Disease-specific selective vulnerability and neuroimmune pathways in dementia revealed by single cell genomics.

The development of successful therapeutics for dementias requires an understanding of their shared and distinct molecular features in the human brain. We performed single-nuclear RNAseq and ATACseq in Alzheimer disease (AD), Frontotemporal degeneration (FTD), and Progressive Supranuclear Palsy (PSP), analyzing 40 participants, yielding over 1.4M cells from three brain regions ranging in vulnerability and pathological burden. We identify 35 shared disease-associated cell types and 14 that are disease-specific, replicating those previously identified in AD. Disease - specific cell states represent molecular features of disease-specific glial-immune mechanisms and neuronal vulnerability in each disorder, layer 4/5 intra-telencephalic neurons in AD, layer 2/3 intra-telencephalic neurons in FTD, and layer 5/6 near-projection neurons in PSP. We infer intrinsic disease-associated gene regulatory networks, which we empirically validate by chromatin footprinting. We find that causal genetic risk acts in specific neuronal and glial cells that differ across disorders, primarily non-neuronal cells in AD and specific neuronal subtypes in FTD and PSP. These data illustrate the heterogeneous spectrum of glial and neuronal composition and gene expression alterations in different dementias and identify new therapeutic targets by revealing shared and disease-specific cell states.

Cell type hierarchy reconstruction via reconciliation of multi-resolution cluster tree.

A wealth of clustering algorithms are available for single-cell RNA sequencing (scRNA-seq) data to enable the identification of functionally distinct subpopulations that each possess a different pattern of gene expression activity. Implementation of these methods requires a choice of resolution parameter to determine the number of clusters, and critical judgment from the researchers is required to determine the desired resolution. This supervised process takes significant time and effort. Moreover, it can be difficult to compare and characterize the evolution of cell clusters from results obtained at one single resolution. To overcome these challenges, we built Multi-resolution Reconciled Tree (MRtree), a highly flexible tree-construction algorithm that generates a cluster hierarchy from flat clustering results attained for a range of resolutions. Because MRtree can be coupled with most scRNA-seq clustering algorithms, it inherits the robustness and versatility of a flat clustering approach, while maintaining the hierarchical structure of cells. The constructed trees from multiple scRNA-seq datasets effectively reflect the extent of transcriptional distinctions among cell groups and align well with levels of functional specializations among cells. Importantly, application to fetal brain cells identified subtypes of cells determined mainly by maturation states, spatial location and terminal specification.

A Single-Cell Transcriptomic Atlas of Human Neocortical Development during Mid-gestation.

We performed RNA sequencing on 40,000 cells to create a high-resolution single-cell gene expression atlas of developing human cortex, providing the first single-cell characterization of previously uncharacterized cell types, including human subplate neurons, comparisons with bulk tissue, and systematic analyses of technical factors. These data permit deconvolution of regulatory networks connecting regulatory elements and transcriptional drivers to single-cell gene expression programs, significantly extending our understanding of human neurogenesis, cortical evolution, and the cellular basis of neuropsychiatric disease. We tie cell-cycle progression with early cell fate decisions during neurogenesis, demonstrating that differentiation occurs on a transcriptomic continuum; rather than only expressing a few transcription factors that drive cell fates, differentiating cells express broad, mixed cell-type transcriptomes before telophase. By mapping neuropsychiatric disease genes to cell types, we implicate dysregulation of specific cell types in ASD, ID, and epilepsy. We developed CoDEx, an online portal to facilitate data access and browsing.

A rare presentation of spinal epidural abscess.

A 77-year-old retired engineer presented to accident and emergency with deteriorating shortness of breath that had been troubling him for several months. At that time, he was being investigated by a chest physician who had identified bilateral diaphragmatic paralysis on ultrasound and was awaiting further imaging. Clinical assessment and nerve conduction studies on this admission were compatible with a diagnosis of motor neuron disease but specialist neurology input recommended an MRI to rule out cord pathology. This proved problematic as the patient was non-invasive ventilation dependent and unable to lay supine as this further compromised his respiratory function. To ensure that a potentially reversible cause for his symptoms was identified, the patient was intubated for an MRI which subsequently demonstrated multi level spinal epidural empyema. The benefits of neurosurgical intervention were judged to be uncertain at best, and following discussion with the family, active care was withdrawn. The patient passed away shortly thereafter.