TMS as a Treatment for Apathy in Alzheimer's Disease

NCT05389644 | Terminated DMC

• 1 other identifier: 2022P001058
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 1

Brief Summary

This proposal will demonstrate that non-invasive brain stimulation is able to modulate cortico-striatal circuits in neurodegenerative patients with apathy, and that doing so results in circuit-specific increases in FC and DA availability. These circuit changes will be accompanied by changes in specific behavioral dimensions of apathy. This work will lead to larger studies which develop personalized, circuit-specific neuromodulation strategies for AD patients suffering from this intractable neuropsychiatric symptom.

Conditions

Alzheimer Disease; Apathy in Dementia

Outcome Measures

Primary Outcomes (7)

• Changes in resting-state connectivity (FC).

  Changes in circuit-specific FC will be assessed with functional magnetic resonance imaging (fMRI) before and after iTBS.

  1 hour

• Changes in dopamine (DA) availability.

  Changes in DA availability after iTBS to each target will be measured by changes in 11C- raclopride binding potential (BPND)

  1 hour

• Changes in fMRI activation on an apathy related task

  Changes in fMRI blood oxygenation level dependent activation on the Philadelphia Apathy Computerized Test (PACT)

  1 hour

• Changes in performance on an apathy related task

  Changes in reaction times on the Philadelphia Apathy Computerized Test (PACT)

  1 hour

• Changes in scores on an apathy scale

  Changes in scores on the Apathy Evaluation Scale (AES); range 0-36, higher scores indicating more apathy.

  1 hour

• Changes in mood scores

  Changes in scores on the Profile of Mood States (POMS); range 0-20, higher scores indicating less apathy.

  1 hour

• Changes in mood scores

  Changes in scores on the Positive and Negative Affect Scale (PANAS); range 10-50, higher scores indicating less apathy.

  1 hour

Study Arms (3)

Dorsal circuit (DLPFC) stimulation

EXPERIMENTAL

This arm will involve stimulation of the dorsal apathy-relevant circuit. Specifically, a target will be individually selected based on resting-state functional connectivity with a given subject's dorsal striatum.

Device: Intermittent Theta Burst Stimulation (iTBS)

Ventral circuit (vmPFC) stimulation

EXPERIMENTAL

This arm will involve stimulation of the ventral apathy-relevant circuit. Specifically, a target will be individually selected based on resting-state functional connectivity with a given subject's ventral striatum.

Device: Intermittent Theta Burst Stimulation (iTBS)

Sham stimulation

SHAM COMPARATOR

This arm will involve sham stimulation to a prefrontal target.

Device: Intermittent Theta Burst Stimulation (iTBS)

Interventions

Intermittent Theta Burst Stimulation (iTBS) DEVICE

iTBS is a form of repetitive TMS. TMS is a form of non-invasive brain stimulation. In this modality, a current is rapidly passed through a TMS coil. This coil is placed on a subject's scalp. The rapidly discharging current creates a magnetic field perpendicular to the plane of the coil. This magnetic field diffuses through the subject's scalp and skull until it reaches the brain parenchyma. There, it causes focal neuronal depolarization.

Also known as: Transcranial Magnetic Stimulation (TMS)

Dorsal circuit (DLPFC) stimulation; Sham stimulation; Ventral circuit (vmPFC) stimulation

Eligibility Criteria

• Age: 50 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 50-80.
• A clinical diagnosis of Alzheimer's disease, including atypical variants of this (e.g., the behavioral/dysexecutive variant, the logopenic Primary Progressive Aphasia variant, Posterior Cortical Atrophy variant, etc.).
• Clinical Dementia Rating of 0.5 or mild 1.0 (MMSE equal to or greater than 22).
• Patients must be accompanied to visits by a study partner/informant (usually a spouse or adult child).
• Prominent symptoms of apathy reported by their primary caregiver/informant and verified with a score of greater than or equal to 45 on the informant version of the Apathy Evaluation Scale (AES-I).

You may not qualify if:

• Any contraindication to MR-PET scanning (e.g., pacemakers, implanted metal, aneurysm clips, etc.)
• Any contraindication to receiving TMS (e.g., a history of seizures, cochlear implants)
• Involvement in any PET studies within 12 months.
• Clinical dependence on psychotropic medications believed to affect dopamine binding (e.g., certain antidepressants or especially neuroleptics). If the patient is clinically able to temporarily wean off of these, they will be included after the medication has been discontinued and fully eliminated (e.g., a duration of five half-lives). Subjects will also be excluded if they have a history of long-term use of these agents (particularly neuroleptics).
• Concurrent use of tobacco or illicit drugs, particularly those affecting dopamine transmission. Patients will be asked to refrain from using caffeine the morning of experimental procedures.

Sponsors & Collaborators

• Massachusetts General Hospital: lead

Study Sites (1)

Martinos Center for Biomedical Imaging/Massachusetts General Hospital

Charlestown, Massachusetts, 02129, United States

Location

MeSH Terms

Conditions

Alzheimer Disease

Interventions

Transcranial Magnetic Stimulation

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Magnetic Field Therapy; Therapeutics

Study Officials

• Mark Eldaief, MD

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: Participants will receive active stimulation to two sites as well as sham stimulation to a third site.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Neurology, Harvard Medical School

Model Details: This study will involve a within-subject crossover design. Every subject will undergo three interventions.

Study Record Dates

• First Submitted: April 19, 2022
• First Posted: May 25, 2022
• Study Start: May 2, 2024
• Primary Completion: October 28, 2024
• Study Completion: October 28, 2024
• Last Updated: May 15, 2025

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)