Biology subjects

Kramer, J.

Publications and source records attributed to Kramer, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Decoherence via Demyelination Hypothesis (DDH): A Mechanism of Cognitive Decline During Aging

Progressive cognitive decline and loss of white matter integrity are observed during aging, but whether these two processes are connected remains unclear. We propose the Decoherence via Demyelination Hypothesis (DDH) as a mechanism linking non-uniform, tract-specific myelin loss during aging, which results in the degradation of conduction timing that is required to coordinate long-range neuronal assemblies. This impairs the dynamic assembly of task-dependent functional networks and promotes age-associated cognitive change. Axonal myelination determines conduction velocity as well as signal transmission fidelity, properties essential for phase-locked integration of long-distance inputs with local oscillations and for the assembly of mesoscale functional brain networks. If myelin loss is heterogeneous across tracts, the resulting timing perturbations should be heterogeneous as well, with disproportionate impact on networks supporting higher-order cognition. To test this, we analyzed structural and microstructural MRI in 638 individuals aged 40-99, quantifying fasciculation in different white matter pathways as well as neurite orientation dispersion and density imaging (NODDI) to the gray-white matter interface beneath cortical regions. We observed tract-specific, non-uniform myelin decline, with significant nonlinear losses in tracts serving high order cognition and memory (uncinate fasciculus, fornix, corpus callosum), consistent with accelerated late-life vulnerability in pathways implicated in cognitive aging and increased risk for neurodegenerative diseases. Tract-level degeneration tracked with age-related shifts in network organization and cognition. These findings may support DDH as a framework for age-associated cognitive change. Particularly, tract-specific timing perturbations drive the breakdown of coordinated network activity in aging.

neuroscience↗

bioRxiv2025

A proteomic signature of vascular dysfunction linked to tauopathy and degeneration in the aging brain

Small vessel disease (SVD) impacts healthy aging of organs across the body, yet its contributions to adverse brain aging remain poorly defined. Here we show thromboinflammation, a core feature of SVD, as a driver of adverse brain aging. We identify cerebrospinal fluid fibrinogen as a marker of brain thromboinflammation and screen neurovascular biosignatures mediating its impact on synaptic vulnerability along the full spectrum of brain aging from cognitively typical, amyloid-negative to cognitively impaired, amyloid-positive older adults. We identified 53 proteins mediating fibrinogens effects on synaptic markers in 1,655 donors from three independent cohorts. Single-cell transcriptomic mapping revealed mediator enrichment in neurovascular unit cells. Pathway analysis demonstrated dysregulation of angiogenesis, fibrosis, and immune signaling. Vascular and microglial-enriched biosignatures associated with compromised white matter integrity. These findings indicate thromboinflammation as an early, amyloid-independent pathway to neurodegeneration and tauopathy, establishing vascular health as fundamental to preserving brain healthspan.

neuroscience↗

bioRxiv2025

Regulation of lipid dysmetabolism and neuroinflammation linked with Alzheimer's disease through modulation of Dgat2

Alzheimers disease (AD), an age-associated neurodegenerative disorder, is characterized by progressive cognitive decline, amyloid-{beta} (A{beta}) deposition, lipid dysregulation, and neuroinflammation. Although mutations in the amyloid precursor protein (APP) and accumulation of A{beta}42 are established drivers of pathology, the mechanisms connecting amyloid toxicity with lipid metabolism and inflammatory responses remain poorly understood. Here, we employed complementary Drosophila and mouse models to dissect these relationships. Expression of AppNLG and A{beta}42 in Drosophila resulted in locomotor deficits, disrupted sleep-circadian rhythms, memory impairments, lipid accumulation, synaptic loss, and neuroinflammatory signatures. Comparable lipid metabolic disturbances and inflammatory alterations were detected in the AppNLG-F knock-in mouse model, underscoring their conserved relevance to AD pathogenesis. We further identified diacylglycerol O-acyltransferase 2 (Dgat2), a key enzyme catalyzing the final step of triglyceride synthesis, as a critical modulator of AD-related phenotypes. Dgat2 expression was altered in both animal models and human AD tissues. Notably, panneuronal knockdown of Dgat2 in Drosophila attenuated lipid accumulation, restored synaptic integrity, and ameliorated locomotor and cognitive deficits, while also reducing neuroinflammation. Dgat2 suppression additionally improved sleep and circadian behavior, highlighting its pleiotropic protective effects. Together, these findings demonstrate a mechanistic link between amyloid pathology, lipid dysregulation, and neuroinflammatory processes. Targeting Dgat2 may therefore represent a novel therapeutic strategy to counteract AD-associated metabolic and neuronal dysfunction. The conservation of lipid homeostasis mechanisms across species underscores the translational potential of this approach for delaying or mitigating AD progression.

physiology↗

bioRxiv2024

Evolutionary conserved reciprocal senescence and tumor suppressor signals limit lifetime cancer

Cellular senescence features a durable exit from the cell cycle triggered by stress or carcinogens. The INK4 locus is inactivated in various cancers, yet in senescence, p16Ink4a is activated. Whether senescence is tumor-suppressing or -promoting remains a conundrum. We discovered an evolutionally-conserved Vertebrata INK4-homolog. This ink4ab triggers senescence upon oxidative- and/or carcinogenic-stress. Adult Ink4ab-deficient animals failed to activate senescence and developed spontaneous cancers. Combined Ink4ab and Tp53 deficiency revealed a reciprocal senescence and apoptosis regulation, controlling tumorigenesis, including retinoblastoma. INK4-hematopoietic-deficient mice exhibited p19Arf-dependent enhanced senescence-like phenotypes, uncontrolled cell proliferation, defective stem cell differentiation, and splenomegaly, with single-splenocytes spatially-enriched in senescence-associated secretory profiles. Our studies reveal the evolutionary origin of paradigms co-regulating senescence and tumor suppression and offer strategies to exploit these reciprocal pathways for cancer prevention and therapy.

cancer biology↗

bioRxiv2024

Impact of O-GlcNAcylation elevation on mitophagy and glia in the dentate gyrus

O-GlcNAcylation is a dynamic and reversible protein post-translational modification of serine or threonine residues which modulates the activity of transcriptional and signaling pathways and controls cellular responses to metabolic and inflammatory stressors. We and others have shown that O-GlcNAcylation has the potential to regulate autophagy and mitophagy to play a critical role in mitochondrial quality control, but this has not been assessed in vivo in the brain. This is important since mitochondrial dysfunction contributes to the development of neurodegenerative disease. We used mito-QC reporter mice to assess mitophagy in diverse cells in the dentate gyrus in response to pharmacological inhibition of OGA with thiamet G which leads to elevation of protein O-GlcNAcylation. We demonstrate that mitophagy occurs predominantly in the GFAP positive astrocytes and is significantly decreased in response to elevated O-GlcNAcylation. Furthermore, with increased O-GlcNAcylation, the levels of astrocyte makers GFAP and S100B, and microglial cell marker IBA1 were decreased in the dentate gyrus, while the levels of microglial cell marker TMEM119 were increased, indicating significant changes in glia homeostasis. These results provide strong evidence of the regulation of mitophagy and glia signatures by the O-GlcNAc pathway.

neuroscience↗

bioRxiv2024

Strain identity effects contribute more to Pseudomonas community functioning than strain interactions

Microbial communities can shape key ecological services, but the determinants of their functioning often remain little understood. While traditional research predominantly focuses on effects related to species identity (community composition and species richness), recent work increasingly explores the impact of species interactions on community functioning. Here, we conducted experiments with replicated small communities of fluorescent Pseudomonas bacteria to quantify the relative importance of strain identity versus interaction effects on two important functions, community productivity and siderophore production. By combining supernatant and competition assays with an established linear model method, we show that both factors have significant effects on functioning, but identity effects generally outweigh strain interaction effects. These results hold irrespective of whether strains interactions are inferred statistically or approximated experimentally. Our results have implications for microbiome engineering, as the success of approaches aiming to induce beneficial (probiotic) strain interactions will be sensitive to strain identity effects in many communities.

ecology↗

bioRxiv2024

Targeting complement C3a receptor resolves mitochondrial hyperfusion and subretinal microglial activation in progranulin-deficient frontotemporal dementia

Mutations in progranulin (GRN) cause frontotemporal dementia (GRN-FTD) due to deficiency of the pleiotropic protein progranulin. GRN-FTD exhibits diverse pathologies including lysosome dysfunction, lipofuscinosis, microgliosis, and neuroinflammation. Yet, how progranulin loss causes disease remains unresolved. Here, we report that non-invasive retinal imaging of GRN-FTD patients revealed deficits in photoreceptors and the retinal pigment epithelium (RPE) that correlate with cognitive decline. Likewise, Grn-/- mice exhibit early RPE dysfunction, microglial activation, and subsequent photoreceptor loss. Super-resolution live imaging and transcriptomic analyses identified RPE mitochondria as an early driver of retinal dysfunction. Loss of mitochondrial fission protein 1 (MTFP1) in Grn-/- RPE causes mitochondrial hyperfusion and bioenergetic defects, leading to NF-kB-mediated activation of complement C3a-C3a receptor signaling, which drives further mitochondrial hyperfusion and retinal inflammation. C3aR antagonism restores RPE mitochondrial integrity and limits subretinal microglial activation. Our study identifies a previously unrecognized mechanism by which progranulin modulates mitochondrial integrity and complement-mediated neuroinflammation.

neuroscience↗

bioRxiv2024

Axolotl mandible regeneration occurs through mechanical gap closure and a shared regenerative program with the limb

The mandible plays an essential part in human life and, thus, defects in this structure can dramatically impair the quality of life in patients. Axolotls, unlike humans, are capable of regenerating their lower jaws; however, the underlying mechanisms and their similarity to those in limb regeneration are unknown. In this work, we used morphological, histological, and transcriptomic approaches to analyze the regeneration of lateral resection defects in the axolotl mandible. We found that this structure can regenerate all missing tissues in 90 days through gap minimization, blastema formation, and finally tissue growth, differentiation, and integration. Moreover, transcriptomic comparisons of regenerating mandibles and limbs showed that they share molecular phases of regeneration, that these similarities peak during blastema stages, and that mandible regeneration occurs at a slower pacing. Altogether, our study demonstrates the existence of a shared regenerative program used in two different regenerating body structures with different embryonic origins in the axolotl, and contributes to our understanding of the minimum requirements for a successful regeneration in vertebrates, bringing us closer to understand similar lesions in human mandibles.

developmental biology↗

bioRxiv2023

Mitigation of TDP-43-induced toxic phenotype by expression of RGNEF N-terminal fragment in ALS models

Aggregation of the RNA-binding protein (RBP) TDP-43 is a hallmark of TDP-proteinopathies including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Since TDP-43 aggregation and dysregulation are causative of neuronal death, there is a special interest in targeting this protein as a therapeutic approach. Previously, we found that TDP-43 extensively co-aggregated with the dual function protein (GEF (guanine exchange factor) and RBP) rho guanine nucleotide exchange factor (RGNEF) in ALS patients. Here, we show that a N-terminal fragment of RGNEF (NF242) interacts directly with the RNA recognition motifs (RRM) of TDP-43 competing with RNA, and that the IPT/TIG domain of NF242 is essential for this interaction. Genetical expression of NF242 in a fruit fly ALS model overexpressing TDP-43 suppressed the neuropathological phenotype increasing lifespan, abolishing motor defects, and preventing neurodegeneration. Intracerebroventricular injections of AAV9/NF242 in a severe TDP-43 murine model (rNLS8) improved lifespan and motor phenotype, and decreased neuroinflammation markers. Our results demonstrate an innovative way to target TDP-43 proteinopathies using a protein fragment with affinity for TDP-43, suggesting a promising therapeutic strategy for TDP-43 proteinopathies such as ALS and FTD.

neuroscience↗

bioRxiv2023

A green-fluorescent siderophore protects bacterial communities from UV damage

Sunlight enables virtually all life on earth, but also entails harmful ultraviolet (UV) radiation inducing DNA damage. In response to UV stress, natural selection has favored both curative and preventive measures such as DNA repair mechanisms and UV-absorbing pigments. While UV protection by pigments is well documented in plants, animals and fungi, little is known about their protective role in bacteria. Here, we combine batch-culture and microscopy experiments to show that the siderophore pyoverdine, a fluorescent pigment produced by the opportunistic pathogen Pseudomonas aeruginosa offers high-level protection against UV radiation. Our results reveal that bacteria up-regulate pyoverdine production following UV exposure, seemingly as part of a general stress response. We further found that pyoverdine cannot curatively alleviate UV-damage but protects cells preventively and collectively from oncoming UV exposures through its accumulation in the environment. Altogether, our results reveal a new and non-canonical function of this iron-scavenging molecule, demonstrating that pyoverdine acts as a public sunscreen protecting bacterial populations from UV damage. Given that many bacteria produce pigments, such protection might be widespread in species colonizing habitats exposed to UV radiation.

microbiology↗

bioRxiv2023

Enlarged Perivascular Spaces are Associated with White Matter Injury, Brain Atrophy, Cognitive Decline and Markers of Inflammation in an Autosomal Dominant Vascular Neurodegenerative Disease (CADASIL)

Background and ObjectivesEnlarged perivascular spaces (ePVS) have been previously reported in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leucoencephalopathy (CADASIL), but their significance and pathophysiology remains unclear. We investigated associations of ePVS with classical imaging measures, cognitive measures and plasma proteins to better understand what ePVS represents in CADASIL and whether radiographic measures of ePVS would be of value in future therapeutic discovery studies for CADASIL. Methods24 individuals with CADASIL and 24 age and sex matched controls were included. Disease status was determined based on presence of NOTCH3 mutation. Brain imaging measures of white matter hyperintensity (WMH), brain parenchymal fraction (BPF), ePVS volumes, clinical, and cognitive measures, as well as plasma proteomics were used in models. Global ePVS volumes were calculated via a novel, semi-automated pipeline and levels of 7363 proteins were quantified in plasma using the SomaScan assay. The relationship of ePVS with global burden of WMH, brain atrophy, functional status, neurocognitive measures, and plasma proteins were modelled with linear regression models. ResultsCADASIL and control groups did not exhibit differences in mean ePVS volumes. However, increased ePVS volumes in CADASIL were associated with increased WMH volume ({beta}=0.57, p=0.05), Clinical Dementia Rating (CDR) Sum-of-Boxes score ({beta}=0.49, p=0.04), and decreased brain parenchymal fraction (BPF) ({beta}=-0.03, p=0.10). In interaction term models, the interaction term between CADASIL disease status and ePVS volume was associated with increased WMH volume ({beta}=0.57, p=0.02), Clinical Dementia Rating (CDR) Sum-of-Boxes score ({beta}=0.52, p=0.02), decreased BPF ({beta}=-0.03, p=0.07) and Mini Mental State Examination (MMSE) score ({beta}=-1.49, p=0.03). Proteins positively associated with ePVS volumes were found to be related to leukocyte migration and inflammation, while negatively associated proteins were related to lipid metabolism. Two central hub proteins were identified in protein networks associated with ePVS volumes: CXCL8/IL-8, and CCL2/MCP-1. The levels of CXCL8/IL8 were also associated with increased WMH volume ({beta}=2.44, p < 0.01), and levels of CCL2/MCP-1 were further associated with decreased BPF ({beta}=-0.0007, p < 0.01), MMSE score ({beta}=-0.02, p < 0.01), and increased Trail Making Test B (TRAILB) completion time ({beta}=0.76, p < 0.01). No protein was associated with all 3 studied imaging measures of pathology (BPF,ePVS,WMH). DiscussionBased on associations uncovered between ePVS volumes and cognitive functions, imaging and plasma proteins, we conclude that ePVS volumes capture pathologies contributing to chronic brain dysfunction and degeneration in CADASIL, with relevance to future clinical trials for novel therapeutic discoveries to prevent decline and injury in individuals carrying NOTCH3 mutations.

neuroscience↗

bioRxiv2023

Sexually dimorphic differences in angiogenesis markers predict brain aging trajectories

Aberrant angiogenesis could contribute to cognitive impairment, representing a therapeutic target for preventing dementia. However, most angiogenesis studies focus on model organisms. To test the relevance of angiogenesis to human cognitive aging, we evaluated associations of circulating blood markers of angiogenesis with brain aging trajectories in two deeply phenotyped human cohorts (n=435, age 74+9) with longitudinal cognitive assessments, biospecimens, structural brain imaging, and clinical data. Machine learning and traditional statistics revealed sex dimorphic associations of plasma angiogenic growth factors with brain aging outcomes. Specifically, angiogenesis is associated with higher executive function and less brain atrophy in younger women (not men), a directionality of association that reverses around age 75. Higher levels of basic fibroblast growth factor, known for pleiotropic effects on multiple cell types, predicted favorable cognitive trajectories. This work demonstrates the relevance of angiogenesis to brain aging with important therapeutic implications for vascular cognitive impairment and dementia.

neuroscience↗

bioRxiv2023

KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss

Synaptic plasticity is obstructed by pathogenic tau in the brain, representing a key mechanism that underlies memory loss in Alzheimers disease (AD) and related tauopathies. Here, we define a mechanism for plasticity repair in vulnerable neurons using the C-terminus of the KIdney/BRAin (KIBRA) protein (CT-KIBRA). We show that CT-KIBRA restores plasticity and memory in transgenic mice expressing pathogenic human tau; however, CT-KIBRA did not alter tau levels or prevent tau-induced synapse loss. Instead, we find that CT-KIBRA binds to and stabilizes protein kinase M{zeta} (PKM{zeta}) to maintain synaptic plasticity and memory despite tau mediated pathogenesis. In humans we find that reduced KIBRA in brain and increased KIBRA in cerebrospinal fluid are associated with cognitive impairment and pathological tau levels in disease. Thus, our results distinguish KIBRA both as a novel biomarker of synapse dysfunction in AD and as the foundation for a synapse repair mechanism to reverse cognitive impairment in tauopathy.

neuroscience↗

bioRxiv2023

Neurophysiological trajectories in Alzheimer's disease progression

Alzheimers disease (AD) is characterized by the accumulation of amyloid-{beta} and misfolded tau proteins causing synaptic dysfunction, and progressive neurodegeneration and cognitive decline. Altered neural oscillations have been consistently demonstrated in AD. However, the trajectories of abnormal neural oscillations in AD progression and their relationship to neurodegeneration and cognitive decline are unknown. Here, we deployed robust event-based sequencing models (EBMs) to investigate the trajectories of long-range and local neural synchrony across AD stages, estimated from resting-state magnetoencephalography. The increases in neural synchrony in the delta-theta band and the decreases in the alpha and beta bands showed progressive changes throughout the stages of the EBM. Decreases in alpha and beta band synchrony preceded both neurodegeneration and cognitive decline, indicating that frequency-specific neuronal synchrony abnormalities are early manifestations of AD pathophysiology. The long-range synchrony effects were greater than the local synchrony, indicating a greater sensitivity of connectivity metrics involving multiple regions of the brain. These results demonstrate the evolution of functional neuronal deficits along the sequence of AD progression.

neuroscience↗

bioRxiv2023

Tet Controls Axon Guidance in Early Brain Development through Glutamatergic Signaling

Mutations in human TET proteins have been found in individuals with neurodevelopmental disorders. Here we report a new function of Tet in regulating Drosophila early brain development. We found that mutation in the Tet DNA-binding domain (TetAXXC) resulted in axon guidance defects in the mushroom body (MB). Tet is required in early brain development during the outgrowth of MB {beta} axons. Transcriptomic study shows that glutamine synthetase 2 (Gs2), a key enzyme in glutamatergic signaling, is significantly downregulated in the TetAXXC mutant brains. CRISPR/Cas9 mutagenesis or RNAi knockdown of Gs2 recapitulates the TetAXXC mutant phenotype. Surprisingly, Tet and Gs2 act in the insulin-producing cells (IPCs) to control MB axon guidance, and overexpression of Gs2 in these cells rescues the axon guidance defects of TetAXXC. Treating TetAXXC with the metabotropic glutamate receptor antagonist MPEP can rescue while treating with glutamate enhances the phenotype confirming Tet function in regulating glutamatergic signaling. TetAXXC and the Drosophila homolog of Fragile X Messenger Ribonucleoprotein protein mutant (Fmr13) have similar axon guidance defects and reduction in Gs2 mRNA levels. Interestingly, overexpression of Gs2 in the IPCs also rescues the Fmr13 phenotype, suggesting functional overlapping of the two genes. Our studies provide the first evidence that Tet can control the guidance of axons in the developing brain by modulating glutamatergic signaling and the function is mediated by its DNA-binding domain.

developmental biology↗

bioRxiv2023

Tet-dependent 5-hydroxymethyl-Cytosine modification of mRNA regulates the axon guidance genes robo2 and slit in Drosophila

Modifications of mRNA, especially methylation of adenosine, have recently drawn much attention. The much rarer modification, 5-hydroxymethylation of cytosine (5hmC), is not well understood and is the subject of this study. Vertebrate Tet proteins are 5-methylcytosine (5mC) hydroxylases and catalyze the transition of 5mC to 5hmC in DNA. These enzymes have recently been shown to have the same function in messenger RNAs in both vertebrates and in Drosophila. The Tet gene is essential in Drosophila as Tet knock-out animals do not reach adulthood. We describe the identification of Tet-target genes in the embryo and larval brain by mapping one, Tet DNA-binding sites throughout the genome and two, the Tet-dependent 5hmrC modifications transcriptome-wide. 5hmrC modifications are distributed along the entire transcript, while Tet DNA-binding sites are preferentially located at the promoter where they overlap with histone H3K4me3 peaks. The identified mRNAs are preferentially involved in neuron and axon development and Tet knock-out led to a reduction of 5hmrC marks on specific mRNAs. Among the Tet-target genes were the robo2 receptor and its slit ligand that function in axon guidance in Drosophila and in vertebrates. Tet knock-out embryos show overlapping phenotypes with robo2 and both Robo2 and Slit protein levels were markedly reduced in Tet KO larval brains. Our results establish a role for Tet-dependent 5hmrC in facilitating the translation of modified mRNAs primarily in cells of the nervous system.

neuroscience↗

bioRxiv2023

Predicting alcohol-related memory problems in older adults: A machine learning study with multi-domain features

Memory problems are common among older adults with a history of alcohol use disorder (AUD). Employing a machine learning framework, the current study investigates the use of multi-domain features to classify individuals with and without alcohol-induced memory problems. A group of 94 individuals (ages 50-81 years) with alcohol-induced memory problems (Memory group) were compared with a matched Control group who did not have memory problems. The Random Forests model identified specific features from each domain that contributed to the classification of Memory vs. Control group (AUC=88.29%). Specifically, individuals from the Memory group manifested a predominant pattern of hyperconnectivity across the default mode network regions except some connections involving anterior cingulate cortex which were predominantly hypoconnected. Other significant contributing features were (i) polygenic risk scores for AUD, (ii) alcohol consumption and related health consequences during the past 5 years, such as health problems, past negative experiences, withdrawal symptoms, and the largest number of drinks in a day during the past 12 months, and (iii) elevated neuroticism and increased harm avoidance, and fewer positive "uplift" life events. At the neural systems level, hyperconnectivity across the default mode network regions, including the connections across the hippocampal hub regions, in individuals with memory problems may indicate dysregulation in neural information processing. Overall, the study outlines the importance of utilizing multidomain features, consisting of resting-state brain connectivity collected [~]18 years ago, together with personality, life experiences, polygenic risk, and alcohol consumption and related consequences, to predict alcohol-related memory problems that arise in later life.

neuroscience↗

bioRxiv2022

Radiogenomics of C9orf72 expansion carriers reveals global transposable element de-repression and enables prediction of thalamic atrophy and clinical impairment

Hexanucleotide repeat expansion (HRE) within C9orf72 is the most common genetic cause of frontotemporal dementia (FTD). Thalamic atrophy occurs in both sporadic and familial FTD but is thought to distinctly affect HRE carriers. Separately, emerging evidence suggests widespread de-repression of transposable elements (TEs) in the brain in several neurodegenerative diseases, including C9orf72 HRE-mediated FTD (C9-FTD). Whether TE activation can be measured in peripheral blood and how the reduction in peripheral C9orf72 expression observed in HRE carriers relates to atrophy and clinical impairment remain unknown. We used the FreeSurfer pipeline and its extensions to assess the effects of C9orf72 HRE and clinical diagnosis (n = 78) on atrophy of thalamic nuclei. We also generated a novel, whole-blood RNA-seq dataset to determine the relationships between peripheral C9orf72 expression, TE activation, thalamic atrophy, and clinical severity (n = 114). We confirmed global thalamic atrophy and reduced C9orf72 expression in HRE carriers. Moreover, we identified disproportionate atrophy of the right mediodorsal lateral nucleus in HRE carriers and showed that C9orf72 expression associated with clinical severity, independent of thalamic atrophy. Strikingly, we found global peripheral activation of TEs, including the human endogenous LINE-1 element, L1HS. L1HS levels were associated with atrophy of multiple pulvinar nuclei, a thalamic region implicated in C9-FTD. Integration of peripheral transcriptomic and neuroimaging data from HRE carriers revealed atrophy of specific thalamic nuclei; demonstrated that C9orf72 levels relate to clinical severity; and identified marked de-repression of TEs, including L1HS, which predicted atrophy of FTD-relevant thalamic nuclei. Significance StatementPathogenic repeat expansion in C9orf72 is the most frequent genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis (C9-FTD/ALS). The clinical, neuroimaging, and pathological features of C9-FTD/ALS are well-characterized, whereas the intersections of transcriptomic dysregulation and brain structure remain largely unexplored. Herein, we utilized a novel radiogenomic approach to examine the relationship between peripheral blood transcriptomics and thalamic atrophy, a neuroimaging feature disproportionately impacted in C9-FTD/ALS. We confirmed reduction of C9orf72 in blood and found broad dysregulation of transposable elements--genetic elements typically repressed in the human genome--in symptomatic C9orf72 expansion carriers, which associated with atrophy of thalamic nuclei relevant to FTD. C9orf72 expression was also associated with clinical severity, suggesting that peripheral C9orf72 levels capture disease-relevant information.

neuroscience↗