Exploring Sympathetic Nervous System Function in Individuals With Down Syndrome

NCT07238465 | Recruiting Phase 3

• 2 other identifiers: 25-0503T32AG000279
• Study Type: interventional
• Target: 200
• Locations: 1 country
• Sites: 1

Brief Summary

Down syndrome (DS), the most common genetic cause of intellectual disability, is associated with widespread organ dysfunction, including abnormalities in the autonomic nervous system (ANS). The ANS regulates critical functions such as heart rate (HR) and blood pressure (BP), both essential for maintaining homeostasis and supporting physical activity. Individuals with DS often exhibit blunted HR responses to exercise-typically \~30 beats per minute below expected levels-suggesting reduced sympathetic nervous system (SNS) activity. The SNS governs rapid changes in HR and BP during stress by releasing catecholamines: epinephrine (from the adrenal medulla) and norepinephrine (from sympathetic nerve endings). Despite its importance, SNS function has not been comprehensively assessed among individuals with DS. This study addresses a critical knowledge gap by evaluating SNS responses to physiological stressors in individuals with DS. The investigators will measure beat-to-beat HR and BP, along with plasma catecholamine levels, in response to sympathetic activation, comparing individuals with DS to age- and sex-matched controls. Understanding the mechanisms of SNS dysfunction in DS is vital, as it likely underlies reduced exercise capacity and contributes to broader clinical challenges. These insights may guide targeted interventions to improve cardiovascular function, physical capacity, and overall quality of life in this understudied population.

Conditions

Down Syndrome; Autonomic Dysfunction

Keywords

Cold Stress; Exercise; Blood Pressure; Heart Rate; Catecholamines; Epinephrine; Norepinephrine; Dopamine; Stress; Post-Exercise Muscle Ischemia; Handgrip; Head Up Tilt Table

Outcome Measures

Primary Outcomes (21)

• Seated Baseline Concentration of Plasma Catecholamines

  Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.

  Seated baseline blood draw, prior to stressors

• Standing Baseline Concentration of Plasma Catecholamines

  Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.

  Blood draw will occur in standing position, prior to head up tilt table testing

• Concentration of Plasma Catecholamines During Cold Pressor Test

  Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.

  During the cold stress test, around or up to 5 minutes

• Concentration of Plasma Catecholamines During Handgrip Test

  Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.

  Blood draws occur around or up to 2-3 minutes into handgrip test

• Concentration of Plasma Catecholamines During Post Exercise Muscle Ischemia

  Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.

  Seated blood draw to occur, around or about 2-3 minutes into post exercise muscle ischemia

• Supine Concentration of Plasma Catecholamines

  Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.

  Blood draws during or around 10 minutes of supine rest

• Supine Concentration of Plasma Catecholamines, 5 Minutes into Head-Up Tilt

  Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.

  At or around 5 minutes into the head-up tilt table stimulus

• Supine Concentration of Plasma Catecholamines, 10 Minutes into Head-Up Tilt

  Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.

  At or around 10 minutes into the head-up tilt table stimulus

• Baseline Standing Concentration of Plasma Catecholamines Prior to Maximal Exercise Test

  Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.

  Standing baseline blood draw, prior to maximal exercise test

• Standing Concentration of Plasma Catecholamines at End of Maximal Exercise Test

  Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.

  This blood draw will occur at the very end or immediately following the maximal exercise test on the treadmill

• Standing Concentration of Plasma Catecholamines, 30 Minutes Post Maximal Exercise

  Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.

  This blood draw will occur around 30 minutes following the maximal exercise test on the treadmill

• Standing Concentration of Plasma Catecholamines, 60 Minutes Post Maximal Exercise

  Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.

  This blood draw will occur at the around 60 minutes following the maximal exercise test on the treadmill

• Seated Baseline Heart Rate, Prior to Cold Pressor Test

  Investigators will collect beat-to-beat heart rate recordings in all participants before, during (in some stressors), and after the four stressor tests. These cardiovascular perturbations will provide insight into sympathetic nervous system modulation in individuals with Down syndrome compared to those without Down syndrome.

  Resting seated baseline, prior to cold pressor test, up to or around 5 minutes

• Heart Rate Collected During Cold Pressor Test

  Investigators will collect beat-to-beat heart rate recordings in all participants before, during, and after the four stressor tests. These cardiovascular perturbations will provide insight into sympathetic nervous system modulation in individuals with Down syndrome compared to those without Down syndrome.

  Collected throughout the Cold Pressor Test, around 6 minutes in total

• Heart Rate, Maximal Exercise Test

  Investigators will collect beat-to-beat heart rate recordings in all participants before, during, and after the four stressor tests. These cardiovascular perturbations will provide insight into sympathetic nervous system modulation in individuals with Down syndrome compared to those without Down syndrome.

  Continuous heart rate recordings will take place throughout the maximal aerobic exercise test on the treadmill, up to or around 20 minutes

• Seated Baseline Blood Pressure, Prior to Cold Pressor Test

  Investigators will collect beat-to-beat blood pressure recordings in all participants before, during, and after the four stressor tests. These cardiovascular perturbations will provide insight into sympathetic nervous system modulation in individuals with Down syndrome compared to those without Down syndrome.

  Resting seated baseline, prior to cold pressor test, up to or around 5 minutes

• Blood Pressure Collected During Cold Pressor Test

  Investigators will collect beat-to-beat blood pressure recordings in all participants before, during, and after the four stressor tests. These cardiovascular perturbations will provide insight into sympathetic nervous system modulation in individuals with Down syndrome compared to those without Down syndrome.

  Collected throughout the Cold Pressor Test, around 6 minutes in total

• Heart Rate Collected During Handgrip with Post-Exercise Muscle Ischemia

  Investigators will collect beat-to-beat heart rate recordings in all participants before, during, and after the four stressor tests. These cardiovascular perturbations will provide insight into sympathetic nervous system modulation in individuals with Down syndrome compared to those without Down syndrome.

  Collected throughout the Handgrip tests with Post-Exercise Muscle Ischemia, around 12 minutes in total

• Heart Rate Collected During Head-Up Tilt Table Test

  Investigators will collect beat-to-beat heart rate recordings in all participants before, during, and after the four stressor tests. These cardiovascular perturbations will provide insight into sympathetic nervous system modulation in individuals with Down syndrome compared to those without Down syndrome.

  Collected throughout the Head-Up Tilt Table Test, around 25 minutes in total

• Blood Pressure Collected During Handgrip Test with Post-Exercise Muscle Ischemia

  Investigators will collect beat-to-beat blood pressure recordings in all participants before, during, and after the four stressor tests. These cardiovascular perturbations will provide insight into sympathetic nervous system modulation in individuals with Down syndrome compared to those without Down syndrome.

  Collected throughout the handgrip test with post-exercise muscle ischemia, up to or around 12 minutes

• Blood Pressure Collected During Head-Up Tilt Table Test

  Investigators will collect beat-to-beat blood pressure recordings in all participants before, during, and after the four stressor tests. These cardiovascular perturbations will provide insight into sympathetic nervous system modulation in individuals with Down syndrome compared to those without Down syndrome.

  Collected throughout the head-up tilt table test, around 25 minutes in total

Secondary Outcomes (3)

• Facial Affective Scale Score, Baseline Assessment

  Baseline Assessment of Facial Affective Scale, this will occur prior to any stressors.

• Facial Affective Scale Score, Cold Pressor Test, 1.5 Minutes

  Assessment occurs around or up to 90 seconds (1.5 minutes) into cold water immersion

• Facial Affective Scale Score, Cold Pressor Test, Finale

  Assessment occurs immediately following or during the last minute of the Cold Pressor Test, up to or around 6 minutes following placement of arm into cold

Study Arms (2)

Individuals with Down syndrome

EXPERIMENTAL

The investigators will be recruiting participants between the ages of 18-50 for the study investigating responses to four sympathetic stressors compared to age and sex matched individuals without Down syndrome.

Other: Cold Stress; Other: Maximal Dynamic Exercise; Other: Isometric Handgrip Exercise with Post-Exercise Muscle Ischemia; Other: Head-up Tilt Table Test

Individuals without Down syndrome

EXPERIMENTAL

The investigators will be recruiting individuals without Down syndrome between the ages of 18-50 to serve as the comparisons for individuals with Down syndrome across the four sympathetic stressors.

Other: Cold Stress; Other: Maximal Dynamic Exercise; Other: Isometric Handgrip Exercise with Post-Exercise Muscle Ischemia; Other: Head-up Tilt Table Test

Interventions

Cold Stress OTHER

Cold triggers the sympathetic nervous system, known as the 'fight-or-flight' response, which prepares the body to respond to a perceived threat by increasing heart rate, blood pressure, and releasing catecholamines. These measurements will be taken to examine how individuals with DS will respond during a cold stress test. The investigators are looking at how plasma catecholamines (i.e., Epinephrine, Norepinephrine, and Dopamine), blood pressure, and heart rate are expressed during a cold stress test in individuals with Down syndrome, who have proposed autonomic dysfunction. This study will compare responses among individuals with Down syndrome to a control group without Down syndrome.

Also known as: Cold Pressor Test, Cold Water

Individuals with Down syndrome; Individuals without Down syndrome

Maximal Dynamic Exercise OTHER

The investigators are looking at how plasma catecholamines (i.e., Epinephrine, Norepinephrine, and Dopamine), blood pressure, and heart rate are expressed during a treadmill maximal exercise test in individuals with Down syndrome, who have proposed autonomic dysfunction. This study will compare responses among individuals with Down syndrome to a control group without Down syndrome.

Also known as: VO2peak, Treadmill Exercise

Individuals with Down syndrome; Individuals without Down syndrome

Isometric Handgrip Exercise with Post-Exercise Muscle Ischemia OTHER

The investigators are looking at how plasma catecholamines (i.e., Epinephrine, Norepinephrine, and Dopamine), blood pressure, and heart rate are expressed during a isometric handgrip exercise followed by an ischemic period which will be induced by a blood pressure cuff in individuals with Down syndrome, who have proposed autonomic dysfunction. This study will compare responses among individuals with Down syndrome to a control group without Down syndrome.

Also known as: Handgrip, Post-Exercise Muscle Ischemia

Individuals with Down syndrome; Individuals without Down syndrome

Head-up Tilt Table Test OTHER

The investigators are looking at how plasma catecholamines (i.e., Epinephrine, Norepinephrine, and Dopamine), blood pressure, and heart rate are expressed during passive head-up tilt testing which is a standardized, noninvasive clinical and research procedure used to characterize cardiovascular autonomic responses to orthostatic stress, among individuals with Down syndrome, who have proposed autonomic dysfunction.

Also known as: Tilt Table, Orthostatic Stress

Individuals with Down syndrome; Individuals without Down syndrome

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• yrs old and apparently healthy individuals
• Ability to understand the study and give assent to participate
• Has a study partner who can attend all visits for the individuals with DS, and answer questionnaires, provide consent when necessary
• Corrected or non-existent congenital heart disease
• Euthyroid or on stable thyroid medication dose for at least 6 months
• Free from cardiovascular, pulmonary, inflammatory, or metabolic disease in the past 6 months that would prevent participation in study procedures
• BMI \<45kg/m2
• Ability to tolerate repeated blood draws / catheter placement

You may not qualify if:

• Hypertension (resting systolic blood pressure \[SBP\] ≥140 and/or diastolic blood pressure \[DBP\] ≥90 mmHg) this includes those on medications to treat hypertension
• Hypotension (resting BP of \<90/60 mmHg)
• Cancer in the last six months
• Any heart-rate-altering medications or any other medication that may modify metabolic responses
• Self-reported diabetes or use of glucose-lowering medication
• Tobacco products, including vaping, or marijuana use
• Currently pregnant
• Post-menopausal women
• Orthopedic limitations that would prohibit exercise or movement for exercise
• Fracture of limb to be immersed for CPT
• Open cut or sore on hand to be immersed for CPT
• Raynaud's syndrome for CPT

Sponsors & Collaborators

• University of Colorado, Denver: lead
• GLOBAL Down Syndrome Foundation: collaborator
• National Institute on Aging (NIA): collaborator
• Linda Crnic Institute for Down Syndrome: collaborator
• University of Colorado Colorado Clinical and Translational Sciences Institute: collaborator

Study Sites (1)

Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus

Aurora, Colorado, 80045, United States

RECRUITING

MeSH Terms

Conditions

Down Syndrome; Primary Dysautonomias; Motor Activity

Interventions

Cold-Shock Response

Condition Hierarchy (Ancestors)

Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Abnormalities, Multiple; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Chromosome Disorders; Genetic Diseases, Inborn; Autonomic Nervous System Diseases; Behavior

Intervention Hierarchy (Ancestors)

Stress, Physiological; Physiological Phenomena

Central Study Contacts

Sara R Sherman, PhD

CONTACT

303-724-0598; sara.r.sherman@cuanschutz.edu

Constance Brecl

CONTACT

constance.brecl@cuanschutz.edu

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 22, 2025
• First Posted: November 20, 2025
• Study Start: April 6, 2026
• Primary Completion (Estimated): December 1, 2029
• Study Completion (Estimated): December 1, 2030
• Last Updated: September 28, 2026

Record last verified: 2026-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)