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Deep Brain Stimulation Targeting the Fornix for Mild Alzheimer Dementia (the ADvance Trial): A Two Year Follow-up Including Results of Delayed Activation.

ABSTRACT: BACKGROUND:Given recent challenges in developing new treatments for Alzheimer dementia (AD), it is vital to explore alternate treatment targets, such as neuromodulation for circuit dysfunction. We previously reported an exploratory Phase IIb double-blind trial of deep brain stimulation targeting the fornix (DBS-f) in mild AD (the ADvance trial). We reported safety but no clinical benefits of DBS-f versus the delayed-on (sham) treatment in 42 participants after one year. However, secondary post hoc analyses of the one-year data suggested a possible DBS-f benefit for participants?65 years. OBJECTIVE:To examine the long-term safety and clinical effects of sustained and delayed-on DBS-f treatment of mild AD after two years. METHODS:42 participants underwent implantation of DBS-f electrodes, with half randomized to active DBS-f stimulation (early on) for two years and half to delayed-on (sham) stimulation after 1 year to provide 1 year of active DBS-f stimulation (delayed on). We evaluated safety and clinical outcomes over the two years of the trial. RESULTS:DBS-f had a favorable safety profile with similar rates of adverse events across both trial phases (years 1 and 2) and between treatment arms. There were no differences between treatment arms on any primary clinical outcomes. However, post-hoc age group analyses suggested a possible benefit among older (>65) participants. CONCLUSION:DBS-f was safe. Additional study of mechanisms of action and methods for titrating stimulation parameters will be needed to determine if DBS has potential as an AD treatment. Future efficacy studies should focus on patients over age 65.

SUBMITTER: Leoutsakos JS

PROVIDER: S-EPMC6518401 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Deep Brain Stimulation Targeting the Fornix for Mild Alzheimer Dementia (the ADvance Trial): A Two Year Follow-up Including Results of Delayed Activation.

Leoutsakos Jeannie-Marie S JS Yan Haijuan H Anderson William S WS Asaad Wael F WF Baltuch Gordon G Burke Anna A Chakravarty M Mallar MM Drake Kristen E KE Foote Kelly D KD Fosdick Lisa L Giacobbe Peter P Mari Zoltan Z McAndrews Mary Pat MP Munro Cynthia A CA Oh Esther S ES Okun Michael S MS Pendergrass Jo Cara JC Ponce Francisco A FA Rosenberg Paul B PB Sabbagh Marwan N MN Salloway Stephen S Tang-Wai David F DF Targum Steven D SD Wolk David D Lozano Andres M AM Smith Gwenn S GS Lyketsos Constantine G CG

Journal of Alzheimer's disease : JAD 20180101 2

<h4>Background</h4>Given recent challenges in developing new treatments for Alzheimer dementia (AD), it is vital to explore alternate treatment targets, such as neuromodulation for circuit dysfunction. We previously reported an exploratory Phase IIb double-blind trial of deep brain stimulation targeting the fornix (DBS-f) in mild AD (the ADvance trial). We reported safety but no clinical benefits of DBS-f versus the delayed-on (sham) treatment in 42 participants after one year. However, secondar ...[more]

PMID: 29914028

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Project description:OBJECT This report describes the stereotactic technique, hospitalization, and 90-day perioperative safety of bilateral deep brain stimulation (DBS) of the fornix in patients who underwent DBS for the treatment of mild, probable Alzheimer's disease (AD). METHODS The ADvance Trial is a multicenter, 12-month, double-blind, randomized, controlled feasibility study being conducted to evaluate the safety, efficacy, and tolerability of DBS of the fornix in patients with mild, probable AD. Intraoperative and perioperative data were collected prospectively. All patients underwent postoperative MRI. Stereotactic analyses were performed in a blinded fashion by a single surgeon. Adverse events (AEs) were reported to an independent clinical events committee and adjudicated to determine the relationship between the AE and the study procedure. RESULTS Between June 6, 2012, and April 28, 2014, a total of 42 patients with mild, probable AD were treated with bilateral fornix DBS (mean age 68.2 ± 7.8 years; range 48.0-79.7 years; 23 men and 19 women). The mean planned target coordinates were x = 5.2 ± 1.0 mm (range 3.0-7.9 mm), y = 9.6 ± 0.9 mm (range 8.0-11.6 mm), z = -7.5 ± 1.2 mm (range -5.4 to -10.0 mm), and the mean postoperative stereotactic radial error on MRI was 1.5 ± 1.0 mm (range 0.2-4.0 mm). The mean length of hospitalization was 1.4 ± 0.8 days. Twenty-six (61.9%) patients experienced 64 AEs related to the study procedure, of which 7 were serious AEs experienced by 5 patients (11.9%). Four (9.5%) patients required return to surgery: 2 patients for explantation due to infection, 1 patient for lead repositioning, and 1 patient for chronic subdural hematoma. No patients experienced neurological deficits as a result of the study, and no deaths were reported. CONCLUSIONS Accurate targeting of DBS to the fornix without direct injury to it is feasible across surgeons and treatment centers. At 90 days after surgery, bilateral fornix DBS was well tolerated by patients with mild, probable AD. Clinical trial registration no.: NCT01608061 ( clinicaltrials.gov ).

Project description:ObjectivesTo examine the long-term efficacy at the 36-month follow-up of an early psychosocial counselling and support programme lasting 8-12 months for community-dwelling patients with mild Alzheimer's disease and their caregivers.DesignMulticentre, randomised, controlled, rater-blinded trial.SettingPrimary care and memory clinics in five Danish districts.Participants330 home-dwelling patients with mild Alzheimer's disease and their primary caregivers (dyads).InterventionsDyads were randomised to receive intervention during the first year after diagnosis. Both intervention and control groups had follow-up visits at 3, 6, 12 and 36 months.Main outcome measuresPrimary outcomes for the patients assessed at 36-month follow-up were changes from baseline in global cognitive function (Mini-Mental State Examination), depressive symptoms (Cornell Depression Scale) and proxy-rated EuroQoL quality of life on visual analogue scale. The primary outcomes for the caregivers were changes from baseline in depressive symptoms (Geriatric Depression Scale) and self-rated EuroQoL quality of life on a visual analogue scale. The secondary outcome measures for the patient were proxy-rated Quality of Life Scale for Alzheimer's disease (QoL-AD), Neuropsychiatric Inventory-Questionnaire, Alzheimer's disease Cooperative Study Activities of Daily Living Scale, all-cause mortality and nursing home placement.ResultsAt a 36-month follow-up, 2 years after the completion of the Danish Alzheimer Intervention Study (DAISY), the unadjusted positive effects previously detected at the 12-month follow-up in one patient primary outcome (Cornell depression score) and one patient secondary outcome (proxy-rated QoL-AD) disappeared (Cornell depression score, p=0.93; proxy-rated QoL-AD, p=0.81). No long-term effect of DAISY intervention on any other primary and secondary outcomes was found at the 36-month follow-up.ConclusionsFor patients with very mild Alzheimer's disease and their caregivers, an intensive, multi-component, semitailored psychosocial intervention programme with counselling, education and support during the first year after diagnosis did not show any positive long-term effect on primary and secondary outcomes.Trial registrationThe study was registered in the Clinical Trial Database (http://www.controlled-trials.com/ISRCTN74848736).

Dataset Information

Deep Brain Stimulation Targeting the Fornix for Mild Alzheimer Dementia (the ADvance Trial): A Two Year Follow-up Including Results of Delayed Activation.

Publications

Deep Brain Stimulation Targeting the Fornix for Mild Alzheimer Dementia (the ADvance Trial): A Two Year Follow-up Including Results of Delayed Activation.

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