T here is mounting evidence that exposure to intravenous gadolinium-based contrast agents (GBCAs) is associated with gadolinium retention in subcortical regions of the brain. However, there has been much less attention to gadolinium retention in the cerebral cortex. The cerebral cortex has critical functions, including higher cognition, sensorimotor coordination, affect and behavior regulation, executive function, and consciousness (1). Moreover, cerebral cortical function is sensitive to disruption by diverse neurotoxicants, including lanthanide series elements and other heavy metals (lead, mercury, manganese) (2,3).GBCAs are widely used in conjunction with MRI and have highly favorable safety profiles (4,5). Recent MRI studies have focused attention on gadolinium retention in subcortical gray matter nuclei in adult and pediatric patients with repeated intravenous GBCA exposure and

Chronic traumatic encephalopathy (CTE) is a progressive tauopathy found in contact sport athletes, military veterans, and others exposed to repetitive head impacts. White matter rarefaction and axonal loss have been reported in CTE but have not been characterized on a molecular or cellular level. Here, we present RNA sequencing profiles of cell nuclei from postmortem dorsolateral frontal white matter from eight individuals with neuropathologically confirmed CTE and eight age- and sex-matched controls. Analyzing these profiles using unbiased clustering approaches, we identified eighteen transcriptomically distinct cell groups (clusters), reflecting cell types and/or cell states, of which a subset showed differences between CTE and control tissue. Independent in situ methods applied on tissue sections adjacent to that used in the single-nucleus RNA-seq work yielded similar findings. Oligodendrocytes were found to be most severely affected in the CTE white matter samples; they were diminished in number and altered in relative proportions across subtype clusters. Further, the CTE-enriched oligodendrocyte population showed greater abundance of transcripts relevant to iron metabolism and cellular stress response. CTE tissue also demonstrated excessive iron accumulation histologically. In astrocytes, total cell numbers were indistinguishable between CTE and control samples, but transcripts associated with neuroinflammation were elevated in the CTE astrocyte groups compared to controls. These results demonstrate specific molecular and cellular differences in CTE oligodendrocytes and astrocytes and suggest that white matter alterations are a critical aspect of CTE neurodegeneration.

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Chronic traumatic encephalopathy (CTE) is a progressive tauopathy found in contact sport athletes, military veterans, and others exposed to repetitive head impacts (RHI)1–6. White matter atrophy and axonal loss have been reported in CTE but have not been characterized on a molecular or cellular level2,7,8. Here, we present RNA sequencing profiles of cell nuclei from postmortem dorsolateral frontal white matter from eight individuals with neuropathologically confirmed CTE and eight age- and sex-matched controls. Analyzing these profiles using unbiased clustering approaches, we identified eighteen transcriptomically distinct cell groups (clusters), reflecting cell types and/or cell states, of which a subset showed differences between CTE and control tissue. Independent in situ methods applied on tissue sections adjacent to that used in the single-nucleus RNA-seq work yielded similar findings. Oligodendrocytes were found to be most severely affected in the CTE white matter samples; they were diminished in number and altered in relative proportions across subtype clusters. Further, the CTE-enriched oligodendrocyte population showed greater abundance of transcripts relevant to iron metabolism and cellular stress response. CTE tissue also demonstrated excessive iron accumulation histologically. Astrocyte alterations were more nuanced; total astrocyte number was indistinguishable between CTE and control samples, but transcripts associated with neuroinflammation were elevated in the CTE astrocyte groups as compared to controls. These results demonstrate specific molecular and cellular differences in CTE oligodendrocytes and astrocytes and may provide a starting point for the development of diagnostics and therapeutic interventions.

Chronic traumatic encephalopathy (CTE) is a progressive tauopathy found in contact sport athletes, military veterans, and others exposed to repetitive head injury (McKee et al. 2009(McKee et al. , 2013(McKee et al. , 2016Omalu et al. 2005Omalu et al. , 2006Martland 1928;Critchley 1949). White matter atrophy and axonal loss have been reported in CTE but have not been characterized on a molecular or cellular level (McKee et al. 2013;Holleran et al. 2017;Hsu et al. 2018). Here, we report 24,735 single nucleus RNA-seq profiles from dorsolateral frontal white matter cell nuclei from eight individuals with neuropathologically confirmed CTE and eight age-and sex-matched controls. We identified eighteen transcriptionally distinct nuclei clusters, as well as cell-type-specific differences between conditions. The findings support a global loss of oligodendrocytes (OLs) in CTE, alterations in OL subpopulations, and suggest pathological iron accumulation in OL subpopulations. Total astrocyte number was not different between CTE and controls but showed upregulation of transcripts associated with neuroinflammation. These findings provide novel insight into the molecular and cellular underpinnings of white matter atrophy in CTE, which may lead to an improved understanding of the disease pathogenesis.

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Adult cognitive disorders exact a staggering burden on worldwide health care, with the need for efficacious and accessible treatments growing every day. The ability to probe questions relevant to normal or aberrant cognition in humans makes animal models indispensable tools in translational research. The use of animal models enables detailed investigation of complex interactions between genes, environment, and cognition that would be difficult or impossible in human subjects or populations. However, special consideration must be given to create specific, translatable models of human cognitive disorders. First, a model must prove statistically reliable, reproducible, and valid. Successful translational research requires thoughtful consideration and careful deployment of reliable, well-chosen animal models that are appropriately matched to their experimental purpose. In addition, to ensure specificity of a model to one disorder, it is prudent to focus on clusters of clinical features and disease-specific phenotypes in addition to environmental and genetic risk factors. Many neurological disorders share symptomatic elements in common, which drives the necessity for relevant cognitive domains to the disease in question to be carefully considered and replicated. Thoughtfully created animal models facilitate translational research aimed at understanding disease mechanisms and developing effective diagnostics, therapeutics, and preventive strategies to achieve better health care outcomes for people affected by cognitive disorders.

BackgroundTau pathology is known as a primary driver of neurodegeneration in Alzheimer’s disease (AD). Understanding its underlying molecular mechanism is critical in expanding our knowledge of AD pathogenesis and developing novel AD therapeutic strategies. However, interrogating tau induced neurotoxicity mechanisms has been difficult due to heterogeneous susceptibility of neurons to tau pathology. Here, we aim to identify the most vulnerable neuronal subpopulation to tau pathology in AD and reveal more clear molecular mechanisms of tau induced neuro‐toxicity/degeneration by analyzing gene expression changes in the vulnerable population.MethodWe performed single nuclei RNA sequencing and tau biochemistry from same tissue blocks of the same AD patients (5 brain regions of 32 AD donors with various Braak stages). About 1.5x106 neurons were enriched in total by NeuN antibody‐based flow cytometry sorting and these cells were clustered into 15 neuronal subpopulations based on their similarity in gene expression. We tested for association between relative neuronal population abundance and tau pathology readouts (phospho‐T231 ELISA, HT7‐HT7 SIMOA and HEK seeding). Based on the strength of correlation, we identified the neuronal subpopulation that reduces relative abundance in association with its tau pathology.ResultWe identified a tau vulnerable neuronal population that showed strong negative correlation between its relative abundance and tau pathology readouts in BA20 and BA46. The population was one of largest excitatory subpopulation distinguished by marker genes, CBLN2 and LINC00507. This outcome was supported by multiple published transcriptomics studies and histologically validated by multiplexed in situ hybridization and immunohistochemistry. Differential gene expression analysis of the vulnerable neuronal population identified a list of genes that potentially links tau pathology and neuronal death.ConclusionThis study with large number of captured neurons for single cell transcriptomics and quantitative tau pathology readout for direct comparison to transcriptomics data enabled the discovery of a vulnerable neuronal subpopulation in more precise manner and revealed genes related to tau associated neurotoxicity more clearly. This result serves as a great starting point to further interrogate fundamental mechanisms of tau‐driven neurodegeneration in AD and accelerate therapeutic target and biomarker discovery.