Subgenual Cingulate Deep Brain Stimulation for Apathetic Behavioral Variant Frontotemporal Dementia - A Pilot Trial
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 6
- 试验地点
- 2
- 主要终点
- Incidence of Treatment-related Adverse Events
研究概览
简要总结
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.
详细描述
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:
- 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.
- 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.
- 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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 40 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Men and women aged 40-85 years
- •Diagnosis of image-supported behavioral variant frontotemporal dementia according to NIC-FTD and NACC FTLD guidelines
- •Apathy as one of the symptoms
- •Stable dose of baseline FTD medications for at least 3 months
- •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.
排除标准
- •Meets diagnostic criteria for other psychiatric diagnosis
- •Has other major Central Nervous System (CNS) disease that impairs motor, sensory or cognitive
- •Alcohol or illegal substance dependence within last 12 months
- •Other medical conditions which render anesthesia and surgery as unsafe as determined by neurosurgeon
- •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.
- •Has a medical condition requiring a repetitive MRI body scan
- •Requires chemotherapy for the treatment of malignancy or requiring chronic oral or intravenous (immunosuppressive or) steroid therapy
- •Is unable to comply with study visit schedule and timeline
- •Past significant intracranial surgery
- •A female lactating or of child-bearing potential, with a positive pregnancy test or not using adequate contraception.
结局指标
主要结局
Incidence of Treatment-related Adverse Events
时间窗: 24 months
Patients will be closely monitored for adverse events following DBS surgery with regular check-ups at 3-months, 6-months, 12-months and 24-months post-DBS surgery
次要结局
- National Institutes of Health - Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (NIH-EXAMINER)(Baseline before DBS surgery, and at 3-months, 6-months, 12-months and 24-months post-DBS surgery)
- Neuropsychiatric index (NPI)(Baseline before DBS surgery, and at 3-months, 6-months, 12-months and 24-months post-DBS surgery)
- Frontotemporal lobar degeneration-modified Clinical Dementia Rating-I (FTLD CDR-I)(Baseline before DBS surgery, and at 3-months, 6-months, 12-months and 24-months post-DBS surgery)
- Plasma neuroinflammatory biomarkers (Olink inflammation panels I and II)(Baseline before DBS surgery, and at 3-months, 6-months, 12-months and 24-months post-DBS surgery)
- Free and Cued Selective Reminding Test (FCSRT)(Baseline before DBS surgery, and at 3-months, 6-months, 12-months and 24-months post-DBS surgery)
- Apathy Evaluation Scale - Clinician version (AES-C)(Baseline before DBS surgery, and at 3-months, 6-months, 12-months and 24-months post-DBS surgery)
- Cerebrospinal fluid biomarkers of neurodegeneration (GFAP and NfL)(Baseline before DBS surgery and at 12-months and 24-months post-DBS surgery)
- Interpersonal reactivity index (IRI)(Baseline before DBS surgery, and at 3-months, 6-months, 12-months and 24-months post-DBS surgery)
- Social Cognition and Emotional Assessment (SEA)/Mini-SEA)(Baseline before DBS surgery, and at 3-months, 6-months, 12-months and 24-months post-DBS surgery)
- Trail making test - A and B (TMT)(Baseline before DBS surgery, and at 3-months, 6-months, 12-months and 24-months post-DBS surgery)
- Neuroimaging studies (FDG PET, rsfMRI, MEG, and vMRI)(Baseline before DBS surgery, and at 6-months, 12-months and 24-months post-DBS surgery)
研究者
Andres M. Lozano
University Professor
University Health Network, Toronto