Biology subjects

Gomez, J.

Publications and source records attributed to Gomez, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Crystalline silica exposure causes latent biomechanical abnormalities along the cardiopulmonary axis

Rationale Crystalline silica exposure is a major global health burden linked to chronic lung disease and cardiopulmonary morbidity, but early lung-vascular-cardiac abnormalities preceding overt functional decline are poorly defined. Objectives To determine whether a single crystalline silica exposure produces subclinical abnormalities across the integrated axis of cardiopulmonary response (lung[->]pulmonary artery[->]right ventricle) and identify associated sex-dependent physiologic patterns and molecular programs. Methods Male and female mice received a single endotracheal instillation of crystalline silica or vehicle (saline). At 28 days, assessments included voluntary wheel running, diffusion capacity, pulmonary function testing, bronchoalveolar lavage analysis, lung histology and electron microscopy, ex vivo proximal pulmonary artery biomechanics and microstructural second harmonic generation imaging, right ventricular pressure, transthoracic echocardiography, and bulk RNA sequencing of lung and right ventricle. Results Despite recovery of body weight and preserved voluntary exercise, silica-exposed mice demonstrated reduced diffusion capacity, ultrastructural thickening, and disruption of the alveolar-capillary barrier. Bronchoalveolar lavage revealed persistent inflammation with elevated macrophages, lymphocytes, neutrophils, and protein, alongside retained particulate and surfactant-rich debris (silicoproteinosis). Lung mechanics were sex-dependent; females showed a parenchymal-dominant phenotype and males showed increased airway resistance. Elevated pulmonary circulatory pressures caused increased functional stiffness and reduced distensibility of the proximal pulmonary arteries. Right ventricular free wall thickening was noted in females. Lung transcriptomics indicated persistent immune activation and extracellular matrix remodeling, while the right ventricle demonstrated metabolic reprogramming with downregulation of structural and reparative programs. Conclusions A single crystalline silica exposure induces a subclinical, multi-compartment cardiopulmonary phenotype characterized by persistent alveolar-capillary injury, pulmonary vascular stiffening, increased right ventricular afterload, sex-dependent pulmonary mechanics, and divergent organ-level transcriptomic responses.

physiology↗

bioRxiv2026

A cold-adapted Cas9 nuclease from the deep ocean

The abundance of CRISPR systems in bacteria and archaea fuels the search for Cas nucleases that perform where established enzymes fail. Deep Ocean 1 Cas9 (DO1Cas9) is to our knowledge the first Cas9 nuclease characterized from the deep ocean, recovered from a metagenomic sample at 1,500 m depth in the Atlantic Ocean. DO1Cas9 shows cold-adapted structural flexibility, thermal susceptibility, salt-dependent stability, higher specificity than SpCas9 and cleaves double-stranded DNA efficiently under cold conditions where mesophilic SpCas9 retains only residual activity. DO1Cas9 edits genomes in diverse organisms such as Caenorhabditis elegans, zebrafish, the marine tunicate Oikopleura dioica, and the malaria parasite Plasmodium falciparum. In the marine bacterium Marinomonas mediterranea, DO1Cas9 programmed against an invading phage reduced plaquing efficiency about 10-fold more than SpCas9. These results expand the CRISPR-Cas9 toolbox with a nuclease for cold-chain editing and marine biotechnology.

genetics↗

bioRxiv2026

Sulcal pleating captures functional boundaries in human visual cortex

The folding of the cortical sheet within the human brain is related to its functional organization at the level of major sulci and gyri. Yet how smaller folding features hidden within the two thirds of cortex buried in sulci may relate to functional specialization of the cortex is not clear. Using human visual cortex as a test bed, we identify four hidden brain folds within the major sulcus which spans the dorsal visual stream and demonstrate that their spatial consistency across individuals is related to functional boundaries of visual cortex. In separate observation and replication participant groups, we combine structural and functional magnetic resonance imaging to show that the boundaries separating the visual field maps comprising the dorsal stream can be predicted from these hidden gyri with an accuracy matching current probabilistic definitions of visual cortex. By further demonstrating that these hidden gyri colocalize with cytoarchitectonic regions of the human brain, and that the variability in their shape and size correlates with individual differences in visual behaviors known to rely on the dorsal stream, we provide evidence for a novel neuroanatomic framework which suggests that mesoscale pleating patterns of the cortex within human sulci are functionally and behaviorally relevant.

neuroscience↗

bioRxiv2026

Dorsal visual stream development improves symmetry of receptive field coverage and spatial attention

The dorsal visual stream is a large retinotopic network in human visual cortex, involved in attentional and spatial aspects of vision critical for attending to, filtering, and interacting with the visual environment. The visual field maps which comprise the dorsal stream have not been characterized across development; a fundamental gap in human neuroscience given this pathways role in critical childhood behaviors. Here, we designed a gamified task to retinotopically map the dorsal stream in both adults and children for the first time. We found that the dorsal representations of visual space undergo protracted development, increasing the area over which they pool information across the visual field. Children show an asymmetry in the way that receptive fields of each cerebral hemisphere tile visual space, with protracted development predominantly in the right hemisphere serving to balance coverage across the left and right sides of space. This divergence between the hemispheres developmental trajectories has behavioral relevance, with individual variability in visuospatial attention biases correlating with receptive field properties from childhood into adulthood.

neuroscience↗

bioRxiv2026

Non-uniform structural development across human thalamus aligns with risk zones for schizophrenia in adulthood

With dense axonal connectivity to every region of cortex, the thalamus plays a central role in the nervous system from sensory processing to cognitive functions. Yet how tissue maturation of the thalamus unfolds during childhood and contributes to typical or atypical development is not clear. Through several large datasets, we provide here a thalamic portrait of fine-scale structural development whose nuclei develop along unique trajectories, some of which diverge from predictions of developmental theory. We find that those thalamic nuclei which show the most protracted development are at the greatest risk for later clinical differences in schizophrenia. The spatial pattern across thalamic nuclei for early psychosis risk is associated with a unique neuroreceptor fingerprint with implications for symptom severity.

neuroscience↗

bioRxiv2026

Deafness and sign language experience shift visual category representations

Childhood visual experiences shape our ability to rapidly recognize faces and objects. Across development, regions processing visual categories that lose relevance, such as hands, are recycled for others. How would visual cortex accommodate a childhood in which hands maintain significance? Through functional magnetic resonance imaging, we demonstrate that high-level visual cortex in Deaf signers develops a unique topography to accommodate the learning of sign language in childhood, with distinct but significant changes observed in hearing signers who acquired sign language in adulthood. These data suggest a new framework for human visual cortex in which the location of regions is not as fixed as once thought, and sociolinguistic experience outside the childhood plasticity period may be sufficient to alter the function of high-level visual cortex.

neuroscience↗

bioRxiv2026

Spatial and Molecular Progression of Neural Progenitor Cells in the Developing Human Dentate Gyrus

The large diversity of neuronal and glial cell types in the human brain is underpinned by foundational cell populations known as neural progenitor cells (NPCs). The dentate gyrus (DG) of the hippocampus, a key structure in learning and memory, maintains a tightly organized NPC population into adulthood across many mammalian species. However, the emergence, organization and persistence of NPCs in the human hippocampus remain poorly characterized. Reports of NPCs in the juvenile, adult, and aged periods have been variable, reflecting differences in identification criteria and highlighting the need for a unified framework across development. In this study, we provide a spatial and molecular map of the developmental trajectory of NPCs in the human DG, combining multimodal transcriptomic analysis within a neuroanatomical context. At mid-gestation, we observed changes in the structural and cellular arrangement of the hippocampus, coinciding with the emergence of a multicellular NPC layer within the DG, herein named the granular-hilar progenitor zone (GHPZ). Neurogenic transcriptomic signatures in the GHPZ were diminished by early infancy, coinciding with a reduction in NPC number as they progressed toward an astrocytic program. At childhood, the GHPZ dissolved with only sparse radial NPCs remaining in the DG. Lastly, we validated WNT signaling pathway-associated genes as NPC identity markers in the developing human DG, observing a decline in their expression after infancy. Our study defines the steep decline of NPCs from gestation to the postnatal period, identifies their progression to an astrocytic nature, and sets the molecular blueprint for NPC identification in the human DG. HighlightsO_LIMultimodal mapping of neural progenitor cells from gestational to postnatal stages in the human hippocampus C_LIO_LIFormation of the granular-hilar progenitor zone within the dentate gyrus at mid-gestation C_LIO_LINeurogenic potential declines sharply from the prenatal period to childhood, with radial glia cells progressively acquiring astrocytic features C_LIO_LIDevelopmental modulation of the WNT signaling pathway accompanies radial glia cell transitions C_LI

neuroscience↗

bioRxiv2026

FBH1 and RAD54L directly interact and cooperate to drive replication fork reversal

Replication fork reversal alleviates DNA replication stress and maintains genome stability. We previously showed that FBH1 and RAD54L cooperate to promote fork reversal in human cells, and that FBH1-dependent fork reversal requires the branch migration activity of RAD54L. However, the molecular basis of this cooperation remained unclear. Here, we identify both a physical and functional interaction between FBH1 and RAD54L. We demonstrate that purified FBH1 and RAD54L interact directly and form a complex at stalled replication forks in cells. Mapping studies revealed that RAD54L Lobe 1 is critical for interaction with the FBH1 2B subdomain. In cells, FBH1-RAD54L complex formation is enhanced in the absence of RAD51. Consistently, purified RAD54L displays a stronger affinity for RAD51 than for FBH1. Using biochemical reconstitution assays, we further show that FBH1 and RAD54L promote fork reversal more efficiently together than either protein alone, with maximal reversal observed when FBH1 acts before RAD54L. Collectively, our findings establish RAD54L as an essential functional partner of FBH1 in replication fork reversal and provide mechanistic insight into the sequential coordination of their activities.

cell biology↗

bioRxiv2026

Comparative Evaluation of Adeno-Associated Virus and Lentivirus Mediated Gene Transfer in Adult Rat Optic Nerve

BackgroundThe optic nerve serves as a vital conduit for visual signaling, and its degeneration in optic neuropathy results in irreversible vision loss. It is also a widely used model for studying central nervous system (CNS) injury and repair. Although adeno-associated virus (AAV) and lentivirus are extensively applied in CNS research, their transduction efficiency and cell-type specificity within the optic nerve remain poorly characterized. This study aimed to identify the most effective viral vector, serotype, and promoter for direct gene delivery to the adult rat optic nerve. MethodsSprague-Dawley rats (7-10 weeks) received intra-optic nerve injections of lentiviral or AAV vectors encoding GFP under different promoters (CAG, CMV, or GFAP). Two to three weeks post-injection, optic nerves were collected for immunohistochemistry with markers of oligodendrocytes (Olig2), astrocytes (GFAP, Sox9), and microglia (IBA1). Transduction efficiency and cell-type specificity were assessed using confocal microscopy. ResultsAAV2, AAV5, and lentivirus showed minimal transduction, with only sparse GFP-positive cells observed near injection sites. In contrast, AAV-PHP.eB carrying the CAG promoter yielded robust and widespread GFP expression near the injection site. Quantitative analysis revealed that approximately 90% of transduced cells were Olig2-positive oligodendrocytes, indicating strong tropism for this glial population. ConclusionAAV-PHP.eB driven by the CAG promoter enables efficient gene delivery to the optic nerve, with a predominant tropism for oligodendrocytes. This targeted intra-optic nerve injection approach offers a reliable platform for manipulating oligodendrocytes and investigating mechanisms of CNS development, injury, and repair relevant to both optic neuropathies and other CNS diseases.

neuroscience↗

bioRxiv2026

Protracted functional and structural reorganization of human prefrontal cortex supports lateralized category geometries

Despite being visually responsive, how prefrontal cortex represents visual categories across development and how this compares to posterior visual cortex remains unknown. Here, we show that ventrolateral prefrontal cortex (VLPFC) follows a fundamentally distinct developmental trajectory. Using functional and quantitative MRI in children and adults, we demonstrate that VLPFC exhibits reliable and structured category-selective responses in childhood that undergo prolonged reorganization into mature, hemisphere-specific representational geometries. Right VLPFC progressively organizes categories along an animate-inanimate axis, while left VLPFC consolidates a word-selective organization, a lateralization that strengthens across development. This restructuring contrasts sharply with ventral temporal cortex (VTC), which exhibits bilaterally organized, adult-like category structure in childhood. Critically, prefrontal representational structure emerges in alignment with conserved folding patterns of the precentral and inferior frontal sulci, suggesting that cortical anatomy provides a stable scaffold for the maturation of abstract representations. Quantitative MRI further reveals a non-linear trajectory of tissue development in right VLPFC, marked by adolescent reductions in macromolecular content and increased microstructural heterogeneity in adulthood, a pattern not observed in VTC. Together, these findings demonstrate that VLPFC undergoes prolonged, anatomically constrained refinement of category-related geometry characterized by hemisphere-specific taxonomies, rather than simply inheriting representational structure from sensory cortex. O_LIUnlike VTC (which shows early, bilateral, and stable category organization), VLPFC contains reliable, category-selective representations from childhood that undergo prolonged, hemisphere-specific developmental refinement rather than simple amplification C_LIO_LIRight VLPFC progressively consolidates an animate-inanimate representational axis across development, while left VLPFC establishes an early, stable word-selective organization consistent with language network maturation C_LIO_LIFunctional boundaries in VLPFC align with conserved intrasulcal folding motifs (plis de passage), demonstrating that anatomical scaffolding of category-selective responses extends beyond sensory cortex to prefrontal association cortex C_LIO_LIRight VLPFC undergoes adolescent pruning of cortical tissue microstructure diverging sharply from the continuous tissue proliferation observed in ventral temporal cortex C_LI

neuroscience↗

bioRxiv2026

Prolonged development of tonotopic tuning in human auditory cortex

Audition is a fundamental sense, underlying critical human behaviors such as communication and recognition. Despite its importance, how the tuning and organization of receptive fields mature from childhood to adulthood in auditory cortex has not been directly measured. Through a gamified neuroimaging approach using functional MRI, we model population receptive field (pRF) tuning for frequency across human auditory cortex in both children and adults. In the same participants, we behaviorally quantify detection thresholds for different frequencies embedded in noise to understand how the functional development of human auditory cortex drives behavior. We find that while the tonotopic organization of pRFs is qualitatively present in early childhood, there is a protracted increase in the representation of low frequencies in tonotopic maps of primary auditory cortex. This maturation of pRF tuning appears to drive basic auditory behaviors, correlating with tone detection thresholds across participants. We also observe protracted development in secondary auditory regions, offering evidence for an anatomically-predictable tonotopic map posterior to Heschls Gyrus. These data provide a new avenue for studying the development of audition in the human brain and lay important groundwork for understanding atypical development in auditory processing disorders.

neuroscience↗

bioRxiv2026

Diet modulates metabolic and hepatic responses to chronic pesticide mixture exposure in mice

Chronic exposure to pesticide mixtures through diet is common, yet their combined metabolic effects and interactions with dietary factors remain unclear. We identified four pesticides prevalent in human exposure (imazalil, thiabendazole, boscalid, lambda-cyhalothrin) and assessed their combined impacts on hepatic metabolism and metabolic homeostasis using human liver cells and male mice fed standard chow or western diets. We found that the pesticide mixture induced metabolic perturbations in human hepatocytes. In addition, the pesticide mixture altered hepatic gene expression in chow-fed mice and exacerbated western diet-induced glucose intolerance, fasting hyperglycemia, and insulin resistance without affecting body weight or liver steatosis. These findings reveal that dietary context influences the metabolic consequences of pesticide mixtures, highlighting the need to consider nutritional status when evaluating environmental contaminant risks. Our results suggest that pesticide mixtures at reference doses may contribute to metabolic dysregulation, particularly under obesogenic dietary conditions. Highlights- Four common pesticides in mixture disrupt metabolism in liver cells - Dietary exposure to this pesticide mixture alters hepatic gene expression in mice - The pesticide mixture exacerbates WD-induced disruptions in glucose homeostasis - Pesticides and diet interact in producing the metabolic effects of a pesticide mixture

pharmacology and toxicology↗

bioRxiv2025

Staphylococcus aureus urease is controlled by a complex regulatory network and promotes dissemination during catheter-associated urinary tract infections (CAUTI)

Catheter-associated urinary tract infections (CAUTIs) are one of the most common hospital-associated infections in the United States, accounting for >1 million cases annually. One CAUTI-associated pathogen, Staphylococcus aureus, is commonly found persisting asymptomatically in the bladder of catheterized individuals, increasing these individuals risk of developing CAUTI. Importantly, S. aureus is not only associated with severe symptoms, including bacteremia and septic shock, but it also produces a common uropathogen associated virulence factor, urease. Despite its importance, urease has only been well-studied in the uropathogen Proteus mirabilis. While previous studies identified three S. aureus urease regulators, CodY, CcpA, and Agr, the environmental signals required for expression and activity, and the contribution of urease to CAUTI have not been explored. In this study, we investigate how the urease regulatory pathways coordinate expression and activity in response to environmental signals present within the catheterized urinary tract. Our findings demonstrate that stationary phase significantly induces S. aureus urease expression and activity. Additionally, we identified predicted binding sites in the urease promoter for three regulators previously implicated in urease expression - CodY, CcpA, and SigB - as well as SrrA - a previously unrecognized regulator of urease. A binding site for Agr was not present in the urease promoter. Expression and activity assays confirm the role of CodY, CcpA, SigB, SrrA, and Agr in regulating urease. Importantly, single nucleotide polymorphisms identified in the urease promoter of clinical isolates enhance urease expression. Additionally, urease promotes biofilm formation under catheterized urinary tract-like conditions in vitro and dissemination from the bladder to the kidneys at 1 day post infection in a mouse CAUTI model. Together, our data not only provide insight into the regulatory pathway controlling S. aureus urease but also emphasize the importance of studying these mechanisms in a model that mimics the host environment. AUTHOR SUMMARYCatheter-associated urinary tract infections (CAUTIs) are common hospital-associated infections and are caused by many different pathogens. Of these pathogens, Staphylococcus aureus is particularly problematic, as it often spreads to the bloodstream and results in septic shock. One of the primary virulence factors that is important for uropathogens is urease. Urease breaks down urea in urine, which results in crystalline structures that encrust urinary catheters and promote reflux to the kidney. Despite producing urease, little is known about how S. aureus regulates the enzyme. In this study, we investigate how regulatory pathways coordinate the expression and activity of urease in response to environmental signals. We show that growth during stationary phase and in conditions that mimic the urinary tract urease expression and activity are increased. We also show that five different regulators - CodY, CcpA, SigB, SrrA, and Agr control urease expression and activity. Additionally, genomic changes identified in the urease regulatory pathway of clinical urinary catheter-associated isolates enhance urease expression. Importantly, urease promotes biofilm formation and dissemination during CAUTI. Our study provides insight into the complex regulatory mechanisms controlling urease and highlights the role urease plays in the development and virulence of S. aureus CAUTI.

microbiology↗

bioRxiv2025

Generation of Valvular Interstitial Cells from Human Pluripotent Stem Cells

Heart valves are living structures whose sophisticated functions are mediated by a specialized population of mesenchymal cells known as valvular interstitial cells (VICs). Given their central role in valve homeostasis, VICs represent a promising cell population for studying heart valve diseases and developing novel therapies to treat them. Here, we describe a strategy for generating VICs from human pluripotent stem cells (hPSCs) by stage-specific manipulation of developmental signalling pathways. Our results demonstrate that hPSC-derived VICs show a high transcriptional similarity to primary human fetal VICs and can secrete key proteins of the valve extracellular matrix. We further investigate the heterogeneity of hPSC-derived VICs and identify two major subpopulations with distinct molecular and functional properties, mirroring the cellular diversity observed in vivo. Finally, we utilize an in vitro model of Noonan syndrome to demonstrate that hPSC-derived VICs can accurately recapitulate key aspects of valve disease. Collectively, these findings provide a reproducible method for the scaled generation of bona fide hPSC-derived VICs and establish their utility in disease modelling and tissue engineering applications. Clinical PerspectiveO_ST_ABSWhat is new?C_ST_ABS- We established a robust platform to generate bona fide valvular interstitial cells (VICs) from human pluripotent stem cells (hPSCs), recapitulating native VIC identity and function. - We delineated signaling pathways that promote the development of two distinct VIC subsets and identified a surface marker to distinguish between them. What are the clinical implications?- A renewable, human-specific source of VICs enables precise mechanistic studies of valve development and disease that are not possible with limited surgical specimens or animal models. - This platform creates opportunities for therapeutic applications, including drug discovery and tissue engineering approaches for valve repair.

cell biology↗

bioRxiv2025

Integrated single cell spatial multi-omics landscape of WHO grades 2-4 diffuse gliomas identifies locoregional metabolomic regulators of glioma growth

Diffuse infiltrating gliomas are aggressive tumors of the central nervous system driven by intra-tumoral heterogeneity and aberrant normal-tumor cell-cell interactions. Grade specific and locoregional metabolic dependencies driving aberrant cell-states linked to treatment resistance, seizures and infiltration of gliomas remain elusive. Here, we applied spatial transcriptomics (stRNAseq), imaging mass cytometry (IMC) and mass spectrometry imaging (MSI; metabolites, peptides and glycans) to the core and edge tumor tissue from patients with World Health Organization (WHO) grades 2-4 diffuse infiltrating gliomas including isocitrate dehydrogenase (IDH) mutant oligodendrogliomas (WHO Grades 2 and 3) and IDH wildtype astrocytomas including anaplastic astrocytoma (prior 2016 WHO histological grade 3) and glioblastoma (GBM, WHO grade 4) stRNAseq identified regions-specific differentially expressed genes with significant overall survival implications particularly in IDH wildtype GBM. Integration of stRNA seq and MSI-derived metabolite expression demonstrated enrichment of L-glutamine in SOX4+ Neural progenitor-like (NPC-like) cells and DL-dopamine in GPNMB+ Mesenchymal-like (MES-like) GBM cells at the tumor edge relative to the core. Our results uncover clinically relevant and locoregional cell state-specific metabolites that may contribute to GBM proliferation, infiltration and seizures. This comprehensive pan-diffuse infiltrating glioma multi-omics study could serve as a resource for uncovering region-specific metabolic vulnerabilities encompassing metabolites, glycans and peptides within transcriptionally defined cell states across WHO 2-4 diffuse glioma.

cancer biology↗

bioRxiv2025

A systematic review of climate-change driven range shifts in mosquito vectors

As global temperatures rise, concerns about shifting mosquito ranges--and accompanying changes in the transmission of malaria, dengue, and other diseases--are mounting. However, systematic evidence for climate-driven changes in mosquito ranges remains limited. We conducted a systematic review of studies documenting expansions or contractions in medically important mosquito species. In total, 178 studies on six continents identified range expansions in 118 mosquito species. While over a third of these studies cited warming as a driver, fewer than 10% performed statistical tests of the role of climate. Instead, most expansions were linked to human-aided dispersal (e.g., trade, travel), land-use changes, and urbanization. Although several studies reported poleward or upward expansions consistent with climate warming, none demonstrated warm-edge contractions driven by rising temperatures, which are theoretically predicted in some settings. Rather than expanding into newly suitable areas, many expansions appear to be filling preexisting thermally suitable habitats. Our findings highlight the need for long-term mosquito monitoring, rigorous climate-attribution methods, and better documentation of confounding factors like land-use change and vector control efforts to disentangle climate-driven changes from other anthropogenic factors.

ecology↗

bioRxiv2024

A protective role for the cerebellum in cognitive aging

BackgroundBrain reserve -- the brains resilience to age-related change or damage -- provides protection against cognitive decline. The cerebellum is relatively unstudied as a contributor to brain reserve. This study investigates cerebellar brain reserve in the largest cohort to date. MethodsWe used data from the Human Connectome Project (n=708, 36-100yrs), UK Biobank (n=45,013, 44-81yrs), and ADNI (n=1,423, 56-95yrs). ADNI participants were cognitively normal or had a diagnosis of mild cognitive impairment or Alzheimers disease (AD) dementia. We examined associations between cerebellar tissue volume, age, Montreal Cognitive Assessment (MoCA) scores, global PET amyloid burden, and APOE genotype. FindingsHCP-Aging data revealed heterogenous aging-associated changes in cerebellar volume, with the greatest effects in posterior hemispheric regions (crus I) (Bonferroni-corrected, p<0{middle dot}05). MoCA scores were associated with higher tissue density in the cerebellum (p<0{middle dot}0001) to the same extent as neocortex, and MoCA scores coupled most strongly with posterior cerebellar cortex. Strikingly, greater volume in MoCA visuospatial-related cerebellar cortex protected against aging-related cognitive decline (p=0{middle dot}0001). We replicated tissue aging results in the UK Biobank with the greatest aging-related effects in posterior cerebellum (p<0{middle dot}0001), and an association of greater cerebellar volumes with less cognitive decline (Trails Making-B: p<0{middle dot}00001; Digit Symbol Substitution: p=0{middle dot}034). AD patients with low amyloid-beta burden (A{beta}-) exhibited the strongest cerebellar association with MoCA (volume x group, A{beta}- AD: p=0{middle dot}0001). In A{beta}- individuals, APOE {varepsilon}4/{varepsilon}4 carriers showed the greatest effect with MoCA (volume x APOE, {varepsilon}4/{varepsilon}4: p=0{middle dot}017). InterpretationOur large-scale study demonstrates a potentially strong role for the cerebellum in mitigating cognitive decline. The persistence of this protection in APOE {varepsilon}4/{varepsilon}4 carriers reshapes our understanding of reserve and AD risk. Our findings open the cerebellum as a novel target for future clinical research on brain reserve in aging populations. FundingNational Science Foundation, National Academies of Sciences, Engineering and Medicine, National Institutes of Health. Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed and GoogleScholar between August 12, 2023, and September 25, 2024 for articles irrespective of language or date of publication, relating to measures of cortical and cerebellar aging. Search terms included "cerebellum", "cognitive aging", "cerebellar reserve", "Alzheimers disease", "covariance", "retrogenesis", and "connectivity". Prior research demonstrated that the cerebellum may play a role in cognitive function. Studies have shown that cerebellar development is spatially heterogenous, with posterior regions undergoing the most protracted change in structure and function. Brain reserve has been predominantly studied in the neocortex, with some studies suggesting the cerebellum may contribute to cognitive changes in diseases like Alzheimers disease (AD) dementia. Cerebellar volume differences between young and older adults have been noted, as well as between healthy adults and neurodegenerative conditions like Parkinsons disease. However, the cerebellums contribution to cognitive reserve, particularly in healthy aging and individuals with a clinical diagnosis of mild cognitive impairment or AD dementia, had not been explored especially in large population-based datasets. Added value of this studyTo our knowledge, this study is the largest to date looking into how cerebellar structures contribute to cognitive outcomes in both healthy older adults, and those with mild cognitive impairment or AD dementia. We leverage three large neuroimaging datasets -- HCP-Aging, UK Biobank, and ADNI -- and demonstrate that cerebellar aging is spatially heterogeneous, with posterior regions showing the greatest age-related decline. We further establish a significant link between larger cerebellar volumes and better cognitive outcomes, suggesting that the cerebellum plays a role in cognitive resilience. Additionally, we identify how cerebellar structures predict cognitive performance and interact with amyloid-beta brain pathology and APOE genotype, particularly in those with low amyloid brain burden and those at greatest risk of AD such as in homozygous APOE e4 allele carriers. Implications of all the available evidenceThe aging of the global population raises the challenge of maintaining cognitive health in older age. Our research focuses on the cerebellum as a novel mediator of preserved cognitive function in old age and clinical dementia. Our findings have profound implications, given that individuals with robust cerebellar structures may be missed during cognitive and clinical screenings. Greater cerebellum volume seems to be most advantageous in those at higher risk for Alzheimers disease based on APOE4 status and those who have yet to accumulate substantial amyloid-beta brain pathology. Our study underscores the importance of the cerebellum as a novel brain reserve mechanism in aging populations.

neuroscience↗

bioRxiv2024

Microstructural pruning in human prefrontal cortex scaffolds its functional reorganization across development

Neural representations in occipitotemporal cortex emerge during development in response to visual experience with ecological stimulus categories, such as faces or words. While similar category-selective representations have also been observed in the frontal lobe, how they emerge across development, whether current models of brain development extend to prefrontal cortex, and the extent to which such high-level representations are anatomically consistent across the lifespan is unknown. Through a combination of functional and quantitative MRI scans, we observe previously undescribed cortical folding patterns in human-specific inferior frontal cortex whose consistency reveals that childhood representations for visual object categories rearrange into stable adulthood patterns. This functional restructuring was distinct from occipitotemporal cortex where adult-like response patterns only scale in magnitude across development. The unique form of functional development in prefrontal cortex was accompanied by restructuring of cortical tissue properties: macromolecules are pruned across adolescence in prefrontal cortex while they proliferate in temporal cortex. These results suggest visual representations in distinct cortical lobes undergo distinct developmental trajectories, and that human-specific prefrontal cortex shows an especially protracted maturational process that necessitates late-stage tissue restructuring detectable in the living brain.

neuroscience↗