Study of the Brain Stimulation Effect on Memory Impairment in Alzheimer Disease

April 11, 2024 updated by: Centre Hospitalier Universitaire de Nice

Study of the Effect of the Chronic Electric Stimulation of the Hypothalamus/Fornix on Memory Impairment in Alzheimer Disease.

Alzheimer's Disease (AD) is the most common cause of dementia. Today no treatment had shown consistent efficacy to stop or slow down the disease. Recent report of enhancement of memory abilities by bilateral chronic deep brain stimulation (DBS) of the fornix in the hypothalamus suggests that neuromodulation of circuits involved in memory processes may have therapeutic implications in AD patients with memory decline.

The primary objectives of this prospective, non-controlled, pilot study are to assess the feasibility and safety of DBS in AD patients with mild cognitive and memory impairment, and to evaluate the efficacy of DBS to slow down or stabilize this decline. Five patients with AD (DSM IV) diagnosed less than two years, with mild cognitive decline (MMSE 20-24), and specific impairment of episodic memory will be included in a 2-year period. The evaluation criteria for feasibility will be the proportion of patients undergoing the procedure, chronic stimulation and evaluation process without adverse event (AE). Efficacy will be evaluated using numerous cognitive and memory testing including classical instrument used in AD clinical trials. Changes in behavioral scales, and changes in hypothalamic functions (clinical, biological and hormonal assessment) will evaluate safety and tolerance. Clinical, neuro-psychological, biological and imaging assessment will be performed 3 and one month before and 3, 6, 12 and 24 months after surgery. Bilateral electrodes (Medtronic 3389) will be implanted, by MR-guided frame-based stereotaxy, in the hypothalamic part of the fornix, and then connected to the generator (Kinetra, Medtronic). Chronic high-frequency stimulation will be delivered immediately after surgery.

The investigators expect to slow down, or to stabilize the spontaneous decline of MMSE and ADAS scores after 6, 12 and 24 months of stimulation. In case of efficacy, DBS might offer to AD patient the possibility to slow down/stabilize their symptoms, which no other treatment can currently offer, and to increase their quality of life.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

Detailed Description

Alzheimer's Disease (AD) is the most common cause of dementia whom estimated prevalence rise to more than 5 millions in the US. AD patients display progressive impairment of episodic memory and instrumental signs including aphasia, apraxia, and agnosia, together with general cognitive decline, death occurring 6-9 years after diagnosis. Up to now, no treatment had shown consistent efficacy to stop or slow down the disease. Recently, it has been shown that memory abilities have been enhanced by bilateral chronic deep brain stimulation (DBS) of the fornix in the hypothalamus, in a patient initially treated for malignant obesity (Hamani C, Ann Neurol, 2008). This report showed that neuro-anatomic circuits involved in memory processes are reachable and can be modulated. This modulation may have therapeutic implications in AD patients with memory decline.

The primary objectives of this prospective, non-controlled, pilot study are to evaluate the feasibility and safety of DBS in AD patients with mild cognitive and memory impairment, and to evaluate the efficacy of DBS to slow down or stabilize this decline. The secondary objectives are to determine which cognitive and memory aspects are improved, and the duration of the efficacy of DBS on AD symptoms.

The inclusion criteria are: patients with AD (DSM IV) diagnosed less than two years, age between 50 and 65, with mild cognitive decline (MMSE between 20 and 24), and specific impairment of episodic memory (using the free and cued selective reminding test: FCSRT ), able to give and sign an informed consent. Patients with associated DSM I axis pathology, contra-indication to surgery or MRI, or preoperative MRI abnormalities will not be included. Five patients will be included in a 2-year period.

The evaluation criteria for feasibility will be the proportion of patients undergoing the procedure, chronic stimulation and evaluation process without adverse event (AE). Efficacy will be evaluated using numerous cognitive and memory testing including WAIS, MMSE, ADAS scales, TMT-A and TMT-B testing, language evaluation, FCSRT and Rey figure. CGI and IADL will evaluate global improvement. Neuro-imaging changes after stimulation will be evaluate by morphological MRI (hippocampal volume) and functional imaging (PET). Changes in behavioral and mood scales, and changes in hypothalamic functions (clinical, biological and hormonal assessment) will evaluate safety and tolerance.

Experimental paradigm: Clinical, neuro-psychological, biological and imaging assessment will be performed 3 and one month before and 3, 6, 12 and 24 months after surgery. Bilateral electrodes (Medtronic 3389) will be implanted, under local anesthesia, by MR-guided frame-based stereotaxy, in the hypothalamic part of the fornix, before its entry in the mamillary body (well defined on T2 weighted sequences). Intraoperative stimulation will be used to search adverse effects or acute effects. Electrodes will be connected to the generator (Kinetra, Medtronic) under general anesthesia. Chronic high-frequency stimulation will be delivered immediately after surgery.

Expected results and perspectives: Spontaneously, neuropsychological scores progressively decline with time in AD patients (MMSE 3-4 points decrease and ADAS 6 points increase per year). We expect to slow down, or to stabilize these scores after 6, 12 and 24 months of stimulation.

In case of efficacy DBS might offer to AD patient the possibility to slow down/stabilize their symptoms, which no other treatment can currently offer, and to increase their quality of life.

Study Type

Interventional

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
      • Nice, France, 06001
        • CMR2 Hôpital de Cimiez
      • Nice, France, 06100
        • Service de Neurochirurgie Hôpital Universitaire de Pasteur

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

50 years to 70 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Patients between 50 and 65 years of age,
  • Patients with Alzheimer disease (according to DSM-IV criteria)
  • Recent diagnosis of Alzheimer disease (less than 2 years ago)
  • Patients with a total score in "Mini Mental Test" between 20 and 24.
  • Patient with impaired performance of their occasional memory, estimated by the test of Grober and Buschke (according to the standards, according to the age, the sex and the sociocultural level).
  • Patients covered by Social Security
  • Patients willing to sign the proper consent forms

Exclusion Criteria:

  • associated DSM I axis pathology,
  • contra-indication to surgery or MRI,
  • preoperative MRI abnormalities
  • Withdrawal of patient consent
  • Study sponsor or investigator decision to suspend the study.
  • Diagnosis of a metabolic or hormonal disorder on the biological assessment realized during the inclusion.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Deep brain stimulation
Electrodes (Medtronic 3389) will be implanted in a bilateral way , under local anesthesia, at fornix level in its way through the hypothalamus, very visible on the MRI just before its entrance to mammilary bodies. Electrodes will be connected under general anesthesia to the pectoral sub-cutaneous pacemaker. The electric chronic stimulation (180 Hz, 2-3 V, 120 ms) will be begun the day after the operation.
Device: Deep brain stimulation
Electrodes (Medtronic 3389) will be implanted in a bilateral way , under local anesthesia, at fornix level in its way through the hypothalamus, very visible on the MRI just before its entrance to mammilary bodies. Electrodes will be connected under general anesthesia to the pectoral sub-cutaneous pacemaker. The electric chronic stimulation (180 Hz, 2-3 V, 120 ms) will be begun the day after the operation
Other Names:
  • Hypothalamus/fornix stimulation
  • Medtronic 3389

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Evaluation criteria for feasibility will be the proportion of patients undergoing the procedure, chronic stimulation and evaluation process without adverse event.
Time Frame: 2012
2012

Secondary Outcome Measures

Outcome Measure
Time Frame
- Efficacy : evaluated using cognitive and memory testing. - Global improvement : CGI and IADL - Neuro-imaging : MRI and functional imaging - Safety/tolerance : Changes in behavioral,in hypothalamic functions and assessment of adverse events
Time Frame: 2012
2012

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Centre Hospitalier Universitaire de Nice

Investigators

  • Principal Investigator: Denys Fontaine, PH, Service de Neurochirurgie
  • Principal Investigator: Philippe Robert, PH PU, CMR2

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 1, 2009

Primary Completion (Actual)

August 1, 2010

Study Completion (Actual)

August 1, 2012

Study Registration Dates

First Submitted

July 27, 2009

First Submitted That Met QC Criteria

July 27, 2009

First Posted (Estimated)

July 28, 2009

Study Record Updates

Last Update Posted (Actual)

April 12, 2024

Last Update Submitted That Met QC Criteria

April 11, 2024

Last Verified

July 1, 2009

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 09 - APN - 04
  • AFSSAPS2009-A00318-49

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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