy of 80 tracts using region of interest analysis. An increased change from baseline to 6 months in fractional anisotropy (a measure of directionality, 0 = no principle direction, 1 = one principle direction) is considered an improvement. | Change from baseline white matter integrity fractional anisotropy at 6 months | 
| Hippocampal Volume - Right | Determine the effect of a 6-month exercise program on hippocampal volume. An increased change from baseline to 6 months in right hippocampal volume in cubic millimeters is considered an improvement. | Change from baseline hippocampal volume at 6 months. | 
| Cerebral Blood Flow | Determine the effect of a 6-month exercise program on cerebral blood flow. Change in global cerebral blood measured in mL/100g/min from baseline to 6 months. An larger change is considered an improvement. | Change from baseline in cerebral blood flow at 6 months. | 
| Vascular Health - Young's Elastic Modulus | Vascular health was assessed by Young's Elastic Modulus (YEM) at the carotid artery. A larger negative change in YEM (measured in kilo pascal, stiffer artery=higher number) from baseline to 6 months is considered an improvement. | Change from baseline in vascular health indices at 6 months | 
| Cognitive Function - Total Cognition | Determine the effect of a 6-month exercise program on cognitive function via the NIH toolbox This composite includes: Flanker, Dimensional Change Card Sort, Picture Sequence Memory, List Sorting and Pattern Comparison. This composite score is derived by averaging the standard scores of each of the measures, and then deriving standard scores based on this new distribution. An Age-Corrected Standard Score was used. Scale runs 140 to 23, a higher score means a better outcome. An increased change from baseline to 6 months is considered an improvement | Mean change from baseline to 6 months. | 
| Motor Function - Grip Strength | Determine the effect of a 6-month exercise program on motor function via the NIH toolbox. Age corrected grip strength on a standard scale. Standard scale 140-23, higher score is better. An increased change from baseline to 6 months is considered an improvement. | Change from baseline in NIH toolbox motor function indices at 6 months | 
| Vascular Health - Pulse Wave Velocity | Vascular function indices of vascular health was assessed using pulse wave velocity of the aorta in meters/second (higher number =more stiff aorta). A larger negative change from baseline to 6 months is considered an improvement. | 6 Months | 
| Vascular Health - Augmentation Index | Vascular function indices of vascular health was assessed using augmentation index at the carotid artery (in percentage, higher percent=more stiff artery). A larger negative change from baseline to 6 months is considered an improvement. | 6 Months | 
| Cognitive Function - Fluid Cognition | Determine the effect of a 6-month exercise program on cognitive function via the NIH toolbox. Fluid cognition. This composite includes: Flanker, Dimensional Change Card Sort, Picture Sequence Memory, List Sorting and Pattern Comparison. This composite score is derived by averaging the standard scores of each of the measures, and then deriving standard scores based on this new distribution. An Age-Corrected Standard Score was used. A larger change from baseline to 6 months is considered an improvement. Scale runs 140 to 23, a higher score means a better outcome. | Mean change from baseline to 6 months. | 
| Cognitive Function - Crystalized Cognition | Change from baseline in NIH toolbox cognitive function indices at 6 months. Crystalized cognition. This composite includes : Flanker, Dimensional Change Card Sort, Picture Sequence Memory, List Sorting and Pattern Comparison. This composite score is derived by averaging the standard scores of each of the measures, and then deriving standard scores based on this new distribution. An Age-Corrected Standard Score was used. An larger change from baseline to 6 months is considered an improvement. Scale runs 140 to 23, a higher score means a better outcome. | Mean change from baseline to 6 months. | 
| Motor Function - Balance | Determine the effect of a 6-month exercise program on motor function via the NIH toolbox. Change in balance age corrected standard score from baseline to 6-months (23-140, higher score is better). A larger change is considered an improvement. | 6 Months | 
| Motor Function - Dexterity | Determine the effect of a 6-month exercise program on motor function via the NIH toolbox. Hand dexterity was determine using age corrected standard scale in the dominant hand. A larger change from baseline to 6 months is considered an improvement. Standard scale range 140-23, higher score is better. | 6 Months | 
| Resting Global Connectivity | Resting global connectivity measured and averaged across 132 regions. A larger change from baseline to 6 months is considered an improvement. Connectivity is a correlation (increased connectivity=higher correlation) | Change from baseline at 6 months | 
| Hippocampal Volume - Left | Determine the effect of a 6-month exercise program on hippocampal volume. An larger change from baseline to 6 months in left hippocampal volume (cubic millimeters) is considered an improvement. | Change from baseline at 6 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cognitive function, Kidney Disease, Exercise, Older adults