Biology subjects

Greve, D.

Publications and source records attributed to Greve, D..

5 recordsLinked to original sources

bioRxiv2025

Reshaping the progranulin/sortilin interaction for targeted degradation of extracellular proteins

Targeted protein degradation (TPD) using PROteolysis TArgeting Chimeras (PROTACs) is a rapidly emerging therapeutic strategy for difficult-to-drug cytosolic proteins. PROTACs are heterobifunctional small molecules that bridge the target with an E3 ubiquitin ligase, destining it for degradation by the proteasome. They have the potential to be orally available and to act catalytically, switching the pharmacology from occupancy-driven to event-driven (1-3). Here we present a strategy for targeted degradation of extracellular proteins by reshaping the interaction between the broadly expressed lysosome sorting receptor sortilin and its ligand progranulin for engineering SORtilin-based lysosome TArgeting Chimeras (SORTACs). SORTACs induce ternary complex formation with the target and sortilin, followed by endocytosis and lysosomal degradation. SORTAC activity can be genetically encoded as demonstrated by converting an IgG binding nanobody to an IgG degrading nanobody or by chemical conjugation, enabling single step conversion of therapeutic antibodies from binding their target to driving its degradation. Importantly, using structure-based design, we generated small molecule SORTACs against the inflammatory cytokine TNFa with nanomolar range potency and with physicochemical properties like PROTACs. Our results demonstrate that SORTACs constitute a versatile and highly modular platform for rapid generation of degraders of in theory any extracellular target and with the potential to have wide impact in drug discovery.

biochemistry↗

bioRxiv2021

Using diffusion MRI data acquired with ultra-high gradients to improve tractography in routine-quality data

The development of scanners with ultra-high gradients, spearheaded by the Human Connectome Project, has led to dramatic improvements in the spatial, angular, and diffusion resolution that is feasible for in vivo diffusion MRI acquisitions. The improved quality of the data can be exploited to achieve higher accuracy in the inference of both microstructural and macrostructural anatomy. However, such high-quality data can only be acquired on a handful of Connectom MRI scanners worldwide, while remaining prohibitive in clinical settings because of the constraints imposed by hardware and scanning time. In this study, we first update the classical protocols for tractography-based, manual annotation of major white-matter pathways, to adapt them to the much greater volume and variability of the streamlines that can be produced from todays state-of-the-art diffusion MRI data. We then use these protocols to annotate 42 major pathways manually in data from a Connectom scanner. Finally, we show that, when we use these manually annotated pathways as training data for global probabilistic tractography with anatomical neighborhood priors, we can perform highly accurate, automated reconstruction of the same pathways in much lower-quality, more widely available diffusion MRI data. The outcomes of this work include both a new, comprehensive atlas of WM pathways from Connectom data, and an updated version of our tractography toolbox, TRActs Constrained by UnderLying Anatomy (TRACULA), which is trained on data from this atlas. Both the atlas and TRACULA are distributed publicly as part of FreeSurfer. We present the first comprehensive comparison of TRACULA to the more conventional, multi-region-of-interest approach to automated tractography, and the first demonstration of training TRACULA on high-quality, Connectom data to benefit studies that use more modest acquisition protocols.

neuroscience↗

bioRxiv2020

Reliability and sensitivity of two whole-brain segmentation approaches included in FreeSurfer - ASEG and SAMSEG

An accurate and reliable whole-brain segmentation is a key aspect of longitudinal neuroimaging studies. The ability to measure structural changes reliably is fundamental to detect confidently biological effects, especially when these affects are small. In this work, we undertake a thorough comparative analysis of reliability, bias, sensitivity to detect longitudinal change and diagnostic sensitivity to Alzheimers disease of two subcortical segmentation methods, Automatic Segmentation (ASEG) and Sequence Adaptive Multimodal Segmentation (SAMSEG). These are provided by the recently released version 7.1 of the open-source neuroimaging package FreeSurfer, with ASEG being the default segmentation method. First, we use a large sample of participants (n = 1629) distributed across the lifespan (age range = 4-93 years) to assess the within-session test-retest reliability in eight bilateral subcortical structures: amygdala, caudate, hippocampus, lateral ventricles, nucleus accumbens, pallidum, putamen and thalamus. We performed the analyses separately for a sub-sample scanned on a 1.5T Siemens Avanto (n = 774) and a sub-sample scanned on a 3T Siemens Skyra (n = 855). The absolute symmetrized percent differences across the lifespan indicated relatively constant reliability trajectories across age except for the younger children in the Avanto dataset for ASEG. Although both methods showed high reliability (ICC > 0.95), SAMSEG yielded significantly lower volumetric differences between repeated measures for all subcortical segmentations (p < 0.05) and higher spatial overlap in all structures except putamen, which had significantly higher spatial overlap for ASEG. Second, we tested how well each method was able to detect neuroanatomic volumetric change using longitudinal follow up scans (n = 491 for Avanto and n = 245 for Skyra; interscan interval = 1-10 years). Both methods showed excellent ability to detect longitudinal change, but yielded age-trajectories with notable differences for most structures, including the hippocampus and the amygdala. For instance, ASEG hippocampal volumes showed a steady age-decline from subjects in their twenties, while SAMSEG hippocampal volumes were stable until their sixties. Finally, we tested sensitivity of each method to clinically relevant change. We compared annual rate of hippocampal atrophy in a group of cognitively normal older adults (n = 20), patients with mild cognitive impairment (n = 20) and patients with Alzheimers disease (n = 20). SAMSEG was more sensitive to detect differences in atrophy between the groups, demonstrating ability to detect clinically relevant longitudinal changes. Both ASEG and SAMSEG were reliable and led to detection of within-person longitudinal change. However, SAMSEG yielded more consistent measurements between repeated scans without a lack of sensitivity to changes.

neuroscience↗

bioRxiv2018

Age-differences in functional asymmetry during memory retrieval revisited: no evidence for contralateral over-activation or compensation

Brain asymmetry is inherent to cognitive processing and seems to reflect processing efficiency. Lower frontal asymmetry is often observed in older adults during memory retrieval, yet it is unclear whether lower asymmetry implies an age-related increase in contralateral recruitment, whether less asymmetry reflects compensation, is limited to frontal regions, or predicts neurocognitive stability or decline. We assessed age-differences in asymmetry across the entire cerebral cortex, using fMRI data from 89 young and 76 older adults during successful retrieval, and surface-based methods that allowed direct homotopic comparison of activity between hemispheres. An extensive left-asymmetric network facilitated retrieval in both young and older adults, whereas diverse frontal and parietal regions exhibited lower asymmetry in older adults. However, lower asymmetry was not associated with age-related increases in contralateral recruitment, but primarily reflected either less deactivation in contralateral regions reliably signalling retrieval failure in the young, or lower recruitment of the dominant hemisphere--suggesting that functional deficits may drive lower asymmetry in older brains, not compensatory activity. Lower asymmetry neither predicted current memory performance, nor the extent of memory change across the preceding [~]8 years in older adults. Together, these findings are inconsistent with a compensation account for lower asymmetry during retrieval and aging.

neuroscience↗

bioRxiv2018

Accurate Nonlinear Mapping between MNI Volumetric and FreeSurfer Surface Coordinate Systems

The results of most neuroimaging studies are reported in volumetric (e.g., MNI152) or surface (e.g., fsaverage) coordinate systems. Accurate mappings between volumetric and surface coordinate systems can facilitate many applications, such as projecting fMRI group analyses from MNI152/Colin27 to fsaverage for visualization, or projecting resting-state fMRI parcellations from fsaverage to MNI152/Colin27 for volumetric analysis of new data. However, there has been surprisingly little research on this topic. Here, we evaluated three approaches for mapping data between MNI152/Colin27 and fsaverage coordinate systems by simulating the above applications: projection of group-average data from MNI152/Colin27 to fsaverage and projection of fsaverage parcellations to MNI152/Colin27. Two of the approaches are currently widely used. A third approach (registration fusion) was previously proposed, but not widely adopted. Two implementations of the registration fusion (RF) approach were considered, with one implementation utilizing the Advanced Normalization Tools (ANTs). We found that RF-ANTs performed the best for mapping between fsaverage and MNI152/Colin27, even for new subjects registered to MNI152/Colin27 using a different software tool (FSL FNIRT). This suggests that RF-ANTs would be useful even for researchers not using ANTs. Finally, it is worth emphasizing that the most optimal approach for mapping data to a coordinate system (e.g., fsaverage) is to register individual subjects directly to the coordinate system, rather than via another coordinate system. Only in scenarios where the optimal approach is not possible (e.g., mapping previously published results from MNI152 to fsaverage), should the approaches evaluated in this manuscript be considered. In these scenarios, we recommend RF-ANTs (https://github.com/ThomasYeoLab/CBIG/tree/master/stable_projects/registration/Wu2017_RegistrationFusion).

neuroscience↗