Biology subjects

Vialle, R.

Publications and source records attributed to Vialle, R..

3 recordsLinked to original sources

bioRxiv2025

Characterizing Post-Mortem Brain Molecular Taxonomy of Cognitive Resilience and Translating it to Living Humans

Here, we define cognitive resilience as slower or faster cognitive decline after we regress out the effects of common brain neuropathologies. Its understanding could provide important insights into the biology underlying cognitive health, enabling the development of more effective strategies to prevent cognitive decline and dementia. However, this requires the development of a practical method to quantify resilience and measure it in living individuals, as well as identifying heterogenous pathways associated with resilience in different individuals. Here, we approach this problem by using a data-driven framework to quantify and characterize molecular signatures underlying cognitive resilience. Using multimodal contrastive trajectory inference (mcTI) on bulk RNA sequencing and tandem mass tag (TMT) proteomic data from 898 post- mortem brain samples from the Religious Orders Study and the Rush Memory and Aging Project (ROSMAP), we derived individual-level molecular pseudotime values reflecting the molecular path from high to low resilience across individuals. Additionally, we identified two distinct molecular subtypes of resilience, each characterized by unique transcriptomic and proteomic signatures, and differing associations with several phenotypes. To translate our brain-derived pseudotime and subtypes to living individuals, we developed prediction models with paired genetics, ante-mortem blood omics, clinical, psychosocial, imaging and device data from the same individuals, demonstrating the potential to predict brain molecular resilience profiles in living persons. Our findings establish a framework for quantifying resilience based on multi- level molecular signatures, identify molecularly distinct resilience subtypes, and demonstrate the feasibility of translating brain-derived molecular profiles to living individuals--laying the groundwork for the development of targeted resilience-promoting interventions in cognitive aging.

neuroscience↗

bioRxiv2025

Systemic Factors Affect Bone Health in SMA Type II Patients and a Mouse Model of SMA

Spinal muscular atrophy (SMA) is a rare developmental disorder affecting multiple tissues. Among the non-central nervous system tissues implicated in SMA is the skeletal system, including bone and cartilage. Low bone mineral density, increased numbers of fractures of the long bones and vertebra, hip pain, and scoliosis have been reported across the spectrum of SMA patients. While lack of ambulation likely contributes significantly to bone pathology, SMA patients have markedly lower bone density compared to other non-ambulatory patients with debilitating diseases such as Duchenne muscular dystrophy, suggesting that there is a cell-intrinsic contribution of SMN to bone homeostasis and function. Mouse models of SMA have also confirmed the presence of bone and cartilage phenotypes. These alterations frequently persist post-treatment. Recent advancements in therapeutic strategies, approved by both the FDA and the EMA, have represented a leap forward in the management of SMA. However, treatment gaps remain. Post-treatment, patients frequently face continued challenges with scoliosis, bone fractures, and persistent muscle weakness--conditions that underscore the urgent need for more comprehensive therapeutic strategies with combination therapies that can support skeletal health. To date, no molecular map exists of the changes that occur in SMA patient bone and cartilage, impeding the ability of finding targeted therapies. To address this clinical need, we profiled the transcriptome of the vertebral bone and cartilage in a cohort of 11 Type II SMA patients who were undergoing surgery for scoliosis correction and compared them to 7 idiopathic scoliosis and 2 DMD controls. Additionally, we characterized the skeletal health of a mouse model of type I SMA. We find that multisystemic factors including liver and muscle health affect the underlying SMA bone pathology. Specifically, we detect alterations in the balance between osteoclasts and osteoblasts, changes in PPAR{gamma} signaling, mitochondrial oxidative phosphorylation and fatty acid beta-oxidation, and alterations in the muscle-derived factor Irisin that play a role in overall SMA bone pathology.

genomics↗

bioRxiv2023

The human microglia responsome: a resource to better understand microglia states in health and disease

Microglia, the immune cells of the brain, are increasingly implicated in neurodegenerative disorders through genetic studies. However, how genetic risk factors for these diseases are related to microglial gene expression, microglial function, and ultimately disease, is still largely unknown. Microglia change rapidly in response to alterations in their cellular environment, which is regulated through changes in transcriptional programs, which are as yet poorly understood. Here, we compared the effects of a set of inflammatory and restorative stimuli (lipopolysaccharide, interferon-gamma, resiquimod, tumor necrosis factor-alpha, adenosine triphosphate, dexamethasone, and interleukin-4) on human microglial cells from 67 different donors (N = 398 samples) at the gene and transcript level. We show that microglia from different anatomical brain regions show distinct responses to inflammatory stimuli. We observed a greater overlap between human stimulated microglia and human monocytes than with mouse microglia. We define specific microglial signatures across conditions which are highly relevant for a wide range of biological functions and complex human diseases. Finally, we used our stimulation signatures to interpret associations from Alzheimers disease (AD) genetic studies and microglia by integrating our inflammatory gene expression profiles with common genetic variants to map cis-expression QTLs (eQTLs). Together, we provide the most comprehensive transcriptomic database of the human microglia responsome. HighlightsO_LIRNA-sequencing of 398 human microglial samples exposed to six different triggers. C_LIO_LIMicroglia from different anatomical regions show distinct stimulation responses. C_LIO_LIResponses in human microglia show a greater overlap with human monocytes than murine microglia. C_LIO_LIMapping of response Quantitative Trait Loci identifies interactions between genotype and effect of stimulation on gene expression. C_LIO_LIOur atlas provides a reference map for interpreting microglia signatures in health and disease. C_LI

neuroscience↗