Could MRI-Guided Ultrasound Facilitate Improved Reduction of Amyloid-Beta Load in Patients with Alzheimer's Disease?

Preliminary research findings in patients with Alzheimer’s disease suggest the use of magnetic resonance imaging (MRI)-guided focused ultrasound to open the blood-brain barrier may significantly improve the effectiveness of aducanumab in reducing amyloid-beta load.

For the prospective proof-of-concept study, recently published in the New England Journal of Medicine, researchers evaluated a monthly combination of aducanumab (Biogen) infusion with a MRI-guided focused ultrasound device (ExAblate-Neuro-Type2, Insightec) to open the blood-brain barrier over a six-month period in three patients diagnosed with mild cognitive impairment due to Alzheimer’s disease.

Noting that the aforementioned use of focused ultrasound was restricted to one hemisphere in the frontal or temporal lobe or hippocampus with high amyloid-beta levels, the study authors noted the controls were contralateral homologous brain regions not exposed to focused ultrasound.

Utilizing positron emission tomography (PET), the researchers found significant declines in amyloid-beta levels in all three patients for the combination treatment at 26 weeks. For the first patient, a 77-year-old man, researchers noted a Centiloid value decrease of 109 from baseline (224.2) to the 26-week assessment (115.2). The second patient, a 59-year-old man, had a Centiloid value decrease of 81 from 185.6 at baseline to 104.6 at 26 weeks. The third patient, a 64-year-old woman, had a 166.6 Centiloid value decrease from 251.5 to 84.9 at the six-month assessment, according to the study authors.

The positron emission tomography (PET) images show amyloid-beta reduction at 26 weeks in brain regions treated with combination treatment including the use of MRI-guided focused ultrasound to open the blood-brain barrier. (Images courtesy of the New England Journal of Medicine.)

“ .. We found that the combination of focused ultrasound to open the blood–brain barrier and administration of aducanumab resulted in numerically greater reductions in (amyloid beta) levels, as measured as both SUVR (standardized uptake value ratio) and Centiloid values, than previously observed in studies that assessed the use of focused ultrasound alone,” wrote lead study author Ali R. Rezai, M.D., the associate dean of neuroscience at West Virginia University (WVU) and executive chair and director of the WVU Rockefeller Neuroscience Institute, and colleagues.

“We observed an average 32% reduction in SUVR after 26 weeks in the regions that had received treatment to open the blood–brain barrier and six combination treatments.”

In contrast, the researchers noted that contralateral control brain regions for the cohort had similar Centiloid values at baseline and the 26-week assessment (219.7 and 218.1 respectively for the first patient; 129.3 and 135.8 respectively for the second patient; and 246.9 and 238.4 respectively for the third patient).

While noting that this trial did not quantify penetration of monoclonal antibody treatment, the study authors said the disparity in amyloid beta levels between brain regions that had combination treatment and homologous regions in the contralateral hemisphere that did not have MRI-focused ultrasound to open the blood-brain barrier aligns with prior research findings.

“These results are consistent with those of experimental studies that have shown increased penetration of aducanumab when combined with focused ultrasound to open the blood-brain barrier,” added Rezai and colleagues.

(Editor’s note: For related content, see “Emerging MRI and PET Research Reveals Link Between Visceral Abdominal Fat and Early Signs of Alzheimer’s Disease,” “Emerging Neuroradiology Concepts: Could Tau-PET be a New Standard in Assessing Possible Alzheimer’s Disease?” and “MRI Shows Focused Ultrasound May Induce Immunological Response in Alzheimer’s Patients.”)

During the six-month follow-up phase (which included monthly aducanumab infusion at 10 mg/k without focused ultrasound), the researchers noted that one patient had passive thoughts of death, which was found to be unrelated to the combined treatment. The study authors said there were no other serious adverse events and mild headache was the most common adverse event.