Subgenual Cingulate Deep Brain STIMulation for Apathetic Behavioral Variant FRONtotemporal Dementia

NCT ID: NCT05699330

Last Updated: 2023-05-10

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 6 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-01-12
• Study Completion Date: 2026-01-12

Brief Summary

Frontotemporal dementia (FTD), the most common dementia in individuals younger than 60 years of age, has no disease-modifying treatment. Neuroimaging studies have revealed salience and default mode network dysfunction, frontotemporal atrophy and hypometabolism as pathophysiological hallmarks of behavioral variant FTD (bvFTD). A key brain structure affected by bvFTD is the subgenual cingulate (SGC), which serves as a hub for multi-axonal projections to and from the ventromedial prefrontal, dorsal anterior cingulate, orbitofrontal, and dorsolateral frontal cortices, and limbic structures.

The disruption of these SGC projections in bvFTD result in the core clinical features of apathy, disinhibition, loss of empathy, compulsivity, hyperorality and loss of executive function. The central goal of this proposal is to use deep brain stimulation (DBS) for modulation of the SGC downstream projections to treat bvFTD. Investigators hypothesize that SGC DBS will drive activity in the dysfunctional networks, reverse hypometabolism, and potentially improve symptoms. To determine the physiologic effects and mechanisms of SGC DBS, investigators will assess cerebral metabolism by FDG-PET, connectivity by rsfMRI and MEG, atrophy by volumetric MRI, and neurodegenerative and neuroinflammatory biomarkers. The safety and preliminary efficacy data obtained in these patients will inform the possible future role of DBS in apathetic bvFTD.

Detailed Description

Study Design:

This is a single-center prospective, open-label, non-blinded, non-randomized, pilot study designed to evaluate the safety of deep brain stimulation (DBS) of the subgenual cingulate (SGC) in subjects diagnosed with apathetic behavioral variant frontotemporal dementia (abvFTD). In addition, the physiological and clinical effects of DBS will be assessed by neuroimaging and neuropsychological testing.

Investigators hypothesize that:

1. Bilateral subgenual cingulate deep brain stimulator implantation will be well-tolerated in apathetic behavioral variant frontotemporal dementia patients. In AIM 1 investigators will assess the safety of SGC DBS, by monitoring intraoperative and postoperative adverse events related to surgery and stimulation in abvFTD patients.

2. Bilateral subgenual cingulate deep brain stimulation will modulate brain circuits that are dysfunctional in patients with apathetic behavioral variant frontotemporal dementia. In AIM 2 investigators will determine the physiological impact and mechanisms of action of SGC DBS in abvFTD, by assessing cerebral metabolism with ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) PET scans, functional connectivity with magnetoencephalography and resting state functional magnetic resonance imaging, cerebral atrophy with volumetric MRI, and plasma and cerebrospinal fluid biomarkers of neurodegeneration (glial fibrillar acidic protein and neurofilament light chain) and neuroinflammation (Olink inflammation panels I and II) in abvFTD patients.

3. Bilateral subgenual deep brain stimulation may improve some of the six core clinical features of behavioral variant frontotemporal dementia. In AIM 3 investigators will assess the clinical consequences of SGC DBS abvFTD, by performing the following neuropsychological tests: Neuropsychiatric index (NPI) and Apathy Evaluation Scale - Clinician version (AES-C) for apathy, NPI for disinhibition, compulsivity and hyperorality; Interpersonal reactivity index (IRI) for loss of empathy; National Institutes of Health - Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (NIHEXAMINER) and Trail making test - A and B (TMT) for executive function; Social Cognition and Emotional Assessment (SEA)/Mini-SEA), and Frontotemporal lobar degeneration-modified Clinical Dementia Rating-I (FTLD CDR-I) for cognitive impairment.

Experimental Approach:

Investigators propose a 3-year open-label, single-arm, phase I study of subgenual cingulate deep brain stimulation for apathetic behavioral variant frontotemporal dementia. In years 1-2 investigators will screen frontotemporal dementia patients and enrol a total of 6 subjects who meet the study inclusion criteria. Prior to SGC DBS surgery, the subjects will undergo baseline neuroimaging (FDG PET, rsfMRI, MEG, vMRI and tractography), measurement of plasma and neuroinflammation (multiplex proximity extension assay (PEA) technology using Olink Explore Inflammation I and II panels), optional lumbar puncture (according to patient preference) for CSF biomarkers of neurodegeneration (GFAP) and NfL assays), and neuropsychological testing (NPI, AES-C, IRI, NIH-EXAMINER, TMT, SEA/mini-SEA and FTLD CDR-I). At 2 weeks after surgery, the DBS device will be turned on, with subsequent programming sessions at 4 weeks, 6 weeks, 8 weeks, 10 weeks, 3 months, 6 months, 9 months, 12 months and 24 months post-DBS surgery to optimize therapy. During programming, the DBS stimulation parameters will be titrated with the patient's apathy score, measured by AES-C, which is a validated 18-item apathy scale that can be easily administered in 10-20 minutes during the programming session. Full neuropsychological testing (NPI, AES-C, IRI, NIH-EXAMINER, TMT, SEA/mini-SEA and FTLD CDR-I ) will be performed at baseline before DBS surgery, and at 3-months, 6-months, 12-months and 24-months post-DBS surgery. Measurement of plasma neuroinflammatory biomarkers (Olink inflammation panels I and II) will be done at baseline before DBS surgery, and at 3-months, 6-months, 9-months, 12-months and 24-months post-DBS surgery. Lumbar puncture to obtain CSF for biomarkers of neurodegeneration (GFAP and NfL) will be optional and will be offered at baseline before DBS surgery and at 12-months and 24-months post-DBS surgery. Neuroimaging studies (FDG PET, rsfMRI, MEG, and vMRI) will be done at baseline before DBS surgery, and at 6-months, 12-months and 24-months post-DBS surgery. The baseline assessments and postoperative follow up will take place at Toronto Western Hospital. Investigators anticipate to complete patient follow-up by the end of year 3. However, it is possible that the 24-month follow up of a few patients may extend into year 4, depending on when their DBS surgery is performed.

Conditions

Frontotemporal Dementia; Deep Brain Stimulation

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Bilateral subgenual cingulate deep brain stimulation (SGC DBS)

Deep Brain Stimulation (DBS) is a neurosurgical procedure involving the implantation of deep brain electrodes, connected via a subcutaneous extension wire, to an implantable pulse generator (IPG, or 'battery') that is implanted below the collarbone. All patients will receive deep brain stimulation (DBS) targeting the subgenual cingulate (SGC) bilaterally. No other changes to pre-existing treatment will be made. This is the only arm in this experiment.

Group Type: EXPERIMENTAL

Bilateral subgenual cingulate deep brain stimulation (SGC DBS)

Intervention Type: DEVICE

Deep Brain Stimulation (DBS) is a neurosurgical procedure involving the implantation of deep brain electrodes, connected via a subcutaneous extension wire, to an implantable pulse generator (IPG, or 'battery') that is implanted below the collarbone. All patients will receive deep brain stimulation (DBS) targeting the subgenual cingulate (SGC) bilaterally. No other changes to pre-existing treatment will be made. This is the only arm in this experiment.

Interventions

Bilateral subgenual cingulate deep brain stimulation (SGC DBS)

Deep Brain Stimulation (DBS) is a neurosurgical procedure involving the implantation of deep brain electrodes, connected via a subcutaneous extension wire, to an implantable pulse generator (IPG, or 'battery') that is implanted below the collarbone. All patients will receive deep brain stimulation (DBS) targeting the subgenual cingulate (SGC) bilaterally. No other changes to pre-existing treatment will be made. This is the only arm in this experiment.

Intervention Type: DEVICE

Eligibility Criteria

Inclusion Criteria

1. Men and women aged 40-85 years

2. Diagnosis of image-supported behavioral variant frontotemporal dementia according to NIC-FTD and NACC FTLD guidelines

3. Apathy as one of the symptoms

4. Stable dose of baseline FTD medications for at least 3 months

5. The patient has an available caregiver or other appropriate knowledgeable informant who can reliably report on daily activities and function. The patient must also have a substitute decision maker, if different from caregiver, to sign the informed consent for participation in the study.

Exclusion Criteria

1. Meets diagnostic criteria for other psychiatric diagnosis

2. Has other major Central Nervous System (CNS) disease that impairs motor, sensory or cognitive

3. Alcohol or illegal substance dependence within last 12 months

4. Other medical conditions which render anesthesia and surgery as unsafe as determined by neurosurgeon

5. Contraindications for MRI scanning, including implanted metallic devices (e.g., non-MRI-safe cardiac pacemaker or neurostimulator; some artificial joints metal pins; surgical clips; or other implanted metal parts), or claustrophobia or discomfort in confined spaces.

6. Has a medical condition requiring a repetitive MRI body scan

7. Requires chemotherapy for the treatment of malignancy or requiring chronic oral or intravenous (immunosuppressive or) steroid therapy

8. Is unable to comply with study visit schedule and timeline

9. Past significant intracranial surgery

10. A female lactating or of child-bearing potential, with a positive pregnancy test or not using adequate contraception.

• Minimum Eligible Age: 40 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Weston Brain Institute

OTHER

Sponsor Role: collaborator

University Health Network, Toronto

OTHER

Sponsor Role: lead

Responsible Party

Andres M. Lozano

University Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Andres M Lozano, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University Health Network, Toronto

Carmela Tartaglia, MD

Role: PRINCIPAL_INVESTIGATOR

University Health Network, Toronto

Cletus Cheyuo, MD, PhD

Role: STUDY_DIRECTOR

University Health Network, Toronto

Locations

Toronto Western Hospital

Toronto, Ontario, Canada

Site Status: RECRUITING

Countries

Canada

Central Contacts

Cletus Cheyuo, MD, PhD

Role: CONTACT

cletus.cheyuo@uhn.ca

6478076845

Tasnuva Hoque

Role: CONTACT

tasnuva.hoque@uhnresearch.ca

416-603-5800 ext. 2797

Facility Contacts

Cletus Cheyuo

Role: primary

cletus.cheyuo@uhn.ca

6478076845

Tasnuva Hoque

Role: backup

tasnuva.hoque@uhnresearch.ca

4166035800 ext. 2797

Other Identifiers

21-6126

Identifier Type: -

Identifier Source: org_study_id