The road ahead to successful BBB opening and drug-delivery with focused ultrasound.

This review delves into the innovative technology of Blood-Brain Barrier (BBB) opening with low-intensity focused ultrasound in combination with microbubbles (LIFU-MB), a promising therapeutic modality aimed at enhancing drug delivery to the central nervous system (CNS). The BBB's selective permeability, while crucial for neuroprotection, significantly hampers the efficacy of pharmacological treatments for CNS disorders. LIFU-MB emerges as a non-invasive, localized method to transiently increase BBB permeability, facilitating the delivery of therapeutic molecules. Here, we review the procedural stages of LIFU-MB interventions, including planning and preparation, sonication, evaluation, and delivery, highlighting the technological diversity and methodological challenges encountered in current clinical applications. With an emphasis on safety and efficacy, we discuss the crucial aspects of ultrasound delivery, microbubble administration, acoustic feedback monitoring and assessment of BBB permeability. Finally, we explore the critical choices for effective BBB opening with LIFU-MB, focusing on selecting therapeutic agents, optimizing delivery methods, and timing for delivery. Overcoming existing barriers to integrate this technology into clinical practice could potentially revolutionize CNS drug delivery and treatment paradigms in the near future.

Longitudinal assessment of social cognition in de novo Parkinson's disease patients and its relationship with dopaminergic innervation.

BACKGROUND: Social Cognition (SC) has been scarcely studied in Parkinson's disease (PD), and findings in early disease are controversial. SC encompasses different capacities such as facial emotion recognition (FER); Theory of Mind (ToM), the ability to understand other people's intentions (cognitive-ToM) and emotions (affective-ToM); and self-monitoring, the ability to regulate one's own behavior in social contexts. A relationship between dopaminergic deficit and SC in PD has been suggested. OBJECTIVES: To prospectively assess, over a two-year period, SC in newly diagnosed drug-naïve, cognitively normal and non-depressed PD patients. Furthermore, we aimed to evaluate the relationship between SC and Fluorodopa (Positron Emission Tomography) Ki uptake, which is a marker of dopaminergic depletion. METHODS: We compared SC performance between 25 de novo PD patients and 20 healthy controls (HC), and within-patients at baseline and two-year follow-up. The SC assessment included FER, ToM, as well as self-monitoring measures. The relationship between SC and dopaminergic innervation was also assessed in patients. RESULTS: SC scores did not differ between PD and HC groups at baseline, nor between baseline and follow-up evaluation in PD. A significant positive correlation between self-monitoring and Fluorodopa Ki uptake in the left pallidum in PD patients was found at baseline. At follow-up, ToM (stories) positively correlated with Fluorodopa Ki uptake in the right thalamus and the left putamen. CONCLUSION: SC appears to be preserved in de novo PD and remains stable in the short-term. Although more evidence is needed, our results support a relationship between dopamine innervation in subcortical regions and SC.

Brain hypometabolism in non-demented microtubule-associated protein tau H1 carriers with Parkinson's disease.

BACKGROUND AND PURPOSE: The microtubule-associated protein tau (MAPT) H1 homozygosity (H1/H1 haplotype) is a genetic risk factor for neurodegenerative diseases, such as Parkinson's disease (PD). MAPT H1 homozygosity has been associated with conversion to PD; however, results are conflicting since some studies did not find a strong influence. Cortical hypometabolism is associated with cognitive impairment in PD. In this study, we aimed to evaluate the metabolic pattern in nondemented PD patients MAPT H1/H1 carriers in comparison with MAPT H1/H2 haplotype. In addition, we evaluated domain-specific cognitive differences according to MAPT haplotype. METHODS: We compared a group of 26 H1/H1 and 20 H1/H2 carriers with late-onset PD. Participants underwent a comprehensive neuropsychological cognitive evaluation and a [18F]-Fluorodeoxyglucose PET-MR scan. RESULTS: MAPT H1/H1 carriers showed worse performance in the digit span forward test of attention compared to MAPT H1/H2 carriers. In the [18F]-Fluorodeoxyglucose PET comparisons, MAPT H1/H1 displayed hypometabolism in the frontal cortex, parahippocampal, and cingulate gyrus, as well as in the caudate and globus pallidus. CONCLUSION: PD patients MAPT H1/H1 carriers without dementia exhibit relative hypometabolism in several cortical areas as well as in the basal ganglia, and worse performance in attention than MAPT H1/H2 carriers. Longitudinal studies should assess if lower scores in attention and dysfunction in these areas are predictors of dementia in MAPT H1/H1 homozygotes.

Lesion 3D modeling in transcranial MR-guided focused ultrasound thalamotomy.

Transcranial magnetic resonance-guided focused ultrasound (tMRgFUS) allows to perform incisionless thermoablation of deep brain structures. This feature makes it a very useful tool for the treatment of multiple neurological and psychiatric disorders. Currently, feedback of the thermoablation process is based on peak temperature readings assessed on real-time two-dimensional MRI thermometry. However, an accurate methodology relating thermal dosimetry with three-dimensional topography and temporal evolution of the lesion is still to be defined, thus hurdling the establishment of well-defined, evidence-based criteria to perform safe and effective treatments. In here we propose threshold-based thermoablation models to predict the volumetric topography of the lesion (whole lesion and necrotic core) in the short-to-mid-term based on thermal dosimetry estimated from intra-treatment MRI thermometry. To define and validate our models we retrospectively analyzed the data of sixty-three tMRgFUS thalamotomies for treating tremor. We used intra-treatment MRI thermometry to estimate whole-treatment three-dimensional thermal dose maps, defined either as peak temperature reached (Tmax) or thermal isoeffective dose (TID). Those maps were thresholded to find the dosimetric level that maximize the agreement (Sorensen-Dice coefficient - SDc) with the boundaries of the whole lesion and its core, assessed on T2w images 1-day (post-24h) and 3-months (post-3M) after treatment. Best predictions were achieved for the whole lesion at post-24h (SDc = 0.71), with Tmax /TID over 50.0 °C/90.5 CEM43. The core at post-24h and whole lesion at post-3M lesions reported a similar behavior in terms of shape accuracy (SDc ~0.35), and thermal dose thresholds ~55 °C/4100.0 CEM43. Finally, the optimal levels for post-3M core lesions were 55.5 °C/5800.0 CEM43 (SDc = 0.21). These thermoablation models could contribute to the real-time decision-making process and improve the outcome of tMRgFUS interventions both in terms of safety and efficacy.

MultiRBE: Treatment planning for protons with selective radiobiological effectiveness.

PURPOSE: Clinical treatment planning protocols for protons recommend a uniform value radiobiological effectiveness (RBE) of protons of 1.1 throughout the treatment field, despite evidence from in-vitro and animal studies that proton RBE increases with linear energy transfer (LET), causing tissues placed distally to the target location to receive a presumably higher biological dose than estimated. While several voices in the medical physics community have advocated for variable RBE-based optimization, the uncertainties in RBE models have prevented its implementation in clinical practice, since an overestimation of RBE could cause significant target underdosage. METHODS: We propose a mixed RBE model (MultiRBE), where a uniform RBE is used in the target contours to ensure an adequate tumor coverage in terms of physical dose, but a variable RBE is used elsewhere. Our model was implemented in the open-source treatment planning system matRad and three example cases were planned: a homogeneous phantom, a prostate tumor and a head-and-neck case. MultiRBE was used for plan optimization, and the produced plans were subsequently evaluated in terms of physical dose coverage (V95% ) and variable RBE-weighted dose in organs at risk and normal tissue complication probabilities (NTCP), where prediction models were available. RESULTS: The planning algorithm showed potential for reducing the biological dose in organs surrounding the planning target and thus decreasing the probability for complications in normal tissue (by up to 62% in the prostate case and 37% in the head-and-neck patient). This was achieved without compromising the target coverage or homogeneity in terms of physical dose, as a result of a smarter redistribution of dose among the surrounding tissues with regard to the optimization constraints. CONCLUSIONS: The results prove the ability of the MultiRBE model to reduce biological dose at healthy tissues without compromising the dose coverage of the tumor, with independence of the variable RBE models used.