Directional DBS of the Fornix in Alzheimer's Disease Achieves Long-Term Benefits: A Case Report

Juan A Barcia, María Aurora Viloria, Raquel Yubero, Leyre Sanchez-Sanchez-Rojas, Amanda López, Bryan Andrew Strange, María Cabrera, Leonides Canuet, Pedro Gil, Cristina Nombela, Juan A Barcia, María Aurora Viloria, Raquel Yubero, Leyre Sanchez-Sanchez-Rojas, Amanda López, Bryan Andrew Strange, María Cabrera, Leonides Canuet, Pedro Gil, Cristina Nombela

Abstract

Background: Current treatments for Alzheimer's disease (AD) modulate global neurotransmission but are neither specific nor anatomically directed. Tailored stimulation of target nuclei will increase treatment efficacy while reducing side effects. We report the results of the first directional deep brain stimulation (dDBS) surgery and treatment of a patient with AD in an attempt to slow the progression of the disease in a woman with multi-domain, amnestic cognitive status.

Methods: We aimed to assess the safety of dDBS in patients with AD using the fornix as stimulation target (primary objective) and the clinical impact of the stimulation (secondary objective). In a registered clinical trial, a female patient aged 81 years with a 2-year history of cognitive decline and diagnoses of AD underwent a bilateral dDBS surgery targeting the fornix. Stimulation parameters were set between 3.9 and 7.5 mA, 90 μs, 130 Hz for 24 months, controlling stimulation effects by 18F-fluoro-2-deoxy-D-glucose (18F-FDG) scans (baseline, 12 and 24 months), magnetoencephalography (MEG) and clinical/neuropsychological assessment (baseline, 6, 12, 18, and 24 months).

Results: There were no important complications related to the procedure. In general terms, the patient showed cognitive fluctuations over the period, related to attention and executive function patterns, with no meaningful changes in any other cognitive functions, as is shown in the clinical dementia rating scale (CDR = 1) scores over the 24 months. Such stability in neuropsychological scores corresponds to the stability of the brain metabolic function, seen in PET scans. The MEG studies described low functional connectivity at baseline and a subsequent increase in the number of significant connections, mainly in the theta band, at 12 months.

Conclusion: The dDBS stimulation in the fornix seems to be a safe treatment for patients in the first stage of AD. Effects on cognition seem to be mild to moderate during the first months of stimulation and return to baseline levels after 24 months, except for verbal fluency.

Clinical trial registration: [https://ichgcp.net/clinical-trials-registry/NCT03290274], identifier [NCT03290274].

Keywords: Alzheimer’s disease; clinical trial; directional deep brain stimulation; fornix (brain); neuropsychology.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Barcia, Viloria, Yubero, Sanchez-Sanchez-Rojas, López, Strange, Cabrera, Canuet, Gil and Nombela.

Figures

FIGURE 1
FIGURE 1
The timeline of the study.
FIGURE 2
FIGURE 2
In amyloid PET images (1), the uptake of the grey matter equals that of the white matter in the lateral temporal, parietal, posterior cingulum/precuneus, and especially in the frontal lobe, thus being considered a positive study for amyloid deposition. 18F-FDG-PET images at diagnosis (2) show only mild mesial hypometabolism, predominantly in the left hemisphere (blue arrow). 18F-FDG-PET studies showed no evolution of hypometabolism at 1 year (3), and 2 years after diagnosis (4) (blue arrows).
FIGURE 3
FIGURE 3
Changes in brain connectivity from the initial study to the end of follow-up (24 months). Red and yellow lines indicate an increase in connectivity, while the blue lines show a decreasing pattern. Functional connections predominate in the bilateral mid-temporal regions with cingulate areas and, to a lesser extent, with frontomedial and orbitofrontal areas. In other words, the connectivity between the temporal and limbic areas remains quite strong. Low frequencies show an earlier decrease in connectivity, but the latest studies would indicate a pattern of reorganisation of activity.

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