Hippocampal volumetry is a critical biomarker of aging and dementia, and it is widely used as a predictor of cognitive performance; however, automated hippocampal segmentation methods are limited ...because the algorithms are (a) not publicly available, (b) subject to error with significant brain atrophy, cerebrovascular disease and lesions, and/or (c) computationally expensive or require parameter tuning. In this study, we trained a 3D convolutional neural network using 259 bilateral manually delineated segmentations collected from three studies, acquired at multiple sites on different scanners with variable protocols. Our training dataset consisted of elderly cases difficult to segment due to extensive atrophy, vascular disease, and lesions. Our algorithm, (HippMapp3r), was validated against four other publicly available state‐of‐the‐art techniques (HippoDeep, FreeSurfer, SBHV, volBrain, and FIRST). HippMapp3r outperformed the other techniques on all three metrics, generating an average Dice of 0.89 and a correlation coefficient of 0.95. It was two orders of magnitude faster than some of the tested techniques. Further validation was performed on 200 subjects from two other disease populations (frontotemporal dementia and vascular cognitive impairment), highlighting our method's low outlier rate. We finally tested the methods on real and simulated “clinical adversarial” cases to study their robustness to corrupt, low‐quality scans. The pipeline and models are available at: https://hippmapp3r.readthedocs.ioto facilitate the study of the hippocampus in large multisite studies.
Basal forebrain cholinergic neurons (BFCNs) regulate circuit dynamics underlying cognitive processing, including attention, memory, and cognitive flexibility. In Alzheimer’s disease and related ...neurodegenerative conditions, the degeneration of BFCNs has long been considered a key player in cognitive decline. The cholinergic system thus represents a key therapeutic target. A long-standing obstacle for the development of effective cholinergic-based therapies is not only the production of biologically active compounds but also a platform for safe and efficient drug delivery to the basal forebrain. The blood-brain barrier (BBB) presents a significant challenge for drug delivery to the brain, excluding approximately 98% of small-molecule biologics and nearly 100% of large-molecule therapeutic agents from entry into the brain parenchyma. Current modalities to achieve effective drug delivery to deep brain structures, such as the basal forebrain, are particularly limited. Direct intracranial injection via a needle or catheter carries risks associated with invasive neurosurgery. Intra-arterial injection of hyperosmotic solutions or therapeutics modified to penetrate the BBB using endogenous transport systems lack regional specificity, which may not always be desirable. Intranasal, intrathecal, and intraventricular administration have limited drug distribution beyond the brain surface. Here, we present a protocol for non-invasively, locally, and transiently increasing BBB permeability using MRI-guided focused ultrasound (MRIgFUS) in the murine basal forebrain for delivery of therapeutic agents targeting the cholinergic system. Ongoing work in preclinical models and clinical trials supports the safety and feasibility of MRIgFUS-mediated BBB modulation as a promising drug delivery modality for the treatment of debilitating neurological diseases.
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