bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2024.09.27.615424

A Water Relaxation Atlas for Age and Region specific Metabolite Concentration Correction

Simegn, G. L.·Song, y.·Murali-Manohar, S.·Zollner, H. J.·Davies-Jenkins, C. W.·Simicic, D.·Hupfeld, K. E.·Gudmundson, A. T.·Musaka, E.·Carter, E.·Hui, S. C. N.·Yedavalli, V.·Oeltzschner, G. C. N.·Dean, D. C.·Ceritoglu, C.·Ratnanather, T.·Porges, E.·Edden, R.
View original source ↗Export metadata ↓

Abstract

Metabolite concentration estimates from Magnetic Resonance Spectroscopy (MRS) are typically quantified using water referencing, correcting for relaxation-time differences between metabolites and water. One common approach is to correct the water reference signal for differential relaxation within three tissue compartments (gray matter, white matter, and cerebrospinal fluid) using fixed literature values. However, water relaxation times (T1 and T2) vary between brain locations, in pathology, and with age. MRS studies, even those measuring metabolite levels across the lifespan, often ignore these effects, because of a lack of reference data. The purpose of this study is to develop a water relaxometry atlas and to integrate location- and age-appropriate relaxation values into the MRS analysis workflow. 101 volunteers (51 men, 50 women; [~]10 male and 10 female participants per decade (from the 20s to 60s), were recruited. T1-weighted MPRAGE images ((1-mm)3 isotropic resolution) were acquired. Whole-brain water T1 and T2 measurements were made with DESPOT ((1.4 mm)3 isotropic resolution). T1 and T2 maps were registered to the JHU MNI-SS/EVE atlas using affine and LDDMM transformation. The atlass 268 parcels were reduced to 130 by combining homologous parcels. Mean T1 and T2 values were calculated for each parcel in each subject. Linear models of T1 and T2 as functions of age were computed, using age - 30 as the predictor. Reference atlases of "age-30-intercept" and age-slope for T1 and T2 were generated. The atlas-based workflow was integrated into Osprey, which co-registers MRS voxels to the atlas and calculates location- and age-appropriate water relaxation parameters for quantification. The water relaxation aging atlas revealed significant regional and tissue differences in water relaxation behavior across adulthood. Using location- and subject-appropriate reference values in the MRS analysis workflow removes a current methodological limitation and is expected to reduce quantification biases associated with water-referenced tissue correction, especially for studies of aging.

Explore related subjects

neurosciencePreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Simegn, G. L., Song, y., Murali-Manohar, S., Zollner, H. J., Davies-Jenkins, C. W., Simicic, D., Hupfeld, K. E., Gudmundson, A. T., Musaka, E., Carter, E., Hui, S. C. N., Yedavalli, V., Oeltzschner, G. C. N., Dean, D. C., Ceritoglu, C., Ratnanather, T., Porges, E., Edden, R.. 2024-09-30. A Water Relaxation Atlas for Age and Region specific Metabolite Concentration Correction. https://doi.org/10.1101/2024.09.27.615424

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

The Unreasonable Effectiveness of Cell Types in Describing Neuronal Physiological Features

Single-cell RNA sequencing (scRNA-seq) captures detailed gene expression profiles at scale, while patch-clamp recordings measure intrinsic neuronal electrophysiological properties. Modeling the relations between these two modalities remains a challenge. Here, we compare how well electrophysiological features can be predicted by traditional transcriptomic cell type classification, representations derived from a foundational model (scGPT) pretrained on large-scale scRNA-seq datasets, ion channel-coding genes, and highly variable genes. Using paired transcriptomic and electrophysiological patch-sequencing data from 495 human neurons from neurosurgical tissue, we find that cluster-level cell type representations consistently outperform highly variable gene selection, ion channel gene selection, and context-enriched scGPT embeddings. Notably, performance varies across model architectures and initializations, and the best results are obtained by combining the outputs of separate cell type and scGPT-based models. Together, these findings suggest that traditional discrete cellular classification is highly effective in predicting physiological features. For maximum performance it can be complemented by pretrained transformer models.

neuroscience↗
bioRxiv2026

A nonlinear inhibition pathway underlying cortical responses to tuned holographic optogenetic perturbations

Optogenetics enables causal manipulation of cortical activity. Perturbation responses can be counterintuitive due to network interactions, making theory essential for predicting them. Existing approaches often rely on linear approximations, which fail for many biologically relevant perturbations. Here we develop a nonlinear theory of responses to holographic perturbations in cell-type-specific recurrent networks with structured connectivity. We fit a nonlinear model to mouse V1 data, which shows cotuned-ensemble suppression: perturbing spatially clustered neurons with similar preferred orientations yields markedly stronger short-range suppression than perturbing untuned ensembles. We show that cotuned-ensemble suppression arises from a feature-tuned, nonlinear inhibition pathway implicating somatostatin-positive (SST) interneurons. The theory predicts that cotuned ensembles suppress parvalbumin-positive (PV) neurons but facilitate SST neurons, and links the degree of cotuned-ensemble suppression or facilitation to the variance of the SST response. This framework identifies mechanisms by which nonlinear inhibition sculpts cortical dynamics and establishes a predictive basis for targeted optogenetic interventions.

neuroscience↗
bioRxiv2026

Proteomic signatures of APOE ε4 across human tissues and cell types in Alzheimers disease

The apolipoprotein E {varepsilon}4 (APOE {varepsilon}4) allele is the strongest genetic risk factor for late-onset Alzheimers disease (AD). However, the underlying molecular mechanisms remain unclear. This study included 1691 participants from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP), 1226 participants from the Accelerating Medicines Partnership - Alzheimers Disease (AMP-AD) Diverse Cohorts Study, and 735 participants from the Alzheimers Disease Neuroimaging Initiative (ADNI). To characterise APOE {varepsilon}4 molecular effects, we analysed proteomic data from plasma, cerebrospinal fluid (CSF), and induced pluripotent stem cell (iPSC)-derived astrocytes and neurons, as well as transcriptomic and proteomic data from multiple brain regions. The association of APOE {varepsilon}4 with AD neuropathology was also examined. APOE {varepsilon}4 carriers shared a plasma proteomic signature enriched for immune processes, irrespective of AD diagnosis. A machine learning classifier trained on this signature discriminated APOE {varepsilon}4 carriers from non-carriers in an independent cohort using CSF proteomics. APOE {varepsilon}4 carriage was associated with higher Braak stages and Consortium to Establish a Registry for Alzheimers Disease (CERAD) score. However, only limited APOE {varepsilon}4-associated transcriptomic and proteomic changes were observed in bulk brain tissue, with poor cross-layer concordance. Proteomic analyses of iPSC-derived astrocytes and neurons further revealed cell-type-specific APOE {varepsilon}4-associated changes. APOE {varepsilon}4 is associated with a consistent proteomic signature across plasma and CSF. Its molecular effects in the brain differ across cell types, brain regions and molecular layers. These findings support the need for cell-type-resolved multi-omic studies to elucidate how APOE {varepsilon}4 confers AD risk.

neuroscience↗