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The Wandering Nerve: Gateway to Boost Alzheimer's Disease Related Cognitive Performance (WALLe)

Primary Purpose

Aging

Status

Recruiting

Phase

Not Applicable

Locations

United States

Study Type

Interventional

Intervention

Active transcutaneous vagus nerve stimulation respiratory-gated non-painful electrical stimulation of the auricle for 10 minute sessions

Sham transcutaneous vagus nerve stimulation respiratory-gated non-painful electrical stimulation of the auricle for 10 minute sessions

About this trial

This is an interventional other trial for Aging focused on measuring Transcutaneous vagus nerve stimulation, Memory, Brainstem, Aging, Preclinical Alzheimer's disease

Eligibility Criteria

60 Years - 85 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

Fluent in English
Willingness and ability to comply with scheduled visits, magnetic resonance imaging (MRI) scanning, laboratory tests, and other study procedures.
Subjects with well-controlled vascular risk factors, such as treated hypertension, treated hyperlipidemia or well controlled Type II diabetes will be included.
Stable medications for at least 30 days.
Mini Mental State Exam adjusted for age and education of 25 to 30, inclusive or a Telephone Interview for Cognitive Status score of at least 32
Perform within 1.5 S.D. of age and education matched norms on the Logical Memory Paragraph Delayed Recall
Geriatric Depression Scale < 11
Aged 60-85, inclusive
Right-handed
Reduced vision is allowed if it can be corrected with MRI-goggles

Exclusion Criteria:

Prior known diagnosis of mild cognitive impairment (MCI) or dementia
Use of investigational drugs or devices within 60 days prior to screening
Subjects with contraindications to MRI cannot participate (i.e., implanted metal including pacemakers, cerebral spinal fluid shunts, aneurysm clips, artificial heart valves, ear implants or metal/foreign objects in the eyes and those with a history of claustrophobia)
Pregnant.
Major psychiatric disorders such as schizophrenia, schizoaffective disorder, major affective disorder in mid-life, or treatment with electroconvulsive therapy (ECT) (Mild depression that is well treated with stable dose of selective serotonergic reuptake inhibitor (SSRI) antidepressants will be allowed).
Have a history of major head trauma defined as a loss of consciousness and/or trauma requiring hospitalization
Substance abuse within the past 2 years
Active hematological, renal, pulmonary, endocrine or hepatic disorders.
Evidence of cortical infarcts or strategically placed lacunar infarct (e.g. dorsal medial nucleus of thalamus). MRI evidence of mild white matter signal abnormalities will be allowed.
Active cancer, metabolic encephalopathy, infection
Active cardiovascular disease, stroke, congestive or severe heart failure
Huntington's disease, hydrocephalus or seizure disorder
Cataracts, glaucoma, detached retina's, eye surgery involving the muscles; droopy eyelids, penetrating eye wounds and use of anticholinergic eye drop use
Weight equal to or greater than 300 lbs (weight limit of the MRI table).
Recurrent vaso-vagal syncopal episodes
Unilateral or bilateral vagotomy
Severe valvular disorder (i.e. prosthetic valve or hemodynamically relevant valvular diseases)
Sick sinus syndrome
Hypotension due to autonomic dysfunction

Sites / Locations

Massachusetts General HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Sham Comparator

Experimental

Other

Arm Label

Sham preceded by cross-over Sham-Stimulation

Sham preceded by cross-over Stimulation-Sham

Stimulation preceded by cross-over Sham-Stimulation

Stimulation preceded by cross-over Stimulation-Sham

cross-over Stimulation-Sham

cross-over Sham-Stimulation

Arm Description

Cross-over: Sham followed by experimental Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS) Wash-out period of four weeks Ten daily sessions of sham during 2 weeks

Cross-over: experimental Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS) followed by Sham Wash-out period of four weeks Ten daily sessions of sham during 2 weeks

Cross-over: Sham followed by experimental Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS) Wash-out period of four weeks Ten daily sessions of RAVANS during 2 weeks

Cross-over: experimental Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS) followed by sham Wash-out period of four weeks Ten daily sessions of RAVANS during 2 weeks

Cross-over: experimental Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS) followed by sham One time RAVANS versus one time Sham Two weeks wash-out

Cross-over: Sham followed by experimental Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS) One time RAVANS versus one time Sham Two weeks wash-out

Outcomes

Primary Outcome Measures

Performance on the Face-name association memory task (FNAME)

Change from baseline at each visit where FNAME is completed: Scores are z-scores with a mean of zero. Higher scores are better (there is no minimum/maximum).

Being a responder as determined by Face-name association memory task (FNAME) change scores

Participants are grouped in being a responder (1) or non-responder (0).

Secondary Outcome Measures

Performance on other cognitive composite scores: this includes a composite score of memory, a composite score of executive function and the Preclinical Alzheimer's disease cognitive composite.

Change from baseline at each visit where neuropsychological data is collected. Composites are calculated following a confirmatory factor analyses. All scores (correct answers) will be expressed in z-scores and higher scores are better (there is no minimum/maximum).

Change in inflammatory responses (aggregated)

Change from baseline to after intervention, these markers will be analyzed from blood: Interleukins (IL): IL-1β, IL-2, IL-6, IL-8 Tumor necreose factor alpha (TNF-α) Macrophage inflammatory protein (MIP1B) Monocyte chemoattractant protein (MCP-1) Complement components: C1q and C3 soluble triggering receptor expressed on myeloid cells (TREM2). Following stability analyses, specific markers will be selected (with advise by Dr. Arnold) and analysed individually (see outcome measures 5-10) and in aggregated form (here). Markers will be combined following a principal component analyses and will be normalised. Values will be expressed in z-scores.

Change in inflammatory responses (interleukins)

Change from baseline to after intervention: - Interleukins (IL): IL-1β, IL-2, IL-6, IL-8 (expressed in IU, international units)

Change in inflammatory responses (TNF)

Change from baseline to after intervention: - Tumor necreose factor alpha (TNF-α) (units/ml)

Change in inflammatory responses (MIP)

Change from baseline to after intervention: - Macrophage inflammatory protein (MIP1B) (units/ml)

Change in inflammatory responses (MCP)

Change from baseline to after intervention: -Monocyte chemoattractant protein (MCP-1) (units/ml)

Change in inflammatory responses (C)

Change from baseline to after intervention: - Complement components: C1q and C3 (units/ml)

Change in inflammatory responses (TREM)

Change from baseline to after intervention: - soluble triggering receptor expressed on myeloid cells (sTREM2) (units/ml)

Full Information

NCT ID

NCT04908358

First Posted

May 4, 2021

Last Updated

February 15, 2023

Sponsor

Massachusetts General Hospital

Collaborators

National Institute on Aging (NIA)

1. Study Identification

Unique Protocol Identification Number

NCT04908358

Brief Title

The Wandering Nerve: Gateway to Boost Alzheimer's Disease Related Cognitive Performance

Acronym

WALLe

Official Title

The Wandering Nerve: Gateway to Boost Alzheimer's Disease Related Cognitive

Study Type

Interventional

2. Study Status

Record Verification Date

February 2023

Overall Recruitment Status

Recruiting

Study Start Date

November 24, 2021 (Actual)

Primary Completion Date

February 28, 2026 (Anticipated)

Study Completion Date

April 30, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Massachusetts General Hospital

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

Yes

5. Study Description

Brief Summary

In this research study the investigators want to find out if a non-invasive electrical brain stimulation method called RAVANS (also called tVNS) can have a beneficial effect on cognition in older individuals. The investigators also want to understand whether certain individual factors contribute to the effect of RAVANS on cognition. RAVANS is only used in research studies.

Detailed Description

The intervention will be studied in 140 older individuals using a randomized cross-over design of sham versus RAVANS stimulation (2 sessions separated by 4 weeks) during a functional magnetic resonance imaging (fMRI) task. Participants will then be randomized to daily tVNS or sham sessions during 10 visits within two weeks, and two follow-up cognitive assessments each after 2 months of the last intervention session. The face-name association task will be the main outcome measure. The investigators will also draw blood twice to examine whether the response on the outcome is dependent on Alzheimer's disease related biomarker, and whether RAVANS has effects on inflammatory responses.

6. Conditions and Keywords

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

Aging

Keywords

Transcutaneous vagus nerve stimulation, Memory, Brainstem, Aging, Preclinical Alzheimer's disease

7. Study Design

Primary Purpose

Other

Study Phase

Not Applicable

Interventional Study Model

Sequential Assignment

Model Description

Randomized cross-over followed by placebo-controlled study (allocation to placebo or control condition takes APOE-E4 status into account and the previous ordering of the cross-over design)

Masking

Participant

Masking Description

Participant will not be informed of condition. The investigators will work with blinded data (but can know the condition during intervention)

Allocation

Randomized

Enrollment

140 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Sham preceded by cross-over Sham-Stimulation

Arm Type

Sham Comparator

Arm Description

Cross-over: Sham followed by experimental Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS) Wash-out period of four weeks Ten daily sessions of sham during 2 weeks

Arm Title

Sham preceded by cross-over Stimulation-Sham

Arm Type

Sham Comparator

Arm Description

Cross-over: experimental Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS) followed by Sham Wash-out period of four weeks Ten daily sessions of sham during 2 weeks

Arm Title

Stimulation preceded by cross-over Sham-Stimulation

Arm Type

Experimental

Arm Description

Cross-over: Sham followed by experimental Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS) Wash-out period of four weeks Ten daily sessions of RAVANS during 2 weeks

Arm Title

Stimulation preceded by cross-over Stimulation-Sham

Arm Type

Experimental

Arm Description

Cross-over: experimental Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS) followed by sham Wash-out period of four weeks Ten daily sessions of RAVANS during 2 weeks

Arm Title

cross-over Stimulation-Sham

Arm Type

Other

Arm Description

Cross-over: experimental Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS) followed by sham One time RAVANS versus one time Sham Two weeks wash-out

Arm Title

cross-over Sham-Stimulation

Arm Type

Other

Arm Description

Cross-over: Sham followed by experimental Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS) One time RAVANS versus one time Sham Two weeks wash-out

Intervention Type

Other

Intervention Name(s)

Active transcutaneous vagus nerve stimulation respiratory-gated non-painful electrical stimulation of the auricle for 10 minute sessions

Other Intervention Name(s)

Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS), transcutaneous vagus nerve stimulation

Intervention Description

Stimulation of vagus nerve in the outer ear

Intervention Type

Other

Intervention Name(s)

Sham transcutaneous vagus nerve stimulation respiratory-gated non-painful electrical stimulation of the auricle for 10 minute sessions

Other Intervention Name(s)

Sham Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS), Sham transcutaneous vagus nerve stimulation

Intervention Description

Sham stimulation of vagus nerve in the outer ear

Primary Outcome Measure Information:

Title

Performance on the Face-name association memory task (FNAME)

Description

Change from baseline at each visit where FNAME is completed: Scores are z-scores with a mean of zero. Higher scores are better (there is no minimum/maximum).

Time Frame

Up to 25 weeks: assessed during week 1, week 2, week 8,week 9, week 17 and week 25

Title

Being a responder as determined by Face-name association memory task (FNAME) change scores

Description

Participants are grouped in being a responder (1) or non-responder (0).

Time Frame

Based on data from the first 4 weeks (cross-over)

Secondary Outcome Measure Information:

Title

Performance on other cognitive composite scores: this includes a composite score of memory, a composite score of executive function and the Preclinical Alzheimer's disease cognitive composite.

Description

Time Frame

Up to 25 weeks: assessed during week 1, week 2, week 8,week 9, week 17 and week 25

Title

Change in inflammatory responses (aggregated)

Description

Time Frame