Targeted Delivery of Neural Stem Cells to the Brain Using MRI-Guided Focused Ultrasound to Disrupt the Blood-Brain Barrier

Stem cell therapy is a promising strategy to treat neurodegenerative diseases, traumatic brain injury, and stroke. For stem cells to progress towards clinical use, the risks associated with invasive intracranial surgery used to deliver the cells to the brain, needs to be reduced. Here, we show that MRI-guided focused ultrasound (MRIgFUS) is a novel method for non-invasive delivery of stem cells from the blood to the brain by opening the blood brain barrier (BBB) in specific brain regions. We used MRI guidance to target the ultrasound beam thereby delivering the iron-labeled, green fluorescent protein (GFP)-expressing neural stem cells specifically to the striatum and the hippocampus of the rat brain. Detection of cellular iron using MRI established that the cells crossed the BBB to enter the brain. After sacrifice, 24 hours later, immunohistochemical analysis confirmed the presence of GFP-positive cells in the targeted brain regions. We determined that the neural stem cells expressed common stem cell markers (nestin and polysialic acid) suggesting they survived after transplantation with MRIgFUS. Furthermore, delivered stem cells expressed doublecortin in vivo indicating the stem cells were capable of differentiating into neurons. Together, we demonstrate that transient opening of the BBB with MRIgFUS is sufficient for transplantation of stem cells from the blood to targeted brain structures. These results suggest that MRIgFUS may be an effective alternative to invasive intracranial surgery for stem cell transplantation

Antibodies Targeted to the Brain with Image-Guided Focused Ultrasound Reduces Amyloid-β Plaque Load in the TgCRND8 Mouse Model of Alzheimer's Disease

Immunotherapy for Alzheimer's disease (AD) relies on antibodies directed against toxic amyloid-beta peptide (Aβ), which circulate in the bloodstream and remove Aβ from the brain [1], [2]. In mouse models of AD, the administration of anti-Aβ antibodies directly into the brain, in comparison to the bloodstream, was shown to be more efficient at reducing Aβ plaque pathology [3], [4]. Therefore, delivering anti-Aβ antibodies to the brain of AD patients may also improve treatment efficiency. Transcranial focused ultrasound (FUS) is known to transiently-enhance the permeability of the blood-brain barrier (BBB) [5], allowing intravenously administered therapeutics to enter the brain [6]–[8]. Our goal was to establish that anti-Aβ antibodies delivered to the brain using magnetic resonance imaging-guided FUS (MRIgFUS) [9] can reduce plaque pathology. To test this, TgCRND8 mice [10] received intravenous injections of MRI and FUS contrast agents, as well as anti-Aβ antibody, BAM-10. MRIgFUS was then applied transcranially. Within minutes, the MRI contrast agent entered the brain, and BAM-10 was later found bound to Aβ plaques in targeted cortical areas. Four days post-treatment, Aβ pathology was significantly reduced in TgCRND8 mice. In conclusion, this is the first report to demonstrate that MRIgFUS delivery of anti-Aβ antibodies provides the combined advantages of using a low dose of antibody and rapidly reducing plaque pathology

Focused ultrasound delivery of BAM-10 to the brain reduces Aβ plaque pathology in TgCRND8 mice.

<p>Coronal sections were stained with streptavadin-Cy2 for (<b>A</b>) biotinylated BAM-10 and (<b>B</b>) anti-Aβ antibody 6F3D for plaques to demonstrate that 6F3D binds to plaques which are strongly (arrows) and weakly (arrowheads) positive for BAM-10 (<b>C</b>). Once it was confirmed that BAM-10 does not interfere with 6F3D plaque detection, sections for mice in each treatment group were stained with 6F3D and the stereology software was used to draw contours outlining the FUS-targeted region (determined from MRI post-treatment scans) on the right side of the brain and an equivalent region on the contralateral side (<b>D</b>). Plaques were counted and measured at high magnification (<b>E</b>), using stereological methods. In 4 days, the mean (<b>F</b>) count, (<b>G</b>) size and (<b>H</b>) surface area of Aβ plaques on the right, MRIgFUS-targeted side of the brain was consistently reduced in comparison to the left side of the brain only for the BAM-10/FUS-treated mice (<b>F–H</b>; n = 6, paired t-tests, p = 0.008, p = 0.048 and p = 0.003, respectively). This difference is unique to BAM-10/FUS treatment as there was no significant difference between right and left side of the brain in mice from other treatment groups (<b>F′–H′</b>: BAM-10 treated group, n = 6, paired t-tests, p = 0.294, p = 0.941 and p = 0.402; <b>F″–H″</b>: Untreated group, n = 6, paired t-tests, p = 0.502, p = 0.690, p = 0.610). Scale bars: A–C = 100 µm (inset = 20 µm); D = 1 mm; E = 50 µm.</p

Aβ levels in TgCRND8 mice after one BAM-10/FUS treatment.

<p>Cortical homogenates were analyzed for total Aβ₄₀ (<b>A</b>), soluble Aβ₄₀ (<b>B</b>), total Aβ₄₂ (<b>C</b>) and soluble Aβ₄₂ (<b>D</b>). There was no significant difference detected any Aβ species and fractions between the left and right hemispheres.</p

Magnetic resonance imaging-guided focused ultrasound (MRIgFUS) increases the permeability of the blood brain barrier (BBB).

<p>T1-weighted contrast-enhanced MRI scans were used to position ultrasound foci prior to treatment (<b>A</b>) and following transcranial FUS (<b>B–D</b>), were used to monitor the entry of gadolinium in the brain. Mice were positioned in a supine position (<b>B</b>) and injected in the tail vein with microbubbles and gadolinium while ultrasound was applied to 4 aligned spots on the right hemisphere of the brain. Increased BBB permeability was monitored by MRI, visualizing contrast enhancement by the influx of gadolinium (<b>B–D</b>). [A–D: 128×128, TE/TR = 10.4/500.0, FOV = 4cm, Slice 1mm, ETL = 4, 3NEX]. Scale bars: A, C, D = 0.5 cm.</p

Community based complex interventions to sustain independence in older people: systematic review and network meta-analysis

To synthesise evidence of the effectiveness of community based complex interventions, grouped according to their intervention components, to sustain independence for older people. Systematic review and network meta-analysis. Medline, Embase, CINAHL, PsycINFO, CENTRAL, clinicaltrials.gov, and International Clinical Trials Registry Platform from inception to 9 August 2021 and reference lists of included studies. Randomised controlled trials or cluster randomised controlled trials with ≥24 weeks' follow-up studying community based complex interventions for sustaining independence in older people (mean age ≥65 years) living at home, with usual care, placebo, or another complex intervention as comparators. Living at home, activities of daily living (personal/instrumental), care home placement, and service/economic outcomes at 12 months. Interventions were grouped according to a specifically developed typology. Random effects network meta-analysis estimated comparative effects; Cochrane's revised tool (RoB 2) structured risk of bias assessment. Grading of recommendations assessment, development and evaluation (GRADE) network meta-analysis structured certainty assessment. The review included 129 studies (74 946 participants). Nineteen intervention components, including "multifactorial action from individualised care planning" (a process of multidomain assessment and management leading to tailored actions), were identified in 63 combinations. For living at home, compared with no intervention/placebo, evidence favoured multifactorial action from individualised care planning including medication review and regular follow-ups (routine review) (odds ratio 1.22, 95% confidence interval 0.93 to 1.59; moderate certainty); multifactorial action from individualised care planning including medication review without regular follow-ups (2.55, 0.61 to 10.60; low certainty); combined cognitive training, medication review, nutritional support, and exercise (1.93, 0.79 to 4.77; low certainty); and combined activities of daily living training, nutritional support, and exercise (1.79, 0.67 to 4.76; low certainty). Risk screening or the addition of education and self-management strategies to multifactorial action from individualised care planning and routine review with medication review may reduce odds of living at home. For instrumental activities of daily living, evidence favoured multifactorial action from individualised care planning and routine review with medication review (standardised mean difference 0.11, 95% confidence interval 0.00 to 0.21; moderate certainty). Two interventions may reduce instrumental activities of daily living: combined activities of daily living training, aids, and exercise; and combined activities of daily living training, aids, education, exercise, and multifactorial action from individualised care planning and routine review with medication review and self-management strategies. For personal activities of daily living, evidence favoured combined exercise, multifactorial action from individualised care planning, and routine review with medication review and self-management strategies (0.16, -0.51 to 0.82; low certainty). For homecare recipients, evidence favoured addition of multifactorial action from individualised care planning and routine review with medication review (0.60, 0.32 to 0.88; low certainty). High risk of bias and imprecise estimates meant that most evidence was low or very low certainty. Few studies contributed to each comparison, impeding evaluation of inconsistency and frailty. The intervention most likely to sustain independence is individualised care planning including medicines optimisation and regular follow-up reviews resulting in multifactorial action. Homecare recipients may particularly benefit from this intervention. Unexpectedly, some combinations may reduce independence. Further research is needed to investigate which combinations of interventions work best for different participants and contexts. PROSPERO CRD42019162195. [Abstract copyright: © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.