Chemical signatures delineate heterogeneous amyloid plaque populations across the Alzheimer's disease spectrum.

Amyloid plaque deposition is recognized as the primary pathological hallmark of Alzheimer's disease(AD) that precedes other pathological events and cognitive symptoms. Plaque pathology represents itself with an immense polymorphic variety comprising plaques with different stages of amyloid fibrillization ranging from diffuse to fibrillar, mature plaques. The association of polymorphic Aß plaque pathology with AD pathogenesis, clinical symptoms and disease progression remains unclear. Advanced chemical imaging tools, such as functional amyloid microscopy combined with MALDI mass spectrometry imaging (MSI), are now enhanced by deep learning algorithms. This integration allows for precise delineation of polymorphic plaque structures and detailed identification of their associated Aß compositions. We here set out to make use of these tools to interrogate heterogenic plaque types and their associated biochemical architecture. Our findings reveal distinct Aß signatures that differentiate diffuse plaques from fibrilized ones, with the latter showing substantially higher levels of Aßx-40. Notably, within the fibrilized category, we identified a distinct subtype known as coarse-grain plaques. Both in sAD and fAD brain tissue, coarse grain plaques contained more Aßx-40 and less Aßx-42 compared with cored plaques. The coarse grain plaques in both sAD and fAD also showed higher levels of neuritic content including paired helical filaments (PHF-1)/phosphorylated phospho Tau-immunopositive neurites. Finally, the Aß peptide content in coarse grain plaques resembled that of vascular Aß deposits (CAA) though with relatively higher levels of Aß1-42 and pyroglutamated Aßx-40 and Aßx-42 species in coarse grain plaques. This is the first of its kind study on spatial in situ biochemical characterization of different plaque morphotypes demonstrating the potential of the correlative imaging techniques used that further increase the understanding of heterogeneous AD pathology. Linking the biochemical characteristics of amyloid plaque polymorphisms with various AD etiologies and toxicity mechanisms is crucial. Understanding the connection between plaque structure and disease pathogenesis can enhance our insights. This knowledge is particularly valuable for developing and advancing novel, amyloid-targeting therapeutics.

CT-based volumetric measures obtained through deep learning: Association with biomarkers of neurodegeneration.

INTRODUCTION: Cranial computed tomography (CT) is an affordable and widely available imaging modality that is used to assess structural abnormalities, but not to quantify neurodegeneration. Previously we developed a deep-learning-based model that produced accurate and robust cranial CT tissue classification. MATERIALS AND METHODS: We analyzed 917 CT and 744 magnetic resonance (MR) scans from the Gothenburg H70 Birth Cohort, and 204 CT and 241 MR scans from participants of the Memory Clinic Cohort, Singapore. We tested associations between six CT-based volumetric measures (CTVMs) and existing clinical diagnoses, fluid and imaging biomarkers, and measures of cognition. RESULTS: CTVMs differentiated cognitively healthy individuals from dementia and prodromal dementia patients with high accuracy levels comparable to MR-based measures. CTVMs were significantly associated with measures of cognition and biochemical markers of neurodegeneration. DISCUSSION: These findings suggest the potential future use of CT-based volumetric measures as an informative first-line examination tool for neurodegenerative disease diagnostics after further validation. HIGHLIGHTS: Computed tomography (CT)-based volumetric measures can distinguish between patients with neurodegenerative disease and healthy controls, as well as between patients with prodromal dementia and controls. CT-based volumetric measures associate well with relevant cognitive, biochemical, and neuroimaging markers of neurodegenerative diseases. Model performance, in terms of brain tissue classification, was consistent across two cohorts of diverse nature. Intermodality agreement between our automated CT-based and established magnetic resonance (MR)-based image segmentations was stronger than the agreement between visual CT and MR imaging assessment.

Deep learning from MRI-derived labels enables automatic brain tissue classification on human brain CT.

Automatic methods for feature extraction, volumetry, and morphometric analysis in clinical neuroscience typically operate on images obtained with magnetic resonance (MR) imaging equipment. Although CT scans are less expensive to acquire and more widely available than MR scans, their application is currently limited to the visual assessment of brain integrity and the exclusion of co-pathologies. CT has rarely been used for tissue classification because the contrast between grey matter and white matter was considered insufficient. In this study, we propose an automatic method for segmenting grey matter (GM), white matter (WM), cerebrospinal fluid (CSF), and intracranial volume (ICV) from head CT images. A U-Net deep learning model was trained and validated on CT images with MRI-derived segmentation labels. We used data from 744 participants of the Gothenburg H70 Birth Cohort Studies for whom CT and T1-weighted MR images had been acquired on the same day. Our proposed model predicted brain tissue classes accurately from unseen CT images (Dice coefficients of 0.79, 0.82, 0.75, 0.93 and 0.98 for GM, WM, CSF, brain volume and ICV, respectively). To contextualize these results, we generated benchmarks based on established MR-based methods and intentional image degradation. Our findings demonstrate that CT-derived segmentations can be used to delineate and quantify brain tissues, opening new possibilities for the use of CT in clinical practice and research.

Comparison of Two-Dimensional- and Three-Dimensional-Based U-Net Architectures for Brain Tissue Classification in One-Dimensional Brain CT.

Brain tissue segmentation plays a crucial role in feature extraction, volumetric quantification, and morphometric analysis of brain scans. For the assessment of brain structure and integrity, CT is a non-invasive, cheaper, faster, and more widely available modality than MRI. However, the clinical application of CT is mostly limited to the visual assessment of brain integrity and exclusion of copathologies. We have previously developed two-dimensional (2D) deep learning-based segmentation networks that successfully classified brain tissue in head CT. Recently, deep learning-based MRI segmentation models successfully use patch-based three-dimensional (3D) segmentation networks. In this study, we aimed to develop patch-based 3D segmentation networks for CT brain tissue classification. Furthermore, we aimed to compare the performance of 2D- and 3D-based segmentation networks to perform brain tissue classification in anisotropic CT scans. For this purpose, we developed 2D and 3D U-Net-based deep learning models that were trained and validated on MR-derived segmentations from scans of 744 participants of the Gothenburg H70 Cohort with both CT and T1-weighted MRI scans acquired timely close to each other. Segmentation performance of both 2D and 3D models was evaluated on 234 unseen datasets using measures of distance, spatial similarity, and tissue volume. Single-task slice-wise processed 2D U-Nets performed better than multitask patch-based 3D U-Nets in CT brain tissue classification. These findings provide support to the use of 2D U-Nets to segment brain tissue in one-dimensional (1D) CT. This could increase the application of CT to detect brain abnormalities in clinical settings.

Imaging biomarkers in neurodegeneration: current and future practices.

There is an increasing role for biological markers (biomarkers) in the understanding and diagnosis of neurodegenerative disorders. The application of imaging biomarkers specifically for the in vivo investigation of neurodegenerative disorders has increased substantially over the past decades and continues to provide further benefits both to the diagnosis and understanding of these diseases. This review forms part of a series of articles which stem from the University College London/University of Gothenburg course "Biomarkers in neurodegenerative diseases". In this review, we focus on neuroimaging, specifically positron emission tomography (PET) and magnetic resonance imaging (MRI), giving an overview of the current established practices clinically and in research as well as new techniques being developed. We will also discuss the use of machine learning (ML) techniques within these fields to provide additional insights to early diagnosis and multimodal analysis.