Biology subjects

Hock, C.

Publications and source records attributed to Hock, C..

At least 19 recordsLinked to original sources

bioRxiv2026

Peripheral T-cell co-signalling states mark vulnerability and resilience to cerebral Aβ pathology

Adaptive immune responses may influence vulnerability and resilience in Alzheimers disease (AD), but relevant T-cell states remain unclear. We profiled peripheral immune cells by mass cytometry in 200 participants across distinct age groups, early AD and exceptional old age without dementia, relating immune features to amyloid-{beta} (A{beta}) PET, plasma biomarkers and longitudinal structural and cognitive outcomes. Inducible T-cell co-stimulator (ICOS) expression across CD4 and CD8 memory T-cells was associated with cerebral A{beta} pathology. In mild cognitive impairment (MCI), higher ICOS expression on CD8 memory T-cells strengthened the association between A{beta} load and hippocampal atrophy. A{beta}-derived peptides induced proliferative ICOS+CD25+ memory CD4 and CD8 T-cell responses predominantly in A{beta}-positive participants in an independent cohort. Conversely, higher programmed cell death protein 1 (PD-1) expression on CD8 effector-memory T-cells was associated with attenuated A{beta}-related episodic-memory decline in exceptionally old participants and was higher in stable MCI than in MCI-to-AD converters. These findings identify distinct co-stimulatory and co-inhibitory T-cell correlates of vulnerability and resilience.

immunology↗

bioRxiv2026

High Resolution Multi-Pass Astral Analyzer Quantification Enables Highly Multiplexed 35-Plex Tandem Mass Tag Proteomics

Tandem mass tags (TMT) allow highly multiplexed and thus high-throughput, precisely quantitative proteomic analysis. Incorporation of additional deuterated reporter channels has near-doubled the multiplexation achieved with Thermo Scientific TMTpro reagents from 18 to 35-plex but requires extremely high [~]100k analyzer resolving power at m/z 128 to differentiate and quantify reporter ion channels, far beyond any single reflection time-of-flight analyzer, and exceeding the multi-reflection Thermo Scientific Astral analyzer in its standard operation. A multi-pass mode of Astral operation has been developed for the Thermo Scientific Orbitrap Astral Zoom mass spectrometer that triples the ion path to 90 m, more than doubling resolving power for a narrow m/z range. This "TMT HR mode" has been integrated into a new method of TMT proteomic analysis that splits regular MS2 analysis of labeled peptides into paired measurements comprising wide mass range scans for peptide identification, and TMT HR mode scans for reporter ion quantification. The method has been shown to accurately quantify 32-plex labeled HeLa protein lysate and provide far greater depth of analysis as state-of-the-art Orbitrap-only methods, while analysis of 11-plex labeled yeast showed no analytical depth sacrificed vs regular Orbitrap Astral TMT analysis. Further comparative measurements of a 2-cell line 35-plex sample demonstrated greater analytical depth, and similar quantitative precision, to "gold standard" Orbitrap MS3 methods.

biochemistry↗

bioRxiv2025

Enhanced ex vivo 3D whole-brain mapping and automated analysis of Parkinson's disease pathologies in mice

The spatiotemporal relationships among -synuclein inclusion formation, dopaminergic degeneration, and white matter microstructural changes remain poorly defined. To address this, we unilaterally injected preformed fibrils (PFFs) or monomeric -synuclein into the substantia nigra pars compacta (SNc) of wild-type mice. At 12 and 20 weeks post-injection (wpi), we performed ex vivo magnetic resonance imaging (MRI) at 9.4T to assess microstructural, volumetric and paramagnetic changes, along with light-sheet microscopy (LSM) to map -synuclein aggregates, and dopaminergic neuron at single-cell resolution across the whole brain. We developed a Python-based, automated registration pipeline that achieves <40 {micro}m alignment error between ex vivo MRI and LSM and computes clearing-induced distortion, enabling scalable deformation analysis and multimodal multiscale data integration. Unilateral SNc injection of -syn PFFs induced dense phospho--syn pathology in the ipsilateral SNc at 12 wpi, which decreased by 20 wpi in parallel with the loss of tyrosine hydroxylase-positive dopaminergic neuron. Pathogenic -synuclein spreads along with dopaminergic denervation in the nigrostriatal pathway to the ipsilateral striatum and contralateral SNc. Our ex vivo MRI-LSM platform provides a scalable, open-source framework for understanding circuit-level and whole-brain propagation of pathology in an -synucleinopathy model and beyond. HighlightsO_LIOpen-source, automated pipeline aligns ex vivo 9.4T MRI with light-sheet microscopy (LSM) at <40 {micro}m error, quantifies clearing-induced tissue distortion, and enables multiscale, whole-brain multimodal analysis. C_LIO_LIWhole-brain, single-cell-resolution mapping of -synuclein pathology and dopaminergic neuron loss in an -synucleinopathy mouse model using an optimized iDISCO+ protocol that achieves uniform antibody penetration even in dense regions like the striatum. C_LIO_LIUnilateral SNc injection of -syn PFFs drives spread of p--syn pathology along the nigrostriatal pathway to the ipsilateral striatum, BST, CEA, and contralateral SNc, along with dopaminergic degeneration. C_LIO_LIIpsilateral SNc shows high pS129 pathology at 12 weeks post-injection but significant reduction by 20 wpi, concurrent with loss of tyrosine hydroxylase-positive neurons. C_LIO_LIMultiparametric MRI reveals microstructural and iron-related alterations in striatum, SNc, and VTA, with cross-modal correlations linking pS129 burden, TH loss, and magnetic susceptibility changes. C_LI

neuroscience↗

bioRxiv2025

Higher-Throughput Proteome Profiling Enabled by Parallelized Pre-Accumulation and Optimized Ion Processing in the Orbitrap Astral Zoom Mass Spectrometer

High-throughput proteomics is critical for understanding biological processes, enabling large-scale studies such as biomarker discovery and systems biology. However, current mass spectrometry technologies face limitations in speed, sensitivity, and scalability for analyzing large sample cohorts. The Thermo Scientific Orbitrap Astral Zoom mass spectrometer (MS) was developed to address these limitations by improving acquisition speed, ion utilization, and spectral processing, which are all essential for advancing proteome depth in high-throughput proteomics. The Orbitrap Astral Zoom MS achieves ultra-fast MS/MS scan rates of up to 270 Hz with enhanced ion utilization through pre-accumulation, enabling the identification of [~]100,000 unique peptides and >8,400 proteins in a single 300 samples-per-day (SPD) analysis of human cell lysate. The optimized system reduces analysis time by 40%, achieves near-complete proteome coverage (>12,000 proteins) in 2.7 hours, and enables ultra-high-throughput workflows, identifying >7,000 proteins in a 500 SPD method with exceptional reproducibility (Pairwise Pearson correlations >0.99). These advancements establish the Orbitrap Astral Zoom MS as a new benchmark in proteomics, significantly enhancing speed, sensitivity, and scalability, paving the way for routine large-scale proteome studies with applications in clinical research and systems biology. TeaserHigh-Speed Human Proteome Analysis using the Orbitrap Astral Zoom Mass Spectrometer

biochemistry↗

bioRxiv2025

Evaluation of an Orbitrap Astral Zoom mass spectrometer prototype for quantitative proteomics - beyond identification lists

Mass spectrometry instrumentation continues to evolve rapidly yet quantifying these advances beyond conventional peptide and protein detections remain challenging. Here, we evaluate a modified Orbitrap Astral Zoom mass spectrometer (MS) prototype and compare its performance to the standard Orbitrap Astral MS. Across a range of acquisition methods and sample inputs, the prototype instrument outperformed the standard Orbitrap Astral MS in precursor and protein identifications, ion beam utilization, and quantitative precision. To enable meaningful cross-platform comparisons, we implemented an ion calibration framework that converts signal intensity from arbitrary units to ion per second. This benchmarking strategy showed that the prototype sampled 30% more ions per peptide than the original Orbitrap Astral MS. This increase in the ion beam utilization resulted in improved sensitivity and quantitative precision. To make these metrics broadly accessible, we added new metrics to the Skyline document grid to report the number of ions measured in a spectrum at the apex of the elution peak or the sum of ions between the peak integration boundaries. Taken together, our results demonstrate the prototype Orbitrap Astral Zoom as a high-performance platform for DIA proteomics and establish a generalizable framework for evaluation of mass spectrometer performance based on the number of ions detected for each analyte. Data are available on Panorama Public and on ProteomeXchange under the identifier PXD064536.

biochemistry↗

bioRxiv2025

Reduced levels of synaptic vesicle protein 2A in the extracellular vesicles and brain of Alzheimer's disease- associations with Aβ, tau and synaptophysin

BackgroundSynaptic dysfunction plays an important role in Alzheimers disease (AD) and is an emerging imaging and fluid biomarker. Here, we aimed to assess the regional expression of synaptic vesicle glycoprotein 2A (SV2A) in the brain and extracellular vesicles of AD patients and its associations with the APOE {varepsilon}4 allele, amyloid-{beta}, tau pathologies, and other synaptic markers. MethodsMass spectrometry-based synaptosome proteomics was performed on brain-derived extracellular vesicles (BdEVs) isolated from the frontal cortex of 17 AD patients and 4 NCs. Immunohistochemical staining for SV2A, synaptophysin, amyloid-{beta} and phospho-tau was performed on postmortem tissue from the frontal, temporal, and entorhinal cortices and hippocampus of 40 AD patients and 44 nondemented controls (NCs). ResultsReduced levels of synaptic proteins, including synaptotagamin, GAP43, SYT1, SNAP25 and 14-3-3{zeta}, were positively correlated with SV2A and negatively correlated with GFAP and NEFL in BdEVs from AD patients and NCs. We detected lower levels of SV2A in the hippocampus and entorhinal cortex of AD compard to NCs, and in APOE {varepsilon}4 carriers than in noncarriers. SV2A levels were positively correlated with synaptophysin and negatively correlated with the levels of the amyloid-{beta}, phospho-tau, and Braak stages. ConclusionsThis study provides postmortem evidence of synaptic markers and reduced regional levels of SV2A in brain tissue slices and BdEVs from AD patients compared with NCs and in APOE {varepsilon}4 carriers compared to non-carriers. SV2A could serve as a valuable marker for monitoring synaptic degeneration in AD.

neuroscience↗

bioRxiv2024

Quantitative Label-Free Single-Cell Proteomics on the Orbitrap Astral MS

Single-cell proteomics by mass spectrometry (scp-MS) holds the potential to provide unprecedented insights into molecular features directly linked to the cellular phenotype, while deconvoluting complex organisms into their basic building blocks. Tailored sample preparation that maximizes the extracted amount of material that is introduced into the mass spectrometer has rapidly propelled the field forward. However, the measured signal is still at the lower edge of detection approaching the sensitivity boundary of current instrumentation. Here, we investigate the capacity of the enhanced sensitivity of the Orbitrap Astral mass spectrometer to facilitate deeper proteome profiles from low-input to single-cell samples. We carry out a comprehensive data acquisition method survey to pinpoint which parameters provide most sensitivity. Furthermore, we explore the quantitative accuracy of the obtained measurements to ensure that the obtained abundances are in line with expected ground truth values. We culminate our technical exploration by generating small datasets from two cultured cell lines and a primary bone marrow sample, to showcase obtainable proteome coverage differences from different source materials. Finally, as a proof of concept we explore protein covariation to showcase how information on known protein complexes is captured inherently in our scp-MS data.

biochemistry↗

bioRxiv2024

Altered T cell reactivity to β-amyloid-related antigens in early Alzheimer's disease

There is growing evidence that the adaptive immune system and neurodegenerative Alzheimers disease (AD) are intertwined in multiple ways. Recent studies have reported alterations of the adaptive immune system in early AD stages, such as preclinical AD and mild cognitive impairment (MCI) due to AD. However, the identity of specific antigenic targets and whether the respective response is beneficial or detrimental during disease progression are still open questions. Herein, we describe cross-sectional analyses of blood and cerebrospinal fluid from three different study populations covering early AD stages. We employed high-dimensional mass cytometry, single-cell RNA-sequencing, in vitro T cell secretome analysis, and antigen presentation assays to achieve a comprehensive characterization of adaptive immune cell populations. Our results show that subjects at the stage of asymptomatic, preclinical AD can mount a CD4+ T helper cell response towards {beta}- amyloid peptide and display an early enrichment of cytotoxic CD8+ effector/TEMRA cells in CSF, combined with a less immunosuppressive gene signature of peripheral regulatory T cells. Conversely, in MCI due to AD, we observed increased frequencies of CD8+ effector/TEMRA cells in the periphery, characterized by a pro-inflammatory gene expression profile and an overall decrease in antigen responsiveness. Our results demonstrate the complexity of adaptive immune changes in early AD and suggest that it may be beneficial in the preclinical stage to promote specific CD4+ T cell responses, while in MCI it may be important to therapeutically target CD8+ T cell responses if these prove to be harmful.

immunology↗

bioRxiv2024

Hippocampal mGluR5 levels are comparable in Alzheimer's and control brains, and divergently influenced by amyloid and tau in control brain

BackgroundMetabotropic glutamate receptor 5 (mGluR5) modulates excitatory glutamatergic synaptic transmission and plays an important role in learning and memory formation and in neurodegeneration and amyloid deposition in Alzheimers disease (AD). Conflicting results on the cerebral mGluR5 levels in AD have been reported based on in vivo and postmortem studies. Here, we aimed to assess alterations in hippocampal mGluR5 expression in AD, and the associations between mGluR5 expression and pathologies. MethodsImmunofluorescence staining for mGluR5 was performed on postmortem brain tissue from 34 AD patients and 31 nondemented controls (NCs) and from aged 3xTg and arcA{beta} model mice of AD. Autoradiography was performed on brain tissue slices from arcA{beta} mice using mGluR5 tracer [18F]PSS232. Analysis of different cellular source of GRM5 RNA in human and mouse brains was performed. Proteomic profiling and pathway analysis were performed on hippocampal tissue from aged 3xTg mice and wild-type mice. ResultsNo differences in hippocampal mGluR5 expression or entorhinal cortical GRM5 RNA levels were detected between the AD and NC groups. Hippocampal mGluR5 levels increased with Braak stage and decreased with amyloid level in the NC group. No correlations were detected between the levels of mGluR5 and amyloid, tau, or Iba1/P2X7R in the hippocampus of AD patients and NC cases. Ex vivo autoradiography revealed comparable cerebral levels of [18F]PSS232 in arcA{beta} mice compared to nontransgenic mice. GO and KEGG pathway enrichment analyses revealed that the Shank3, Grm5 and glutamatergic pathways were upregulated in hippocampal tissue from aged 3xTg mice compared to wild-type mice. ConclusionThis study revealed no difference in hippocampal mGluR5 levels between AD patients and NCs and revealed the divergent influence of amyloid and tau pathologies on hippocampal mGluR5 levels in NCs. Species differences were observed in the GRM5 RNA level as well as at the cellular location. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/595868v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@17c69aorg.highwire.dtl.DTLVardef@efbaf9org.highwire.dtl.DTLVardef@dc3c2corg.highwire.dtl.DTLVardef@f27038_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Spinal cord perfusion impairments in the M83 mouse model of Parkinson's disease

Metabolism and bioenergetics in the central nervous system play important roles in the pathophysiology of Parkinsons disease (PD). Here, we employed a multimodal imaging approach to assess oxygenation changes in the spinal cord of a transgenic M83 murine model of PD in comparison to non-transgenic littermates at 9-12 months-of-age. A lower oxygen saturation (SO2)SVOT was detected in vivo with spiral volumetric optoacoustic tomography (SVOT) in the spinal cord of M83 mice compared to non-transgenic littermate mice. Ex-vivo high-field T1-weighted magnetic resonance imaging (MRI) and immunostaining for alpha-synuclein (phospho-S129) and vascular organisation (CD31 and GLUT1) were used to investigate the nature of the abnormalities detected via in vivo imaging. Ex-vivo analysis showed that the vascular network in the spinal cord was not impaired in the spinal cord of M83 mice. Ex-vivo MRI assisted with deep learning-based automatic segmentation showed no volumetric atrophy in the spinal cord of M83 mice compared to non-transgenic littermates, whereas nuclear alpha-synuclein phosphorylated at Ser129 site could be linked to early pathology and metabolic dysfunction. The proposed and validated non-invasive high-resolution imaging tool to study oxygen saturation in the spinal cord of PD mice holds promise for assessing early changes preceding motor deficits in PD mice.

neuroscience↗

bioRxiv2024

Hippocampal purinergic P2X7 receptor level is increased in Alzheimer's disease patients, and associated with amyloid and tau pathologies

INTRODUCTIONThe purinergic receptor P2X7R, which is expressed on microglia and astrocytes, plays an important role in Alzheimers disease (AD). We aimed to characterize the alterations in P2X7R expression in AD patients by APOE {varepsilon}4 allele, age and sex, as well as its association with amyloid and tau pathology. METHODSP2X7R staining and quantitative analysis of amyloid, tau, astrocytes and microglia were performed on postmortem hippocampal tissues from 35 AD patients; 31 nondemented controls; caudate/putamen tissue from corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) patients; and bran tissue from aged 3xTg mouse model of AD. RESULTSActivated microglia and reactive astrocytes were observed in the hippocampi of AD patients and exhibited altered morphology with denser cells and pronounced ramifications. Hippocampal P2X7R intensity was greater in the hippocampal subfields of AD patients than in those of nondemented controls and was correlated with amyloid level and Braak stage and was not affected by sex, APOE{varepsilon}4 allele, or age. P2X7R expression increased around A{beta} plaques, cerebral amyloid angiopathy, tau inclusions in the hippocampus from AD patients and tau inclusions in the caudate/putamen from CBD and PSP patients. DISCUSSIONWe found an increased hippocampal P2X7R level in AD compared to non-demented control, which correlated with amyloid and tau pathologies. P2X7R is a potential marker for neuroinflammation in AD.

neuroscience↗

bioRxiv2023

One-Hour Phosphoproteome Analysis with the Orbitrap Astral Mass Spectrometer

Owing to its roles in cellular signal transduction, protein phosphorylation plays critical roles in myriad cell processes. That said, detecting and quantifying protein phosphorylation has remained a challenge. We describe the use of a novel mass spectrometer (Orbitrap Astral) coupled with data-independent acquisition (DIA) to achieve rapid and deep analysis of human and mouse phosphoproteomes. With this method we map approximately 30,000 unique human phosphorylation sites within a half-hour of data collection. The technology was benchmarked to other state-of-the-art MS platforms using both synthetic peptide standards and with EGF-stimulated HeLa cells. We applied this approach to generate a phosphoproteome multi-tissue atlas of the mouse. Altogether, we detected 81,120 unique phosphorylation sites within 12 hours of measurement. With this unique dataset, we examine the sequence, structural, and kinase specificity context of protein phosphorylation. Finally, we highlight the discovery potential of this resource with multiple examples of novel phosphorylation events relevant to mitochondrial and brain biology.

systems biology↗

bioRxiv2023

Evaluating the capabilities of the Astral mass analyzer for single-cell proteomics

The complexity of human physiology arises from well-orchestrated interactions between trillions of single cells in the body. While single-cell RNA sequencing (scRNA-seq) has enhanced our understanding of cell diversity, gene expression alone does not fully characterize cell phenotypes. Additional molecular dimensions, such as proteins, are needed to define cellular states accurately. Mass spectrometry (MS)-based proteomics has emerged as a powerful tool for comprehensive protein analysis, including single-cell applications. However, challenges remain in terms of throughput and proteomic depth, in order to maximize the biological impact of single-cell proteomics by Mass Spectrometry (scp-MS) workflows. This study leverages a novel high-resolution, accurate mass (HRAM) instrument platform, consisting of both an Orbitrap and an innovative HRAM Asymmetric Track Lossless (Astral) analyzer. The Astral analyzer offers high sensitivity and resolution through lossless ion transfer and a unique flight track design. We evaluate the performance of the Thermo Scientific Orbitrap Astral MS using Data-Independent Acquisition (DIA) and assess proteome depth and quantitative precision for ultra-low input samples. Optimal DIA method parameters for single-cell proteomics are identified, and we demonstrate the ability of the instrument to study cell cycle dynamics in Human Embryonic Kidney (HEK293) cells, and cancer cell heterogeneity in a primary Acute Myeloid Leukemia (AML) culture model.

systems biology↗

bioRxiv2023

Narrow-window DIA: Ultra-fast quantitative analysis of comprehensive proteomes with high sequencing depth

Mass spectrometry (MS)-based proteomics aims to characterize comprehensive proteomes in a fast and reproducible manner. Here, we present an ultra-fast scanning data-independent acquisition (DIA) strategy consisting on 2-Th precursor isolation windows, dissolving the differences between data-dependent and independent methods. This is achieved by pairing a Quadrupole Orbitrap mass spectrometer with the asymmetric track lossless (Astral) analyzer that provides >200 Hz MS/MS scanning speed, high resolving power and sensitivity, as well as low ppm-mass accuracy. Narrow-window DIA enables profiling of up to 100 full yeast proteomes per day, or [~]10,000 human proteins in half-an-hour. Moreover, multi-shot acquisition of fractionated samples allows comprehensive coverage of human proteomes in [~]3h, showing comparable depth to next-generation RNA sequencing and with 10x higher throughput compared to current state-of-the-art MS. High quantitative precision and accuracy is demonstrated with high peptide coverage in a 3-species proteome mixture, quantifying 14,000+ proteins in a single run in half-an-hour. TeaserAccurate and precise label-free quantification with comprehensive proteome coverage using narrow-window DIA

systems biology↗

bioRxiv2023

Parallelized Acquisition of Orbitrap and Astral Analyzers Enables High-Throughput Quantitative Analysis.

The growing trend towards high-throughput proteomics demands rapid liquid chromatography-mass spectrometry (LC-MS) cycles that limit the available time to gather the large numbers of MS/MS fragmentation spectra required for identification. Orbitrap analyzers scale performance with acquisition time, and necessarily sacrifice sensitivity and resolving power to deliver higher acquisition rates. We developed a new mass spectrometer that combines a mass resolving quadrupole, the Orbitrap and the novel Asymmetric Track Lossless (Astral) analyzer. The new hybrid instrument enables faster acquisition of high-resolution accurate mass (HRAM) MS/MS spectra compared to state-of-the-art mass spectrometers. Accordingly, new proteomics methods were developed that leverage the strengths of each HRAM analyzer, whereby the Orbitrap analyzer performs full scans with high dynamic range and resolution, synchronized with Astral analyzers acquisition of fast and sensitive HRAM MS/MS scans. Substantial improvements are demonstrated over previous methods using current state-of-the-art mass spectrometers. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/543408v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@1eedfdeorg.highwire.dtl.DTLVardef@1ab7939org.highwire.dtl.DTLVardef@a3b2f8org.highwire.dtl.DTLVardef@13ac46b_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2023

Evaluating the performance of the Astral mass analyzer for quantitative proteomics using data independent acquisition

We evaluate the quantitative performance of the newly released Asymmetric Track Lossless (Astral) analyzer. Using data independent acquisition, the Thermo Scientific Orbitrap Astral mass spectrometer quantifies 5 times more peptides per unit time than state-of-the-art Thermo Scientific Orbitrap mass spectrometers, which have long been the gold standard for high resolution quantitative proteomics. Our results demonstrate that the Orbitrap Astral mass spectrometer can produce high quality quantitative measurements across a wide dynamic range. We also use a newly developed extra-cellular vesicle enrichment protocol to reach new depths of coverage in the plasma proteome, quantifying over 5,000 plasma proteins in a 60-minute gradient with the Orbitrap Astral mass spectrometer.

biochemistry↗

bioRxiv2023

Analysis of skull thickness, scalp-to-cortex distance and association with age and sex in cognitively normal elderly

Personalized neurostimulation has been a potential treatment for many brain diseases, which requires insights into brain/skull geometry. Here, we developed an open source efficient pipeline BrainCalculator for automatically computing the skull thickness map, scalp-to-cortex distance (SCD), and brain volume based on T1-weighted magnetic resonance imaging (MRI) data. We examined the influence of age and sex cross-sectionally in 407 cognitively normal older adults (71.9{+/-}8.0 years, 60.2% female) from the ADNI. We demonstrated the compatibility of our pipeline with commonly used preprocessing packages and found that BrainSuite Skullfinder was better suited for such automatic analysis compared to FSL Brain Extraction Tool 2 and SPM12- based unified segmentation using ground truth. We found that the sphenoid bone and temporal bone were thinnest among the skull regions in both females and males. There was no increase in regional minimum skull thickness with age except in the female sphenoid bone. No sex difference in minimum skull thickness or SCD was observed. Positive correlations between age and SCD were observed, faster in females (0.307%/y) than males (0.216%/y) in temporal SCD. A negative correlation was observed between age and whole brain volume computed based on brain surface (females -1.031%/y, males -0.998%/y). In conclusion, we developed an automatic pipeline for MR-based skull thickness map, SCD, and brain volume analysis and demonstrated the sex-dependent association between minimum regional skull thickness, SCD and brain volume with age. This pipeline might be useful for personalized neurostimulation planning.

neuroscience↗

bioRxiv2023

Early beta-amyloid accumulation in the brain is associated with peripheral T cell alterations

Fast and minimally invasive approaches for early, preclinical diagnosis of neurodegenerative Alzheimers disease (AD) are highly anticipated. Evidence of adaptive immune cells responding to cerebral {beta}-amyloidosis, one of the pathological hallmarks of AD, has raised the question of whether immune markers could be used as proxies for {beta}-amyloid accumulation in the brain. Here, we deploy multidimensional mass cytometry combined with unbiased machine learning techniques to immunophenotype peripheral blood mononuclear cells from study participants in cross-sectional and longitudinal cohorts. We show that increases in antigen-experienced adaptive immune cells in the blood, particularly CD45RA-reactivated T effector memory (TEMRA) cells, are associated with early accumulation of brain {beta}-amyloid and with changes in plasma AD biomarkers in still cognitively healthy subjects. Our results suggest that preclinical AD pathology is linked to systemic alterations of the adaptive immune system. These immunophenotype changes may help in the future to identify and develop novel diagnostic tools for early AD assessment and to better understand clinical outcomes.

immunology↗