Page 19 - JCTR-11-2

Journal of Clinical and
Translational Research US-mediated drug delivery

the trial intervention. Headaches were the most frequently midbrain, leading to impaired motor control. A hallmark of
reported adverse events. Interestingly, the effects of the PD is the presence of Lewy bodies, which are intracellular
US in this study might be pleiotropic, involving actions aggregates of misfolded proteins, including α-synuclein
of the therapeutic molecule, blood-borne factors entering (synucleinopathy).
cerebral tissue due to BBB opening, and neuromodulatory The clinical presentation of PD primarily includes motor
effects of the US itself through associated radiation forces. 97
symptoms, such as bradykinesia, cogwheel rigidity, resting
In addition, a pilot study demonstrated the safety and tremor, a slow shuffling gait, and imbalance. However, non-
repeatability of BBB opening in the left supramarginal motor symptoms are also present and include orthostatic
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gyrus of mild AD patients using the SonoCloud -1 device hypotension, rapid eye movement sleep behavioral
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and SonoVue MBs . Recently, Bae et al. designed and disorder, and hallucinations. 101,102 Present pharmacologic
69
98
validated a portable clinical neuronavigation-guided US treatments focus on increasing dopamine levels to address
device for BBB opening using Definity MBs. This device the dopamine deficiency observed in PD patients. The most
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successfully opened the BBB in the right frontal lobe of AD common treatment is levodopa (L-DOPA), a dopamine
patients without severe side effects (Table 5) pre-cursor that crosses the BBB, unlike dopamine itself.
6. Applications in PD Dopamine agonists and enzyme inhibitors, such as
DOPA decarboxylase inhibitor (carbidopa), catechol-O-
6.1. PD methyltransferase inhibitors, and monoamine oxidase B
PD is the second most common neurodegenerative (MAO-B) inhibitors, are often prescribed as adjuvants to
disease after AD. It affects approximately 4 million people levodopa to manage motor complications. In addition,
worldwide, with an average onset age of 60 years. While rare numerous molecules with therapeutic potential are under
cases occur in individuals under 40 years, 3% of people over investigation for the treatment of PD. 103,104
80 years are affected by PD. The disease has a prevalence of 6.2. Pre-clinical phase
99
1 – 2/1000 and an incidence of 13.5/100,000 people/year.
100
PD is an idiopathic neurodegenerative disorder primarily MB-assisted US has been demonstrated to effectively deliver
characterized by the degeneration of dopaminergic therapeutics to neurotoxic-lesioned (i.e., 6-hydroxydopamine,
neurons in the pars compacta of the substantia nigra in the 6-OHDA; 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,

Table 5. Drug delivery with MB‑assisted US for clinical studies in Alzheimer’s disease
References Drug, dye, Patients US devices/parameters Targeted area MBs Therapy
particle duration
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Lipsman et al., 2018 74 Gadolinium 5 patients with ExAblate Neuro Type 2 Frontal lobe Definity MBs 2 sonications
early AD 300 ms burst length, repetition (4 µL/kg) separated by
interval of 2.7 s, DC 0.74%, for 50 s 1 month
Rezai et al., 2020 95 Gadolinium 6 patients with ExAblate Neuro Type 2 Hippocampus Definity MBs 3 sonications
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early AD separated by
2 weeks
Mehta et al., 2021 94 Gadolinium 3 patients with ExAblate Neuro Type 2 Hippocampus Definity MBs 3 sonications
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early AD 2.6 ms pulses spaced by 30.4 ms, separated by
10 cycles, 1550 ms rest period, 4 – 2 weeks
11.5 W, for 90 s
Epelbaum et al., 2022 69 Gadolinium 9 patients with SonoCloud-1 device Left SonoVue MBs 1 sonication every
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mild AD 25,000-cycle pulse, every second, supra-marginal (0.1 mL/kg) 2 weeks for a total
for 4 min gyrus of 7
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Bae et al., 2024 98 Gadolinium 6 patients Portable clinical Right frontal lobe Definity MBs 1 sonication
neuronavigation-guided US device (0.1 mL/kg)
PNP 200 kPa, MI 0.4, center
frequency 0.25 MHz, pulse length
10 ms, 2 Hz PRF, for 2 min
Rezai et al., 2024 96 Aducanumab 3 patients ExAblate Neuro Type 2 Left frontal, Definity MBs 1 sonication
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parietal, per month for
temporal lobes, 6 months
hippocampus
Abbreviations: AD: Alzheimer’s disease; DC: Duty cycle; MB: Microbubble; PRF: Pulse repetition frequency; US: Ultrasound.
Volume 11 Issue 2 (2025) 13 doi: 10.36922/jctr.24.00061